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Liquid biopsies to guide therapeutic decisions in rheumatoid arthritis

  • Roxana Coras
    Affiliations
    Department of Medicine, School of Medicine, La Jolla, California

    University of California San Diego, San Diego, California

    Department of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
    Search for articles by this author
  • Rekha Narasimhan
    Affiliations
    Department of Medicine, School of Medicine, La Jolla, California

    University of California San Diego, San Diego, California
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  • Monica Guma
    Correspondence
    Reprint requests: Monica Guma, Division of Rheumatology, Allergy and Immunology, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0663.
    Affiliations
    Department of Medicine, School of Medicine, La Jolla, California

    University of California San Diego, San Diego, California

    Department of Medicine, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
    Search for articles by this author
      Rheumatoid arthritis (RA) is a systemic, immune-mediated inflammatory disease that has transitioned from a debilitating disease to a chronic, controllable disease. This has been possible due to the introduction of new treatment strategies like “treat-to-target,” in which the clinician treats the patient aggressively enough to reach low disease activity or remission, and the introduction of new therapeutic agents, such as biological therapies, which can lead to the prevention of damage by early diagnosis and initiation of treatment. Attention is now being directed toward identifying the optimal treatment for each patient, one that will be the most efficient and have the least number of side effects. Much work has been done to find serologic and synovial biomarkers of response to various RA treatments. Proteomics, genomics and, in the past few years, metabolomics, have all been used in the quest of identifying these biomarkers. Blood-based liquid biopsies provide a minimally invasive alternative to synovial biopsies to identify cellular and molecular signatures that can be used to longitudinally monitor response and allow for personalized medicine approach. Liquid biopsies are comprised of cell-free DNA, immune circulating cells, and extracellular vesicles, and are being increasingly and successfully used in the field of oncology for diagnosis, progression, prognosis, and prediction of response to treatment. Recently, researchers have also begun investigating the usefulness of liquid biopsies in the field of rheumatology; in this review, we will focus on the potential of liquid biopsy blood samples as biomarkers of response to treatment in patients with RA.

      Abbreviations:

      cfDNA (circulating cell-free DNA), CIC (circulating immune cells), DMARDs (disease-modifying disease drugs), ExV (extracellular vesicles), FLS (fibroblast-like synoviocytes), IFN (interferon), IL (interleukin), NSAIDs (nonsteroidal anti-inflammatory drugs), RA (rheumatoid arthritis), TNF (tumor necrosis factor)
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      REFERENCES

        • Tobón GJ
        • Youinou P
        • Saraux A
        The environment, geo-epidemiology, and autoimmune disease: rheumatoid arthritis.
        J Autoimmun. 2010; 35: 10-14
      1. Widdifield J, Paterson JM, Huang A, Bernatsky S. Causes of death in rheumatoid arthritis: Hhow do they compare to the general population? Arthritis Care Res. 2018. [Epub ahead of print].

        • Zink A
        • Albrecht K
        Rheumatoid arthritis: the benefits of early treatment after decades.
        Nat Rev Rheumatol. 2017; 13: 458-459
        • Hess EV
        • Luggen ME
        Remodeling the pyramid–a concept whose time has not yet come.
        J Rheumatol. 1989; 16: 1175-1176
        • van Vollenhoven RF
        Treatment of rheumatoid arthritis: state of the art 2009.
        Nat Rev Rheumatol. 2009; 5: 531-541
      2. Bergstra SA, Allaart CF. What is the optimal target for treat-to-target strategies in rheumatoid arthritis? Curr Opin Rheumatol. 2018;30:282–287.

        • Fleischmann R
        • Cutolo M
        • Genovese MC
        • et al.
        Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs.
        Arthritis Rheum. 2012; 64: 617-629
      3. Robinson WH, Mao R. Biomarkers to guide clinical therapeutics in rheumatology? Curr Opin Rheumatol. 2016;28:168–175.

