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Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis

Abstract

At least 30% of patients with rheumatoid arthritis (RA) do not respond to biologic agents, which emphasizes the need of predictive biomarkers. We aimed to identify microRNAs (miRNAs) predictive of response to adalimumab in 180 treatment-naïve RA patients enrolled in the OPtimized treatment algorithm for patients with early RA (OPERA) Study, an investigator-initiated, prospective, double-blind placebo-controlled study. Patients were randomized to adalimumab 40 mg (n=89) or placebo–adalimumab (n=91) subcutaneously in combination with methotrexate. Expressions of 377 miRNAs were determined using TaqMan Human MicroRNA LDA, A Card v2.0 (Applied Biosystems). Associations between miRNAs and treatment response were tested using interaction analyses. MiRNAs with a P-value <0.05 using three different normalizations were included in a multivariate model. After backwards elimination, the combination of low expression of miR-22 and high expression of miR-886.3p was associated with EULAR good response. Future studies to assess the utility of these miRNAs as predictive biomarkers are needed.

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References

  1. Hetland ML, Christensen IJ, Tarp U, Dreyer L, Hansen A, Hansen IT et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum 2010; 62: 22–32.

    Article  CAS  PubMed  Google Scholar 

  2. Prajapati R, Plant D, Barton A . Genetic and genomic predictors of anti-TNF response. Pharmacogenomics 2011; 12: 1571–1585.

    Article  CAS  PubMed  Google Scholar 

  3. Hyrich KL, Watson KD, Silman AJ, Symmons DP . British Society for Rheumatology Biologics Register, et al. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 2006; 45: 1558–1565.

    Article  CAS  Google Scholar 

  4. Trenkmann M, Brock M, Ospelt C, Gay S . Epigenetics in rheumatoid arthritis. Clin Rev Allergy Immunol 2010; 39: 10–19.

    Article  CAS  PubMed  Google Scholar 

  5. Iorio MV, Croce CM . MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol 2009; 27: 5848–5856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zamore PD, Haley B . Ribo-gnome: the big world of small RNAs. Science 2005; 309: 1519–1524.

    Article  CAS  PubMed  Google Scholar 

  7. O'Connell RM, Rao DS, Baltimore D . MicroRNA regulation of inflammatory responses. Annu Rev Immunol 2012; 30: 295–312.

    Article  CAS  PubMed  Google Scholar 

  8. Boldin MP, Baltimore D . MicroRNAs, new effectors and regulators of NF-kappaB. Immunol Rev 2012; 246: 205–220.

    Article  PubMed  Google Scholar 

  9. Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EK . Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther 2008; 10: R101.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Stanczyk J, Pedrioli DM, Brentano F, Sanchez-Pernaute O, Kolling C, Gay RE et al. Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum 2008; 58: 1001–1009.

    Article  Google Scholar 

  11. Nakasa T, Miyaki S, Okubo A, Hashimoto M, Nishida K, Ochi M et al. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum 2008; 58: 1284–1292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nakamachi Y, Kawano S, Takenokuchi M, Nishimura K, Sakai Y, Chin T et al. MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum 2009; 60: 1294–1304.

    Article  PubMed  Google Scholar 

  13. Li J, Wan Y, Guo Q, Zou L, Zhang J, Fang Y et al. Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis. Arthritis Res Ther 2010; 12: R81.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Murata K, Yoshitomi H, Tanida S, Ishikawa M, Nishitani K, Ito H et al. Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 2010; 12: R86.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Niimoto T, Nakasa T, Ishikawa M, Okuhara A, Izumi B, Deie M et al. MicroRNA-146a expresses in interleukin-17 producing T cells in rheumatoid arthritis patients. BMC Musculoskelet Disord 2010; 11: 209.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Alsaleh G, Suffert G, Semaan N, Juncker T, Frenzel L, Gottenberg JE et al. Bruton's tyrosine kinase is involved in miR-346-related regulation of IL-18 release by lipopolysaccharide-activated rheumatoid fibroblast-like synoviocytes. J Immunol 2009; 182: 5088–5097.

    Article  CAS  PubMed  Google Scholar 

  17. Fulci V, Scappucci G, Sebastiani GD, Giannitti C, Franceschini D, Meloni F et al. miR-223 is overexpressed in T-lymphocytes of patients affected by rheumatoid arthritis. Hum Immunol 2010; 71: 206–211.

    Article  CAS  PubMed  Google Scholar 

  18. Chatzikyriakidou A, Voulgari PV, Georgiou I, Drosos AA . A polymorphism in the 3'-UTR of interleukin-1 receptor-associated kinase (IRAK1), a target gene of miR-146a, is associated with rheumatoid arthritis susceptibility. Joint Bone Spine 2010; 77: 411–413.

