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Inflammatory immune cell responses and Toll-like receptor expression in synovial tissues in rheumatoid arthritis patients treated with biologics or DMARDs

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Abstract

Biologic antirheumatic drugs (BIO) have been reported to be potent therapeutic agents in the prevention of inflammatory joint destruction in rheumatoid arthritis (RA). The aim of this study was to investigate the immune-inflammatory cells, including Toll-like receptor (TLR)-equipped cells, in synovial tissue samples from RA patients on BIO compared to patients, who are only on conventional disease-modifying antirheumatic drug (DMARD). We analyzed immune-inflammatory cells in RA synovitis in patients of BIO group (n = 20) or DMARD group (n = 20). The grading scores of synovitis was 1.7 and 1.8 in each BIO and DMARD group and correlated best with the CD3+ T (r = 0.71/0.70, p < 0.05) and CD20+ B (r = 0.80/0.84, p < 0.05) cells in the both groups, but less well with the CD68+ macrophages and S-100+ dendritic cells (DCs). Interestingly, both T (116 vs. 242, p < 0.05) and B (80 vs. 142, p < 0.05) cell counts were lower in the BIO than in the DMARD group, whereas macrophage and DC counts did not differ. In contrast, the C-reactive protein (CRP) and disease activity score DAS28-CRP did not show clear-cut correlations with the inflammatory grade of the synovitis (r range, 0–0.35). Similar numbers of cells immunoreactive for TLR-1 to TLR-6 and TLR-9 were found in synovitis in both groups. Patients clinically responding to biologics might still have the potential of moderate/severe local joint inflammation, composed in particular of and possibly driven by the autoinflammatory TLR+ cells.

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References

  1. Siegel RM (2009) Effector mechanisms of autoimmunity and inflammation. In: Firestein GS, Budd RC, Harris ED Jr, Mclnnes IB, Ruddy S, Sergent JS (eds) Text book of rheumatology, 8th edn. WB Saunders, Philadelphia, pp 259–263

    Google Scholar 

  2. Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361

    Article  PubMed  CAS  Google Scholar 

  3. Santiago-Schwarz F, Anand P, Liu S, Carsons SE (2001) Dendritic cells (DCs) in rheumatoid arthritis (RA): progenitor cells and soluble factors contained in RA synovial fluid yield a subset of myeloid DCs that preferentially activate Th1 inflammatory-type responses. J Immunol 167:1758–1768

    PubMed  CAS  Google Scholar 

  4. Theofilopoulos AN, Gonzalez-Quintial R, Lawson BR et al (2010) Sensors of the innate immune system: their link to rheumatic diseases. Nat Rev Rheumatol 6:146–156

    Article  PubMed  CAS  Google Scholar 

  5. Radstake TR, van Lieshout AW, van Riel PL, van den Berg WB, Adema GJ (2005) Dendritic cells, Fc gamma receptors, and Toll-like receptors: potential allies in the battle against rheumatoid arthritis. Ann Rheum Dis 64:1532–1538

    Article  PubMed  CAS  Google Scholar 

  6. Huang QQ, Pope RM (2009) The role of toll-like receptors in rheumatoid arthritis. Curr Rheumatol Rep 11:357–364

    Article  PubMed  CAS  Google Scholar 

  7. Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675–680

    Article  PubMed  CAS  Google Scholar 

  8. Tamaki Y, Takakubo Y, Goto K et al (2009) Increased expression of toll-like receptors in aseptic loose periprosthetic tissues and septic synovial membranes around total hip implants. J Rheumatol 36:598–608

    Article  PubMed  CAS  Google Scholar 

  9. Khan S, Greenberg JD, Bhardwaj N (2009) Dendritic cells as targets for therapy in rheumatoid arthritis. Nat Rev Rheumatol 5:566–571

    Article  PubMed  CAS  Google Scholar 

  10. Roelofs MF, Joosten LA, Abdollahi-Roodsaz S et al (2005) The expression of toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells. Arthritis Rheum 52:2313–2322

    Article  PubMed  CAS  Google Scholar 

  11. Radstake TR, Roelofs MF, Jenniskens YM et al (2004) Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma. Arthritis Rheum 50:3856–3865

    Article  PubMed  CAS  Google Scholar 

  12. Goronzy JJ, Weyand CM (2009) Developments in the scientific understanding of rheumatoid arthritis. Arthritis Res Ther 11:249

    Article  PubMed  Google Scholar 

  13. Lipsky PE, van der Heijde DM, St Clair EW et al (2000) Infliximab and methotrexate in thetreatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med 30:1594–1602

    Article  Google Scholar 

  14. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF et al (2005) Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 52:3381–3390

    Article  PubMed  CAS  Google Scholar 

  15. Klareskog L, van der Heijde D, de Jager JP et al (2004) Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 363:675–681

    Article  PubMed  CAS  Google Scholar 

  16. Takakubo Y, Takagi M, Tamaki Y et al (2010) Mid-term results of joint-preserving procedures by a modified Mann method for big toe deformities in rheumatoid patients undergoing forefoot surgeries. Mod Rheumatol 20:147–153

    Article  PubMed  Google Scholar 

  17. Abdollahi-Roodsaz S, Joosten LA, Roelofs MF et al (2007) Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum 56:2957–2967

    Article  PubMed  CAS  Google Scholar 

  18. Felson DT, Anderson JJ, Boers M et al (1995) American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 38:727–735

    Article  PubMed  CAS  Google Scholar 

  19. Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38:44–48

    Article  PubMed  CAS  Google Scholar 

  20. Maeda K, Matsuda M, Degawa N et al (1995) In vitro immune complex binding assay to examine the mechanism of immune complex trapping by human follicular dendritic cells (FDC). Adv Exp Med Biol 378:317–319