        • Bardelli A
        • Pantel K
        Liquid biopsies, what we do not know (yet)..
        Cancer Cell. 2017; 31: 172-179
        • Keith MP
        • Edison JD
        • Gilliland WR
        Progress toward personalized treatment of rheumatoid arthritis.
        Clin Pharmacol Ther. 2012; 92: 440-442
        • Orr C
        • Vieira-Sousa E
        • Boyle DL
        • et al.
        Synovial tissue research: a state-of-the-art review.
        Nat Rev Rheumatol. 2017; 13: 463-475
        • Ramwadhdoebe TH
        • Hahnlein J
        • Maijer KI
        • et al.
        Lymph node biopsy analysis reveals an altered immunoregulatory balance already during the at-risk phase of autoantibody positive rheumatoid arthritis.
        Eur J Immunol. 2016; 46: 2812-2821
        • Rodriguez-Carrio J
        • Hahnlein JS
        • Ramwadhdoebe TH
        • et al.
        Brief report: altered innate lymphoid cell subsets in human lymph node biopsy specimens obtained during the at-risk and earliest phases of rheumatoid arthritis.
        Arthritis Rheumatol. 2017; 69: 70-76
        • van Baarsen LG
        • de Hair MJ
        • Ramwadhdoebe TH
        • et al.
        The cellular composition of lymph nodes in the earliest phase of inflammatory arthritis.
        Ann Rheum Dis. 2013; 72: 1420-1424
        • Wong RA
        • Alexander RB
        • Puri RK
        • Rosenberg SA
        In vivo proliferation of adoptively transferred tumor-infiltrating lymphocytes in mice.
        J Immunother (1991). 1991; 10: 120-130
        • Tak PP
        • Smeets TJ
        • Daha MR
        • et al.
        Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity.
        Arthritis Rheum. 1997; 40: 217-225
        • Mandelin AM
        • Homan PJ
        • Shaffer AM
        • et al.
        Transcriptional profiling of synovial macrophages using minimally invasive ultrasound-guided synovial biopsies in rheumatoid arthritis.
        Arthritis Rheumatol. 2018; ([Epub ahead of print])
      4. Filkova M, Cope A, Mant T, Galloway J. Is there a role of synovial biopsy in drug development? BMC Musculoskelet Disord. 2016;17:172.

