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BioMed Research International
Volume 2014, Article ID 698313, 12 pages
http://dx.doi.org/10.1155/2014/698313
Review Article

Interleukin 6 and Rheumatoid Arthritis

1Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
2Department of Clinical Application of Biologics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan
3Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan

Received 20 September 2013; Revised 19 November 2013; Accepted 11 December 2013; Published 12 January 2014

Academic Editor: Juan-Manuel Anaya

Copyright © 2014 Yuji Yoshida and Toshio Tanaka. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. I. B. McInnes and G. Schett, “The pathogenesis of rheumatoid arthritis,” The New England Journal of Medicine, vol. 365, no. 23, pp. 2205–2219, 2011. View at Google Scholar · View at Scopus
  2. J. S. Smolen, D. Aletaha, J. W. Bijlsma et al., “Treating rheumatoid arthritis to target: recommendations of an international task force,” Annals of the Rheumatic Diseases, vol. 69, no. 4, pp. 631–637, 2010. View at Publisher · View at Google Scholar
  3. T. Tanaka, A. Ogata, and M. Narazaki, “Tocilizumab for the treatment of rheumatoid arthritis,” Expert Review of Clinical Immunology, vol. 6, no. 6, pp. 843–854, 2010. View at Publisher · View at Google Scholar · View at Scopus
  4. T. Tanaka, M. Narazaki, and T. Kishimoto, “Therapeutic targeting of the interleukin-6 receptor,” Annual Review of Pharmacology and Toxicology, vol. 52, pp. 199–219, 2012. View at Publisher · View at Google Scholar · View at Scopus
  5. T. Tanaka, A. Ogata, and T. Kishimoto, “Targeting of interleukin-6 for the treatment of rheumatoid arthritis: a review and update,” Rheumatology: Current Research, vol. 3, no. 2, article S4:002, 2013. View at Google Scholar
  6. K. Yoshizaki, T. Nakagawa, T. Kaieda, A. Muraguchi, Y. Yamamura, and T. Kishimoto, “Induction of proliferation and Ig production in human B leukemic cells by anti-immunoglobulins and T cell factors,” The Journal of Immunology, vol. 128, no. 3, pp. 1296–1301, 1982. View at Google Scholar · View at Scopus
  7. T. Kishimoto, “Factors affecting B-cell growth and differentiation,” Annual Review of Immunology, vol. 3, pp. 133–157, 1985. View at Google Scholar · View at Scopus
  8. T. Hirano, K. Yasukawa, H. Harada et al., “Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin,” Nature, vol. 324, no. 6092, pp. 73–76, 1986. View at Google Scholar · View at Scopus
  9. S. Suematsu, T. Matsusaka, T. Matsuda et al., “Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 1, pp. 232–235, 1992. View at Google Scholar · View at Scopus
  10. J. Gauldie, C. Richards, D. Harnish, P. Lansdorp, and H. Baumann, “Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 20, pp. 7251–7255, 1987. View at Google Scholar · View at Scopus
  11. P. C. Heinrich, J. V. Castell, and T. Andus, “Interleukin-6 and the acute phase response,” Biochemical Journal, vol. 265, no. 3, pp. 621–636, 1990. View at Google Scholar · View at Scopus
  12. T. Hirano, S. Akira, T. Taga, and T. Kishimoto, “Biological and clinical aspects of interleukin 6,” Immunology Today, vol. 11, no. 12, pp. 443–449, 1990. View at Google Scholar · View at Scopus
  13. S. Akira, T. Taga, and T. Kishimoto, “Interleukin-6 in biology and medicine,” Advances in Immunology, vol. 54, pp. 1–78, 1993. View at Google Scholar · View at Scopus
  14. T. Kishimoto, “Interleukin-6: from basic science to medicine—40 years in immunology,” Annual Review of Immunology, vol. 23, pp. 1–21, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. K. Yamasaki, T. Taga, Y. Hirata et al., “Cloning and expression of the human interleukin-6 (BSF-2/IFNβ 2) receptor,” Science, vol. 241, no. 4867, pp. 825–828, 1988. View at Google Scholar · View at Scopus