    Article  CAS  PubMed  Google Scholar 

  19. Sebastiani GD, Fulci V, Niccolini S, Giannitti C, Bugatti S, Minisola G et al. Over-expression of miR-223 in T-lymphocytes of early rheumatoid arthritis patients. Clin Exp Rheumatol 2011; 29: 1058–1059.

    PubMed  Google Scholar 

  20. Blüml S, Bonelli M, Niederreiter B, Puchner A, Mayr G, Hayer S et al. Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum 2011; 63: 1281–1288.

    Article  PubMed  Google Scholar 

  21. Stanczyk J, Ospelt C, Karouzakis E, Filer A, Raza K, Kolling C et al. Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum 2011; 63: 373–381.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kurowska-Stolarska M, Alivernini S, Ballantine LE, Asquith DL, Millar NL, Gilchrist DS et al. MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci USA 2011; 108: 11193–11198.

    Article  CAS  PubMed  Google Scholar 

  23. Semaan N, Frenzel L, Alsaleh G, Suffert G, Gottenberg JE, Sibilia J et al. miR-346 controls release of TNF-alpha protein and stability of its mRNA in rheumatoid arthritis via tristetraprolin stabilization. PLoS One 2011; 6: e19827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nakasa T, Shibuya H, Nagata Y, Niimoto T, Ochi M . The inhibitory effect of microRNA-146a expression on bone destruction in collagen-induced arthritis. Arthritis Rheum 2011; 63: 1582–1590.

    Article  CAS  PubMed  Google Scholar 

  25. Abou-Zeid A, Saad M, Soliman E . MicroRNA 146a expression in rheumatoid arthritis: association with tumor necrosis factor-alpha and disease activity. Genet Test Mol Biomarkers 2011; 15: 807–812.

    Article  CAS  PubMed  Google Scholar 

  26. Philippe L, Alsaleh G, Suffert G, Meyer A, Georgel P, Sibilia J et al. TLR2 expression is regulated by microRNA miR-19 in rheumatoid fibroblast-like synoviocytes. J Immunol 2012; 188: 454–461.

    Article  CAS  Google Scholar 

  27. Filková M, Aradi B, Senolt L, Ospelt C, Vettori S, Mann H et al. Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis. Ann Rheum Dis 2014; 73: 1898–1904.

    Article  PubMed  Google Scholar 

  28. Murata K, Furu M, Yoshitomi H, Ishikawa M, Shibuya H, Hashimoto M et al. Comprehensive microRNA analysis identifies miR-24 and miR-125a-5p as plasma biomarkers for rheumatoid arthritis. PLoS One 2013; 8: e69118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Duroux-Richard I, Pers YM, Fabre S, Ammari M, Baeten D, Cartron G et al. Circulating miRNA-125b is a potential biomarker predicting response to rituximab in rheumatoid arthritis. Mediators Inflamm 2014; 2014: 342524.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hørslev-Petersen K, Hetland ML, Junker P, Pødenphant J, Ellingsen T, Ahlquist P et al. Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial. Ann Rheum Dis 2014; 73: 654–661.

    Article  PubMed  Google Scholar 

  31. Fransen J, Creemers MC, Van Riel PL . Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatology (Oxford) 2004; 43: 1252–1255.

    Article  CAS  Google Scholar 

  32. Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis 2011; 70: 404–413.

    Article  PubMed  Google Scholar 

  33. Kruhøffer M, Dyrskjøt L, Voss T, Lindberg RL, Wyrich R, Thykjaer T et al. Isolation of microarray-grade total RNA, microRNA, and DNA from a single PAXgene blood RNA tube. J Mol Diagn 2007; 9: 452–458.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mar JC, Kimura Y, Schroder K, Irvine KM, Hayashizaki Y, Suzuki H et al. Data-driven normalization strategies for high-throughput quantitative RT-PCR. BMC Bioinformatics 2009; 10: 110.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mestdagh P, Van Vlierberghe P, De Weer A, Muth D, Westermann F, Speleman F et al. A novel and universal method for microRNA RT-qPCR data normalization. Genome Biol 2009; 10: R64.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Massey F Jr. . The Kolmogorov-Smirnov test for goodness of fit. J Am Stat Assoc 1951; 46: 68–78.

    Article  Google Scholar 

  37. Zhang J, Yang Y, Yang T, Liu Y, Li A, Fu S et al. microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. Br J Cancer 2010; 103: 1215–1220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Pandey DP, Picard D . miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA. Mol Cell Biol 2009; 29: 3783–3790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cunningham M, Gilkeson G . Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol 2011; 40: 66–73.