        • Wijbrandts CA
        • Tak PP
        Prediction of response to targeted treatment in rheumatoid arthritis.
        Mayo Clin Proc. 2017; 92: 1129-1143
        • Walsh AM
        • Wechalekar MD
        • Guo Y
        • et al.
        Triple DMARD treatment in early rheumatoid arthritis modulates synovial T cell activation and plasmablast/plasma cell differentiation pathways.
        PLoS One. 2017; 12e0183928
        • Ducreux J
        • Durez P
        • Galant C
        • et al.
        Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium.
        Arthritis Rheumatol. 2014; 66: 15-23
        • van Oosterhout M
        • Levarht EW
        • Sont JK
        • Huizinga TW
        • Toes RE
        • van Laar JM
        Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF alpha and IL18 but not CXCL12.
        Ann Rheum Dis. 2005; 64: 537-543
        • Gerlag DM
        • Tak PP
        How to perform and analyse synovial biopsies.
        Best Pract Res Clin Rheumatol. 2013; 27: 195-207
        • Thurlings RM
        • Wijbrandts CA
        • Mebius RE
        • et al.
        Synovial lymphoid neogenesis does not define a specific clinical rheumatoid arthritis phenotype.
        Arthritis Rheum. 2008; 58: 1582-1589
        • Cantaert T
        • Kolln J
        • Timmer T
        • et al.
        B lymphocyte autoimmunity in rheumatoid synovitis is independent of ectopic lymphoid neogenesis.
        J Immunol. 2008; 181: 785-794
        • Klaasen R
        • Thurlings RM
        • Wijbrandts CA
        • et al.
        The relationship between synovial lymphocyte aggregates and the clinical response to infliximab in rheumatoid arthritis: a prospective study.
        Arthritis Rheum. 2009; 60: 3217-3224
        • Bugatti S
        • Manzo A
        • Bombardieri M
        • et al.
        Synovial tissue heterogeneity and peripheral blood biomarkers.
        Curr Rheumatol Rep. 2011; 13: 440-448
        • Pitzalis C
        • Kelly S
        • Humby F
        New learnings on the pathophysiology of RA from synovial biopsies.
        Curr Opin Rheumatol. 2013; 25: 334-344
        • Gerlag DM
        • Haringman JJ
        • Smeets TJ
        • et al.
        Effects of oral prednisolone on biomarkers in synovial tissue and clinical improvement in rheumatoid arthritis.
        Arthritis Rheum. 2004; 50: 3783-3791
        • Dolhain RJ
        • Tak PP
        • Dijkmans BA
        • De Kuiper P
        • Breedveld FC
        • Miltenburg AM
        Methotrexate reduces inflammatory cell numbers, expression of monokines and of adhesion molecules in synovial tissue of patients with rheumatoid arthritis.
        Br J Rheumatol. 1998; 37: 502-508
        • Meijer B
        • Gearry RB
        • Day AS
        The role of S100A12 as a systemic marker of inflammation.
        Int J Inflam. 2012; 2012907078
        • Smeets TJ
        • Kraan MC
        • van Loon ME
        • Tak PP
        Tumor necrosis factor alpha blockade reduces the synovial cell infiltrate early after initiation of treatment, but apparently not by induction of apoptosis in synovial tissue.
        Arthritis Rheum. 2003; 48: 2155-2162
        • Thurlings RM
        • Vos K
        • Wijbrandts CA
        • Zwinderman AH
        • Gerlag DM
        • Tak PP
        Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response.
        Ann Rheum Dis. 2008; 67: 917-925
        • Walsh CA
        • Fearon U
        • FitzGerald O
        • Veale DJ
        • Bresnihan B
        Decreased CD20 expression in rheumatoid arthritis synovium following 8 weeks of rituximab therapy.
        Clin Exp Rheumatol. 2008; 26: 656-658
        • Vos K
        • Thurlings RM
        • Wijbrandts CA
        • van Schaardenburg D
        • Gerlag DM
        • Tak PP
        Early effects of rituximab on the synovial cell infiltrate in patients with rheumatoid arthritis.
        Arthritis Rheum. 2007; 56: 772-778
        • Bresnihan B
        • Gerlag DM
        • Rooney T
        • et al.
        Synovial macrophages as a biomarker of response to therapeutic intervention in rheumatoid arthritis: standardization and consistency across centers.
        J Rheumatol. 2007; 34: 620-622
        • Haringman JJ
        • Gerlag DM
        • Zwinderman AH
        • et al.
        Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis.
        Ann Rheum Dis. 2005; 64: 834-838
        • Smith MD
        • Kraan MC
        • Slavotinek J
        • et al.