  16. T. Kishimoto, S. Akira, and T. Taga, “Interleukin-6 and its receptor: a paradigm for cytokines,” Science, vol. 258, no. 5082, pp. 593–597, 1992. View at Google Scholar · View at Scopus
  17. T. Taga, M. Hibi, Y. Hirata et al., “Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130,” Cell, vol. 58, no. 3, pp. 573–581, 1989. View at Google Scholar · View at Scopus
  18. M. Hibi, M. Murakami, M. Saito, T. Hirano, T. Taga, and T. Kishimoto, “Molecular cloning and expression of an IL-6 signal transducer, gp130,” Cell, vol. 63, no. 6, pp. 1149–1157, 1990. View at Publisher · View at Google Scholar · View at Scopus
  19. C. Lutticken, U. M. Wegenka, J. Yuan et al., “Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130,” Science, vol. 263, no. 5143, pp. 89–92, 1994. View at Google Scholar · View at Scopus
  20. N. Stahl, T. G. Boulton, T. Farruggella et al., “Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 β receptor components,” Science, vol. 263, no. 5143, pp. 92–95, 1994. View at Google Scholar · View at Scopus
  21. S. Rose-John, “IL-6 trans-signaling via the soluble IL-6 receptor: importance for the proinflammatory activities of IL-6,” International Journal of Biological Sciences, vol. 8, no. 9, pp. 1237–1247, 2012. View at Google Scholar
  22. S. Akira, Y. Nishio, M. Inoue et al., “Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway,” Cell, vol. 77, no. 1, pp. 63–71, 1994. View at Google Scholar · View at Scopus
  23. N. Stahl, T. J. Farruggella, T. G. Boulton, Z. Zhong, J. E. Darnell Jr., and G. D. Yancopoulos, “Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors,” Science, vol. 267, no. 5202, pp. 1349–1353, 1995. View at Google Scholar · View at Scopus
  24. C. Gerhartz, B. Heesel, J. Sasse et al., “Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleukin 6 signal transducer gp130: I. Definition of a novel phosphotyrosine motif mediating STAT1 activation,” The Journal of Biological Chemistry, vol. 271, no. 22, pp. 12991–12998, 1996. View at Google Scholar · View at Scopus
  25. K. K. Kuropatwinski, C. de Imus, D. Gearing, H. Baumann, and B. Mosley, “Influence of subunit combinations on signaling by receptors for oncostatin M, leukemia inhibitory factor, and interleukin-6,” The Journal of Biological Chemistry, vol. 272, no. 24, pp. 15135–15144, 1997. View at Publisher · View at Google Scholar · View at Scopus
  26. M. Tomida, T. Heike, and T. Yokota, “Cytoplasmic domains of the leukemia inhibitory factor receptor required for STAT3 activation, differentiation, and growth arrest of myeloid leukemic cells,” Blood, vol. 93, no. 6, pp. 1934–1941, 1999. View at Google Scholar · View at Scopus
  27. B. T. Hennessy, D. L. Smith, P. T. Ram, Y. Lu, and G. B. Mills, “Exploiting the PI3K/AKT pathway for cancer drug discovery,” Nature Reviews Drug Discovery, vol. 4, no. 12, pp. 988–1004, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. C.-M. Chien, K.-L. Lin, J.-C. Su et al., “Naphtho[1,2-b]furan-4,5-dione induces apoptosis of oral squamous cell carcinoma: involvement of EGF receptor/PI3K/Akt signaling pathway,” The European Journal of Pharmacology, vol. 636, no. 1–3, pp. 52–58, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Suematsu, T. Matsuda, K. Aozasa et al., “IgG1 plasmacytosis in interleukin 6 transgenic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 19, pp. 7547–7551, 1989. View at Google Scholar · View at Scopus
  30. M. Rincón, J. Anguita, T. Nakamura, E. Fikrig, and R. A. Flavell, “Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells,” The Journal of Experimental Medicine, vol. 185, no. 3, pp. 461–469, 1997. View at Publisher · View at Google Scholar · View at Scopus