    Article  PubMed  CAS  Google Scholar 

  21. Krenn V, Morawietz L, Haupl T, Neidel J, Petersen I, Konig A (2002) Grading of chronic synovitis—a histopathological grading system for molecular and diagnostic pathology. Pathol Res Pract 198:317–325

    Article  PubMed  CAS  Google Scholar 

  22. Takakubo Y, Takagi M, Maeda K et al (2008) Distribution of myeloid dendritic cells and plasmacytoid dendritic cells in the synovial tissues of rheumatoid arthritis. J Rheumatol 35:1919–1931

    PubMed  CAS  Google Scholar 

  23. Tsuge K, Takeda H, Kawada S, Maeda K, Yamakawa M (2005) Characterization of dendritic cells in differentiated thyroid cancer. J Pathol 205:565–576

    Article  PubMed  CAS  Google Scholar 

  24. Page G, Miossec P (2004) Paired synovium and lymph nodes from rheumatoid arthritis patients differ in dendritic cell and chemokine expression. J Pathol 204:28–38

    Article  PubMed  CAS  Google Scholar 

  25. Kavousanaki M, Makrigiannakis A, Boumpas D, Verginis P (2010) Novel role of plasmacytoid dendritic cells in humans: induction of interleukin-10-producing Treg cells by plasmacytoid dendritic cells in patients with rheumatoid arthritis responding to therapy. Arthritis Rheum 62:53–63

    Article  PubMed  CAS  Google Scholar 

  26. van Gestel AM, Haagsma CJ, van Riel PL (1998) Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum 41:1845–1850

    Article  PubMed  Google Scholar 

  27. Baldwin HM, Ito-Ihara T, Isaacs JD, Hilkens CM (2010) Tumour necrosis factor alpha blockade impairs dendritic cell survival and function in rheumatoid arthritis. Ann Rheum Dis 69:1200–1207

    Article  PubMed  CAS  Google Scholar 

  28. Roelofs MF, Wenink MH, Brentano F et al (2009) Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA). Ann Rheum Dis 68:1486–1493

    Article  PubMed  CAS  Google Scholar 

  29. Iwahashi M, Yamamura M, Aita T et al (2004) Expression of Toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum 50:1457–1467

    Article  PubMed  CAS  Google Scholar 

  30. Miyasaka N, Takeuchi T, Eguchi K (2005) Proposed [corrected] Japanese guidelines for the use of infliximab for rheumatoid arthritis. Mod Rheumatol 15:4–8

    Article  PubMed  CAS  Google Scholar 

  31. Cañete JD, Celis R, Moll C et al (2009) Clinical significance of synovial lymphoid neogenesis and its reversal after anti-tumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis 68:751–756

    Article  PubMed  Google Scholar 

  32. Van de Sande MG, Gerlag DM, Lodde BM et al (2011) Evaluating antirheumatic treatments using synovial biopsy: a recommendation for standardisation to be used in clinical trials. Ann Rheum Dis 70:423–427

    Article  PubMed  Google Scholar 

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Acknowledgment

We sincerely thank a lot Ms. Eiko Saito for her skillful technical support in immunohistochemistry. Y. Takakubo from Japan was supported by the Excellent Young Researchers Overseas Visit Program, the Japan Society for the Promotion of Science (21–8117), and Y. T. Konttinen from Finland by ORTON Orthopedic Hospital, Helsinki University Central Hospital, Sigrid Jusélius Foundation, Finska Läkaresällskapet, and the Danish Council for Strategic Research (“Individualized musculoskeletal medicine”).

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Authors and Affiliations

  1. Department of Orthopedic Surgery, Yamagata University School of Medicine, 2-2-2 Iida Nishi, Yamagata, 990-9585, Japan

    Yuya Takakubo, Yasunobu Tamaki, Tomoyuki Hirayama, Kiyoshi Iwazaki, Kan Sasaki, Akiko Sasaki, Hiroharu Ohki & Michiaki Takagi

  2. Department of Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, 00014 HY, Finland

    Yuya Takakubo, Noe Takakubo & Yrjö T. Konttinen

  3. Department of Clinical Medicine, Yamagata Saisei Hospital, Yamagata, 990-8545, Japan

    Noe Takakubo

  4. Department of Medicine/Invärtes medicin, Helsinki University Central Hospital, Helsinki, 00029 HUS, Finland

    Yrjö T. Konttinen

  5. ORTON Orthopedic Hospital of the ORTON Foundation, Helsinki, 00281, Finland

    Yrjö T. Konttinen

  6. COXA Hospital for Joint Replacement, Tampere, 33101, Finland

    Yrjö T. Konttinen

Authors
  1. Yuya Takakubo
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  2. Yasunobu Tamaki
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  3. Tomoyuki Hirayama
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  4. Kiyoshi Iwazaki
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  5. Kan Sasaki
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  7. Hiroharu Ohki
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  8. Noe Takakubo
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  9. Yrjö T. Konttinen
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  10. Michiaki Takagi
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Correspondence to Yuya Takakubo.

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Takakubo, Y., Tamaki, Y., Hirayama, T. et al. Inflammatory immune cell responses and Toll-like receptor expression in synovial tissues in rheumatoid arthritis patients treated with biologics or DMARDs. Clin Rheumatol 32, 853–861 (2013). https://doi.org/10.1007/s10067-013-2209-3

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  • DOI: https://doi.org/10.1007/s10067-013-2209-3

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