        Treatment-induced remission in rheumatoid arthritis patients is characterized by a reduction in macrophage content of synovial biopsies.
        Rheumatology. 2001; 40: 367-374
        • Kraan MC
        • Reece RJ
        • Barg EC
        • et al.
        Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers.
        Arthritis Rheum. 2000; 43: 1820-1830
        • Wijbrandts CA
        • Dijkgraaf MG
        • Kraan MC
        • et al.
        The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium.
        Ann Rheum Dis. 2008; 67: 1139-1144
        • Cunnane G
        • Madigan A
        • Murphy E
        • FitzGerald O
        • Bresnihan B
        The effects of treatment with interleukin-1 receptor antagonist on the inflamed synovial membrane in rheumatoid arthritis.
        Rheumatology. 2001; 40: 62-69
        • Bartok B
        • Firestein GS
        Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis.
        Immunol Rev. 2010; 233: 233-255
        • Ai R
        • Laragione T
        • Hammaker D
        • et al.
        Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes.
        Nat Commun. 2018; 9: 1921
        • Mizoguchi F
        • Slowikowski K
        • Wei K
        • et al.
        Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis.
        Nat Commun. 2018; 9: 789
        • Ulfgren AK
        • Andersson U
        • Engström M
        • Klareskog L
        • Maini RN
        • Taylor PC
        Systemic anti-tumor necrosis factor alpha therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor alpha synthesis.
        Arthritis Rheum. 2000; 43: 2391-2396
        • Rooney M
        • Whelan A
        • Feighery C
        • Bresnihan B
        Changes in lymphocyte infiltration of the synovial membrane and the clinical course of rheumatoid arthritis.
        Arthritis Rheum. 1989; 32: 361-369
        • Boyle DL
        • Soma K
        • Hodge J
        • et al.
        The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.
        Ann Rheum Dis. 2015; 74: 1311-1316
        • van der Pouw Kraan TC
        • Wijbrandts CA
        • van Baarsen LG
        • et al.
        Responsiveness to anti-tumour necrosis factor alpha therapy is related to pre-treatment tissue inflammation levels in rheumatoid arthritis patients.
        Ann Rheum Dis. 2008; 67: 563-566
        • Badot V
        • Galant C
        • Nzeusseu Toukap A
        • et al.
        Gene expression profiling in the synovium identifies a predictive signature of absence of response to adalimumab therapy in rheumatoid arthritis.
        Arthritis Res Ther. 2009; 11: R57
        • Dennis G
        • Holweg CT
        • Kummerfeld SK
        • et al.
        Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics.
        Arthritis Res Ther. 2014; 16: R90
        • Lindberg J
        • Wijbrandts CA
        • van Baarsen LG
        • et al.
        The gene expression profile in the synovium as a predictor of the clinical response to infliximab treatment in rheumatoid arthritis.
        PLoS One. 2010; 5: e11310
        • Buder A
        • Tomuta C
        • Filipits M
        The potential of liquid biopsies.
        Curr Opin Oncol. 2016; 28: 130-134
        • Siravegna G
        • Marsoni S
        • Siena S
        • Bardelli A
        Integrating liquid biopsies into the management of cancer.
        Nat Rev Clin Oncol. 2017; 14: 531-548
        • Ishii H
        • Azuma K
        • Sakai K
        • et al.
        Digital PCR analysis of plasma cell-free DNA for non-invasive detection of drug resistance mechanisms in EGFR mutant NSCLC: Correlation with paired tumor samples.
        Oncotarget. 2015; 6: 30850-30858
        • Thress KS
        • Brant R
        • Carr TH
        • et al.
        EGFR mutation detection in ctDNA from NSCLC patient plasma: a cross-platform comparison of leading technologies to support the clinical development of AZD9291.
        Lung Cancer. 2015; 90: 509-515
        • Spindler KL
        • Pallisgaard N
        • Vogelius I
        • Jakobsen A
        Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan.
        Clin Cancer Res. 2012; 18: 1177-1185
        • Mandel P
        • Metais P
        C R Seances Soc Biol Fil. 1948; 142 ([Not Available]): 241-243
        • Leon SA
        • Shapiro B
        • Sklaroff DM
        • Yaros MJ
        Free DNA in the serum of cancer patients and the effect of therapy.
        Cancer Res. 1977; 37: 646-650
        • Fleischhacker M
        • Schmidt B
        Circulating nucleic acids (CNAs) and cancer—a survey.