  31. T. Korn, E. Bettelli, M. Oukka, and V. K. Kuchroo, “IL-17 and Th17 cells,” Annual Review of Immunology, vol. 27, pp. 485–517, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. A. Kimura and T. Kishimoto, “IL-6: regulator of Treg/Th17 balance,” European Journal of Immunology, vol. 40, no. 7, pp. 1830–1835, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. R. Nurieva, X. O. Yang, G. Martinez et al., “Essential autocrine regulation by IL-21 in the generation of inflammatory T cells,” Nature, vol. 448, no. 7152, pp. 480–483, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. A. Suto, D. Kashiwakuma, S.-I. Kagami et al., “Development and characterization of IL-21-producing CD4+ T cells,” The Journal of Experimental Medicine, vol. 205, no. 6, pp. 1369–1379, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. O. Dienz, S. M. Eaton, J. P. Bond et al., “The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells,” The Journal of Experimental Medicine, vol. 206, no. 1, pp. 69–78, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. M. Suzuki, M. Hashizume, H. Yoshida, and M. Mihara, “Anti-inflammatory mechanism of tocilizumab, a humanized anti-IL-6R antibody: effect on the expression of chemokine and adhesion molecule,” Rheumatology International, vol. 30, no. 3, pp. 309–315, 2010. View at Publisher · View at Google Scholar · View at Scopus
  37. S. Kotake, K. Sato, K. J. Kim et al., “Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation,” Journal of Bone and Mineral Research, vol. 11, no. 1, pp. 88–95, 1996. View at Google Scholar · View at Scopus
  38. P. Palmqvist, E. Persson, H. H. Conaway, and U. H. Lerner, “IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-κB ligand, osteoprotegerin, and receptor activator of NF-κB in mouse calvariae,” The Journal of Immunology, vol. 169, no. 6, pp. 3353–3362, 2002. View at Google Scholar · View at Scopus
  39. M. Suzuki, M. Hashizume, H. Yoshida, M. Shiina, and M. Mihara, “IL-6 and IL-1 synergistically enhanced the production of MMPs from synovial cells by up-regulating IL-6 production and IL-1 receptor I expression,” Cytokine, vol. 51, no. 2, pp. 178–183, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. H. Nakahara, J. Song, M. Sugimoto et al., “Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis,” Arthritis & Rheumatism, vol. 48, no. 6, pp. 1521–1529, 2003. View at Publisher · View at Google Scholar · View at Scopus
  41. E. Nemeth, S. Rivera, V. Gabayan et al., “IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin,” The Journal of Clinical Investigation, vol. 113, no. 9, pp. 1271–1276, 2004. View at Publisher · View at Google Scholar · View at Scopus
  42. T. Ishibashi, H. Kimura, Y. Shikama et al., “Interleukin-6 is a potent thrombopoietic factor in vivo in mice,” Blood, vol. 74, no. 4, pp. 1241–1244, 1989. View at Google Scholar · View at Scopus
  43. T. Hirano, T. Matsuda, M. Turner et al., “Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis,” European Journal of Immunology, vol. 18, no. 11, pp. 1797–1801, 1988. View at Google Scholar · View at Scopus
  44. I. Holt, R. G. Cooper, and S. J. Hopkins, “Relationships between local inflammation, interleukin-6 concentration and the acute phase protein response in arthritis patients,” European Journal of Clinical Investigation, vol. 21, no. 5, pp. 479–484, 1991. View at Google Scholar · View at Scopus
  45. B. Dasgupta, M. Corkill, B. Kirkham, T. Gibson, and G. Panayi, “Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis,” The Journal of Rheumatology, vol. 19, no. 1, pp. 22–25, 1992. View at Google Scholar · View at Scopus
  46. R. Madhok, A. Crilly, J. Watson, and H. A. Capell, “Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity,” Annals of the Rheumatic Diseases, vol. 52, no. 3, pp. 232–234, 1993. View at Google Scholar · View at Scopus
  47. R. H. Straub, U. Müller-Ladner, T. Lichtinger, J. Schölmerich, H. Menninger, and B. Lang, “Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying anti-rheumatic drugs,” British Journal of Rheumatology, vol. 36, no. 12, pp. 1298–1303, 1997. View at Google Scholar · View at Scopus