    Article  CAS  PubMed  Google Scholar 

  40. Schmidt M, Hartung R, Capellino S, Cutolo M, Pfeifer-Leeg A, Straub RH . Estrone/17beta-estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis. Arthritis Rheum 2009; 60: 2913–2922.

    Article  CAS  PubMed  Google Scholar 

  41. Lin J, Huo R, Xiao L, Zhu X, Xie J, Sun S et al. A novel p53/microRNA-22/Cyr61 axis in synovial cells regulates inflammation in rheumatoid arthritis. Arthritis Rheumatol 2014; 66: 49–59.

    Article  CAS  PubMed  Google Scholar 

  42. Lin J, Zhou Z, Huo R, Xiao L, Ouyang G, Wang L et al. Cyr61 induces IL-6 production by fibroblast-like synoviocytes promoting Th17 differentiation in rheumatoid arthritis. J Immunol 2012; 188: 5776–5784.

    Article  CAS  PubMed  Google Scholar 

  43. Xiong Y, Zhang L, Holloway AK, Wu X, Su L, Kebebew E . MiR-886-3p regulates cell proliferation and migration, and is dysregulated in familial non-medullary thyroid cancer. PLoS One 2011; 6: e24717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gao W, Shen H, Liu L, Xu J, Xu J, Shu Y . MiR-21 overexpression in human primary squamous cell lung carcinoma is associated with poor patient prognosis. J Cancer Res Clin Oncol 2011; 137: 557–566.

    Article  CAS  PubMed  Google Scholar 

  45. Pillai MM, Yang X, Balakrishnan I, Bemis L, Torok-Storb B . MiR-886-3p down regulates CXCL12 (SDF1) expression in human marrow stromal cells. PLoS One 2010; 5: e14304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nanki T, Hayashida K, El-Gabalawy HS, Suson S, Shi K, Girschick HJ et al. Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol 2000; 165: 6590–6598.

    Article  CAS  PubMed  Google Scholar 

  47. Hansen IB, Ellingsen T, Hornung N, Poulsen JH, Lottenburger T, Stengaard-Pedersen K . Plasma level of CXC-chemokine CXCL12 is increased in rheumatoid arthritis and is independent of disease activity and methotrexate treatment. J Rheumatol 2006; 33: 1754–1759.

    CAS  PubMed  Google Scholar 

  48. Rykova EY, Wunsche W, Brizgunova OE, Skvortsova TE, Tamkovich SN, Senin IS et al. Concentrations of circulating RNA from healthy donors and cancer patients estimated by different methods. Ann NY Acad Sci 2006; 1075: 328–333.

    Article  CAS  PubMed  Google Scholar 

  49. García JM, García V, Peña C, Domínguez G, Silva J, Diaz R et al. Extracellular plasma RNA from colon cancer patients is confined in a vesicle-like structure and is mRNA-enriched. RNA 2008; 14: 1424–1432.

    Article  PubMed  PubMed Central  Google Scholar 

  50. McDonald JS, Milosevic D, Reddi HV, Grebe SK, Algeciras-Schimnich A . Analysis of circulating microRNA: preanalytical and analytical challenges. Clin Chem 2010; 57: 833–840.

    Article  Google Scholar 

  51. Schwarzenbach H, Nishida N, Calin GA, Pantel K . Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol 2014; 11: 145–156.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank technician Teresa Rozenfeld, the Glostrup Hospital, the Copenhagen University Hospital, Denmark for help with handling of the blood samples from the different departments. Mogens Kruhøffer from AROS, Applied Biotechnology A/S, Aarhus, Denmark is thanked for excellent technical assistance with the miRNA array analysis. The study was supported by grants from the ‘Research Council at Herlev Hospital’, ‘The Danish Rheumatism Association’ and the following private funds; ‘The Danish Medical Association Research Foundation’, ‘Aase og Ejnar Danielsens Fond’, ‘Fonden til Lægevidenskabens Fremme’, ‘Scandinavian Journal of Rheumatology’, ‘Dagmar Marshalls Fond’, ‘The Bevica Foundation’, ‘Direktør Jacob Madsen og Hustru Olga Madsens Fond’, ‘Torben og Alice Frimodts Fond’ and the ‘Axel Muusfeldt fond’. The investigator-initiated clinical study was supported by grants from the Abbvie/Abbott Laboratories, Denmark and the Meda Pharmaceuticals, Denmark.

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Correspondence to S B Krintel.

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Krintel, S., Dehlendorff, C., Hetland, M. 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 16, 141–146 (2016). https://doi.org/10.1038/tpj.2015.30

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