        Biochim Biophys Acta. 2007; 1775: 181-232
        • Schwarzenbach H
        • Hoon DS
        • Pantel K
        Cell-free nucleic acids as biomarkers in cancer patients.
        Nat Rev Cancer. 2011; 11: 426-437
        • Pisetsky DS
        • Fairhurst AM
        The origin of extracellular DNA during the clearance of dead and dying cells.
        Autoimmunity. 2007; 40: 281-284
        • Stroun M
        • Anker P
        Nucleic acids spontaneously released by living frog auricles.
        Biochem J. 1972; 128: 100P-101P
        • Anker P
        • Stroun M
        • Maurice PA
        Spontaneous release of DNA by human blood lymphocytes as shown in an in vitro system.
        Cancer Res. 1975; 35: 2375-2382
        • Stroun M
        • Lyautey J
        • Lederrey C
        • Olson-Sand A
        • Anker P
        About the possible origin and mechanism of circulating DNA apoptosis and active DNA release.
        Clin Chim Acta. 2001; 313139142
        • Altrichter J
        • Zedler S
        • Kraft R
        • et al.
        Neutrophil-derived circulating free DNA (cf-DNA/NETs), a potential prognostic marker for mortality in patients with severe burn injury.
        Eur J Trauma Emerg Surg. 2010; 36: 551-557
        • Sur Chowdhury C
        • Giaglis S
        • Walker UA
        • Buser A
        • Hahn S
        • Hasler P
        Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility.
        Arthritis Res Ther. 2014; 16: R122
        • Khandpur R
        • Carmona-Rivera C
        • Vivekanandan-Giri A
        • et al.
        NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis.
        Sci Transl Med. 2013; 5: 178ra40
        • Dunaeva M
        • Buddingh' BC
        • Toes RE
        • Luime JJ
        • Lubberts E
        • Pruijn GJ
        Decreased serum cell-free DNA levels in rheumatoid arthritis.
        Auto Immun Highlights. 2015; 6: 23-30
        • Rykova E
        • Sizikov A
        • Roggenbuck D
        • et al.
        Circulating DNA in rheumatoid arthritis: pathological changes and association with clinically used serological markers.
        Arthritis Res Ther. 2017; 19: 85
        • Hashimoto T
        • Yoshida K
        • Hashimoto N
        • Nakai A
        • Kaneshiro K
        • Suzuki K
        • et al.
        Circulating cell-free DNA: a marker to predict the therapeutic response for biological DMARDs in rheumatoid arthritis.
        Int J Rheum Dis. 2017; 20: 722-730
        • Leon SA
        • Ehrlich GE
        • Shapiro B
        • Labbate VA
        Free DNA in the serum of rheumatoid arthritis patients.
        J Rheumatol. 1977; 4: 139-143
        • Koffler D
        • Agnello V
        • Winchester R
        • Kunkel HG
        The occurrence of single-stranded DNA in the serum of patients with systemic lupus erythematosus and other diseases.
        J Clin Invest. 1973; 52: 198-204
        • Zhong XY
        • von Mühlenen I
        • Li Y
        • et al.
        Increased concentrations of antibody-bound circulatory cell-free DNA in rheumatoid arthritis.
        Clin Chem. 2007; 53: 1609-1614
        • García-Olmo D
        • García-Olmo DC
        • Ontañón J
        • Martinez E
        • Vallejo M
        Tumor DNA circulating in the plasma might play a role in metastasis. The hypothesis of the genometastasis..
        Histol Histopathol. 1999; 14: 1159-1164
        • Kawane K
        • Ohtani M
        • Miwa K
        • et al.
        Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages.
        Nature. 2006; 443: 998-1002
        • Snyder MW
        • Kircher M
        • Hill AJ
        • Daza RM
        • Shendure J
        Cell-free DNA Comprises an in vivo nucleosome footprint that informs its tissues-of-origin.
        Cell. 2016; 164: 57-68
        • Lehmann-Werman R
        • Neiman D
        • Zemmour H
        • et al.
        Identification of tissue-specific cell death using methylation patterns of circulating DNA.
        Proc Natl Acad Sci U S A. 2016; 113: E1826-E1834
        • Rao DA
        • Gurish MF
        • Marshall JL
        • et al.
        Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.
        Nature. 2017; 542: 110-114
        • García-Vicuña R
        • Gómez-Gaviro MV
        • Domínguez-Luis MJ
        • et al.
        CC and CXC chemokine receptors mediate migration, proliferation, and matrix metalloproteinase production by fibroblast-like synoviocytes from rheumatoid arthritis patients.
        Arthritis Rheum. 2004; 50: 3866-3877