  48. N. Nishimoto, K. Amano, Y. Hirabayashi et al., “Drug free REmission/low disease activity after cessation of tocilizumab (Actemra) Monotherapy (DREAM) study,” Modern Rheumatology, vol. 24, no. 1, pp. 17–25, 2014. View at Publisher · View at Google Scholar
  49. T. Alonzi, E. Fattori, D. Lazzaro et al., “Interleukin 6 is required for the development of collagen-induced arthritis,” The Journal of Experimental Medicine, vol. 187, no. 4, pp. 461–468, 1998. View at Publisher · View at Google Scholar · View at Scopus
  50. M. Sasai, Y. Saeki, S. Ohshima et al., “Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice,” Arthritis & Rheumatism, vol. 42, no. 8, pp. 1635–1643, 1999. View at Google Scholar
  51. N. Takagi, M. Mihara, Y. Moriya et al., “Blockade of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis,” Arthritis & Rheumatism, vol. 41, no. 12, pp. 2117–2121, 1998. View at Google Scholar
  52. M. Fujimoto, S. Serada, M. Mihara et al., “Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses,” Arthritis & Rheumatism, vol. 58, no. 12, pp. 3710–3719, 2008. View at Publisher · View at Google Scholar · View at Scopus
  53. S. Ohshima, Y. Saeki, T. Mima et al., “Interleukin 6 plays a key role in the development of antigen-induced arthritis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 14, pp. 8222–8226, 1998. View at Publisher · View at Google Scholar · View at Scopus
  54. P. K. K. Wong, J. M. W. Quinn, N. A. Sims, A. van Nieuwenhuijze, I. K. Campbell, and I. P. Wicks, “Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis,” Arthritis & Rheumatism, vol. 54, no. 1, pp. 158–168, 2006. View at Publisher · View at Google Scholar · View at Scopus
  55. N. Sakaguchi, T. Takahashi, H. Hata et al., “Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice,” Nature, vol. 426, no. 6965, pp. 454–460, 2003. View at Publisher · View at Google Scholar · View at Scopus
  56. H. Hata, N. Sakaguchi, H. Yoshitomi et al., “Distinct contribution of IL-6, TNF-α, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice,” The Journal of Clinical Investigation, vol. 114, no. 4, pp. 582–588, 2004. View at Publisher · View at Google Scholar · View at Scopus
  57. K. Hirota, M. Hashimoto, H. Yoshitomi et al., “T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis,” The Journal of Experimental Medicine, vol. 204, no. 1, pp. 41–47, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. K. Sato, M. Tsuchiya, J. Saldanha et al., “Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth,” Cancer Research, vol. 53, no. 4, pp. 851–856, 1993. View at Google Scholar · View at Scopus
  59. N. Nishimoto, M. Sasai, Y. Shima et al., “Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy,” Blood, vol. 95, no. 1, pp. 56–61, 2000. View at Google Scholar · View at Scopus
  60. N. Nishimoto, Y. Kanakura, K. Aozasa et al., “Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease,” Blood, vol. 106, no. 8, pp. 2627–2632, 2005. View at Publisher · View at Google Scholar · View at Scopus
  61. E. H. S. Choy, D. A. Isenberg, T. Garrood et al., “Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial,” Arthritis & Rheumatism, vol. 46, no. 12, pp. 3143–3150, 2002. View at Publisher · View at Google Scholar · View at Scopus
  62. N. Nishimoto, K. Yoshizaki, K. Maeda et al., “Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study,” The Journal of Rheumatology, vol. 30, no. 7, pp. 1426–1435, 2003. View at Google Scholar · View at Scopus
  63. R. N. Maini, P. C. Taylor, J. Szechinski et al., “Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate,” Arthritis & Rheumatism, vol. 54, no. 9, pp. 2817–2829, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. J. S. Smolen, A. Beaulieu, A. Rubbert-Roth et al., “Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial,” The Lancet, vol. 371, no. 9617, pp. 987–997, 2008. View at Publisher · View at Google Scholar · View at Scopus