        • Woods JM
        • Klosowska K
        • Spoden DJ
        • et al.
        A cell-cycle independent role for p21 in regulating synovial fibroblast migration in rheumatoid arthritis.
        Arthritis Res Ther. 2006; 8: R113
        • Lefèvre S
        • Knedla A
        • Tennie C
        • et al.
        Synovial fibroblasts spread rheumatoid arthritis to unaffected joints.
        Nat Med. 2009; 15: 1414-1420
        • Ermann J
        • Rao DA
        • Teslovich NC
        • Brenner MB
        • Raychaudhuri S
        Immune cell profiling to guide therapeutic decisions in rheumatic diseases.
        Nat Rev Rheumatol. 2015; 11: 541-551
        • Burska AN
        • Roget K
        • Blits M
        • et al.
        Gene expression analysis in RA: towards personalized medicine.
        Pharmacogenomics J. 2014; 14: 93-106
        • Bombard Y
        • Rozmovits L
        • Trudeau M
        • Leighl NB
        • Deal K
        • Marshall DA
        Access to personalized medicine: factors influencing the use and value of gene expression profiling in breast cancer treatment.
        Curr Oncol. 2014; 21: e426-e433
        • Raterman HG
        • Vosslamber S
        • de Ridder S
        • et al.
        The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients.
        Arthritis Res Ther. 2012; 14: R95
        • Thurlings RM
        • Boumans M
        • Tekstra J
        • et al.
        Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients.
        Arthritis Rheum. 2010; 62: 3607-3614
        • Vosslamber S
        • Raterman HG
        • van der Pouw Kraan TC
        • et al.
        Pharmacological induction of interferon type I activity following treatment with rituximab determines clinical response in rheumatoid arthritis.
        Ann Rheum Dis. 2011; 70: 1153-1159
        • Niu Q
        • Cai B
        • Huang ZC
        • Shi YY
        • Wang LL
        Disturbed Th17/Treg balance in patients with rheumatoid arthritis.
        Rheumatol Int. 2012; 32: 2731-2736
        • Wang W
        • Shao S
        • Jiao Z
        • Guo M
        • Xu H
        • Wang S
        The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis.
        Rheumatol Int. 2012; 32: 887-893
        • Pawlik A
        • Ostanek L
        • Brzosko I
        • et al.
        The expansion of CD4+CD28− T cells in patients with rheumatoid arthritis.
        Arthritis Res Ther. 2003; 5: R210-R213
        • Berner B
        • Wolf G
        • Hummel KM
        • Müller GA
        • Reuss-Borst MA
        Increased expression of CD40 ligand (CD154) on CD4+ T cells as a marker of disease activity in rheumatoid arthritis.
        Ann Rheum Dis. 2000; 59: 190-195
        • Ponchel F
        • Morgan AW
        • Bingham SJ
        • et al.
        Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis.
        Blood. 2002; 100: 4550-4556
        • Scarsi M
        • Ziglioli T
        • Airò P
        Decreased circulating CD28-negative T cells in patients with rheumatoid arthritis treated with abatacept are correlated with clinical response.
        J Rheumatol. 2010; 37: 911-916
        • Vital EM
        • Dass S
        • Rawstron AC
        • et al.
        Management of nonresponse to rituximab in rheumatoid arthritis: predictors and outcome of re-treatment.
        Arthritis Rheum. 2010; 62: 1273-1279
        • Sellam J
        • Rouanet S
        • Hendel-Chavez H
        • et al.
        Blood memory B cells are disturbed and predict the response to rituximab in patients with rheumatoid arthritis.
        Arthritis Rheum. 2011; 63: 3692-3701
        • Daien CI
        • Gailhac S
        • Mura T
        • Combe B
        • Hahne M
        • Morel J
        High levels of memory B cells are associated with response to a first tumor necrosis factor inhibitor in patients with rheumatoid arthritis in a longitudinal prospective study.
        Arthritis Res Ther. 2014; 16: R95
        • Vital EM
        • Dass S
        • Buch MH
        • Rawstron AC
        • Emery P
        An extra dose of rituximab improves clinical response in rheumatoid arthritis patients with initial incomplete B cell depletion: a randomised controlled trial.
        Ann Rheum Dis. 2015; 74: 1195-1201
        • Duffy D
        • Rouilly V
        • Libri V
        • et al.
        Functional analysis via standardized whole-blood stimulation systems defines the boundaries of a healthy immune response to complex stimuli.
        Immunity. 2014; 40: 436-450
        • Valadi H