  65. M. C. Genovese, J. D. McKay, E. L. Nasonov et al., “Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study,” Arthritis & Rheumatism, vol. 58, no. 10, pp. 2968–2980, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. P. Emery, E. Keystone, H. P. Tony et al., “IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial,” Annals of the Rheumatic Diseases, vol. 67, no. 11, pp. 1516–1523, 2008. View at Publisher · View at Google Scholar · View at Scopus
  67. J. M. Kremer, R. Blanco, M. Brzosko et al., “Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year,” Arthritis & Rheumatism, vol. 63, no. 3, pp. 609–621, 2011. View at Publisher · View at Google Scholar · View at Scopus
  68. G. Jones, A. Sebba, J. Gu et al., “Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study,” Annals of the Rheumatic Diseases, vol. 69, no. 1, pp. 88–96, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. N. Nishimoto, J. Hashimoto, N. Miyasaka et al., “Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab,” Annals of the Rheumatic Diseases, vol. 66, no. 9, pp. 1162–1167, 2007. View at Publisher · View at Google Scholar · View at Scopus
  70. N. Nishimoto, N. Miyasaka, K. Yamamoto et al., “Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy,” Modern Rheumatology, vol. 19, no. 1, pp. 12–19, 2009. View at Publisher · View at Google Scholar · View at Scopus
  71. H. Yamanaka, Y. Tanaka, E. Inoue et al., “Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily clinical practice in Japan: results from a retrospective study (REACTION study),” Modern Rheumatology, vol. 21, no. 2, pp. 122–133, 2011. View at Publisher · View at Google Scholar · View at Scopus
  72. T. Takeuchi, Y. Tanaka, K. Amano et al., “Clinical, radiographic and functional effectiveness of tocilizumab for rheumatoid arthritis patients-REACTION 52-week study,” Rheumatology, vol. 50, no. 10, pp. 1908–1915, 2011. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Dougados, K. Kissel, T. Sheeran et al., “Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY),” Annals of the Rheumatic Diseases, vol. 72, no. 1, pp. 43–50, 2012. View at Publisher · View at Google Scholar · View at Scopus
  74. C. Gabay, P. Emery, R. van Vollenhoven et al., “Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial,” The Lancet, vol. 381, no. 9877, pp. 1541–1550, 2013. View at Google Scholar
  75. P. Emery, A. Sebba, and T. W. Huizinga, “Biologic and oral disease-modifying antirheumatic drug monotherapy in rheumatoid arthritis,” Annals of the Rheumatic Diseases, 2013. View at Publisher · View at Google Scholar
  76. J. A. Singh, B. Saba, and M. A. Lopez-Olivo, “Tocilizumab for rheumatoid arthritis: a cochrane systematic review,” The Journal of Rheumatology, vol. 38, no. 1, pp. 10–20, 2011. View at Publisher · View at Google Scholar · View at Scopus
  77. A. Ogata, K. Tanimura, T. Sugimoto et al., “A phase 3 study of the efficacy and safety of subcutaneous versus intravenous tocilizumab monotherapy in patients with rheumatoid arthritis (MUSASHI),” Arthritis Care & Research, 2013. View at Publisher · View at Google Scholar
  78. G. R. Burmester, A. Rubbert-Roth, A. Cantagrel et al., “A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study),” Annals of the Rheumatic Diseases, vol. 73, no. 1, pp. 69–74, 2013. View at Publisher · View at Google Scholar
  79. M. H. Schiff, J. M. Kremer, A. Jahreis, E. Vernon, J. D. Isaacs, and R. F. van Vollenhoven, “Integrated safety in tocilizumab clinical trials,” Arthritis Research and Therapy, vol. 13, no. 5, article R141, 2011. View at Publisher · View at Google Scholar · View at Scopus
  80. T. Koike, M. Harigai, S. Inokuma et al., “Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients,” Annals of the Rheumatic Diseases, vol. 70, no. 12, pp. 2148–2151, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. J. A. Singh, G. A. Wells, R. Christensen et al., “Adverse effects of biologics: a network meta-analysis and Cochrane overview,” Cochrane Database of Systematic Reviews, vol. 2, Article ID CD008794, 2011. View at Google Scholar · View at Scopus