        • Ekström K
        • Bossios A
        • Sjöstrand M
        • Lee JJ
        • Lötvall JO
        Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.
        Nat Cell Biol. 2007; 9: 654-659
        • Alexander M
        • Hu R
        • Runtsch MC
        • et al.
        Exosome-delivered microRNAs modulate the inflammatory response to endotoxin.
        Nat Commun. 2015; 6: 7321
        • Ratajczak J
        • Miekus K
        • Kucia M
        • et al.
        Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery.
        Leukemia. 2006; 20: 847-856
        • Herrera MB
        • Fonsato V
        • Gatti S
        • et al.
        Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats.
        J Cell Mol Med. 2010; 14: 1605-1618
        • Urciuoli E
        • Giorda E
        • Scarsella M
        • Petrini S
        • Peruzzi B
        Osteosarcoma-derived extracellular vesicles induce a tumor-like phenotype in normal recipient cells.
        J Cell Physiol. 2018;
        • Peinado H
        • Alečković M
        • Lavotshkin S
        • et al.
        Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.
        Nat Med. 2012; 18: 883-891
        • Sellam J
        • Proulle V
        • Jüngel A
        • et al.
        Increased levels of circulating microparticles in primary Sjögren's syndrome, systemic lupus erythematosus and rheumatoid arthritis and relation with disease activity.
        Arthritis Res Ther. 2009; 11: R156
        • Skriner K
        • Adolph K
        • Jungblut PR
        • Burmester GR
        Association of citrullinated proteins with synovial exosomes.
        Arthritis Rheum. 2006; 54: 3809-3814
        • Tanaka Y
        • Kamohara H
        • Kinoshita K
        • et al.
        Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma.
        Cancer. 2013; 119: 1159-1167
        • Ogata-Kawata H
        • Izumiya M
        • Kurioka D
        • et al.
        Circulating exosomal microRNAs as biomarkers of colon cancer.
        PLoS One. 2014; 9: e92921
        • Bhagirath D
        • Yang TL
        • Bucay N
        • et al.
        microRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer.
        Cancer Res. 2018; 78: 1833-1844
        • Melo SA
        • Luecke LB
        • Kahlert C
        • et al.
        Glypican-1 identifies cancer exosomes and detects early pancreatic cancer.
        Nature. 2015; 523: 177-182
        • Kim VN.
        MicroRNA biogenesis: coordinated cropping and dicing.
        Nat Rev Mol Cell Biol. 2005; 6: 376-385
        • Wittmann J
        • Jäck HM
        microRNAs in rheumatoid arthritis: midget RNAs with a giant impact.
        Ann Rheum Dis. 2011; 70 (Suppl 1)): i92-i96
        • Filková M
        • Jüngel A
        • Gay RE
        • Gay S
        MicroRNAs in rheumatoid arthritis: potential role in diagnosis and therapy.
        BioDrugs. 2012; 26: 131-141
        • Filková M
        • Aradi B
        • Senolt L
        • 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
        • Castro-Villegas C
        • Pérez-Sánchez C
        • Escudero A
        • et al.
        Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFα.
        Arthritis Res Ther. 2015; 17: 49
        • Krintel SB
        • Dehlendorff C
        • Hetland ML
        • 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. 2016; 16: 141-146
      5. Cuppen BV, Rossato M, Fritsch-Stork RD, et al. Can baseline serum microRNAs predict response to TNF-alpha inhibitors in rheumatoid arthritis? Arthritis Res Ther. 2016;18:189.

        • Sode J
        • Krintel SB
        • Carlsen AL
        • et al.
        Plasma MicroRNA profiles in patients with early rheumatoid arthritis responding to adalimumab plus methotrexate vs methotrexate alone: a placebo-controlled clinical trial.
        J Rheumatol. 2018; 45: 53-61
        • Hruskova V
        • Jandova R
        • Vernerova L
        • et al.
        MicroRNA-125b: association with disease activity and the treatment response of patients with early rheumatoid arthritis.
        Arthritis Res Ther. 2016; 18: 124
        • Duroux-Richard I
        • Pers YM
        • Fabre S
        • et al.
        Circulating miRNA-125b is a potential biomarker predicting response to rituximab in rheumatoid arthritis.
        Mediators Inflamm. 2014; 2014342524
        • Sweeney SR
        • Kavanaugh A
        • Lodi A
        • et al.
        Metabolomic profiling predicts outcome of rituximab therapy in rheumatoid arthritis.
        RMD Open. 2016; 2e000289