  82. M. C. Genovesse, A. Rubbert-Roth, J. S. Smolen et al., “Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumulative analysis of up to 4.6 years of exposure,” The Journal of Rheumatology, vol. 40, no. 6, pp. 768–780, 2013. View at Google Scholar
  83. T. Gout, A. J. K. Östör, and M. K. Nisar, “Lower gastrointestinal perforation in rheumatoid arthritis patients treated with conventional DMARDs or tocilizumab: a systematic literature review,” Clinical Rheumatology, vol. 30, no. 11, pp. 1471–1474, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. M. Hashizume, H. Yoshida, N. Koike, M. Suzuki, and M. Mihara, “Overproduced interleukin 6 decreases blood lipid levels via upregulation of very-low-density lipoprotein receptor,” Annals of the Rheumatic Diseases, vol. 69, no. 4, pp. 741–746, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. T. W. Huizinga, A. J. Kivitz, M. Rell-Bakalarska et al., “Sarilumab for the treatment of moderate to severe rheumatoid arthritis: results of a phase 2, randomized, double-blind, placebo-controlled, international study,” Annals of the Rheumatic Diseases, vol. 71, supplement 3, p. 60, 2012. View at Google Scholar
  86. B. Hsu, S. Sheng, J. S. Smolen, and M. E. Weinblatt, “Results from a 2-part, proof of concept, dose ranging, randomized, double-blind, placebo-controlled, phase 2 study of sirukumab, a human anti-interleukin-6 monoclonal antibody, in patients with active rheumatoid arthritis despite methotrexate therapy,” Annals of the Rheumatic Diseases, vol. 71, supplement 3, p. 188, 2012. View at Google Scholar
  87. K. Kanbe, A. Nakamura, Y. Inoue, and K. Hobo, “Osteoprotegerin expression in bone marrow by treatment with tocilizumab in rheumatoid arthritis,” Rheumatology International, vol. 32, no. 9, pp. 2669–2674, 2012. View at Publisher · View at Google Scholar · View at Scopus
  88. E. Terpos, K. Fragiadaki, M. Konsta, C. Bratengeier, A. Papatheodorou, and P. P. Sfikakis, “Early effects of IL-6 receptor inhibition on bone homeostasis: a pilot study in women with rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 29, no. 6, pp. 921–925, 2011. View at Google Scholar · View at Scopus
  89. A. C. Bay-Jensen, A. Platt, I. Byrjalsen, P. Vergnoud, C. Christiansen, and M. A. Karsdal, “Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium, cartilage, and bone in the LITHE study,” Seminars in Arthritis and Rheumatism, 2013. View at Publisher · View at Google Scholar
  90. T. Tanaka, “Can IL-6 blockade rectify imbalance between Tregs and Th17 cells?” Immunotherapy, vol. 5, no. 7, pp. 695–697, 2013. View at Google Scholar
  91. M. Samson, S. Audia, N. Janikashvili et al., “Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis,” Arthritis & Rheumatism, vol. 64, no. 8, pp. 2499–2503, 2012. View at Google Scholar
  92. B. Pesce, L. Soto, F. Sabugo et al., “Effect of interleukin-6 receptor blockade on the balance between regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients,” Clinical & Experimental Immunology, vol. 171, no. 3, pp. 237–242, 2013. View at Google Scholar
  93. G. Carbone, A. Wilson, S. A. Diehl, J. Bunn, S. M. Cooper, and M. Ricon, “Interleukin-6 receptor blockade selectively reduces IL-21 production by CD4 T cells and IgG4 autoantibodies in rheumatoid arthritis,” International Journal of Biological Sciences, vol. 9, no. 3, pp. 279–288, 2013. View at Google Scholar
  94. R. Liu, Q. Wu, D. Su et al., “A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis,” Arthritis Research & Therapy, vol. 23, no. 14, article R255, 2012. View at Publisher · View at Google Scholar
  95. D. Fishman, G. Faulds, R. Jeffey et al., “The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic- onset juvenile chronic arthritis,” The Journal of Clinical Investigation, vol. 102, no. 7, pp. 1369–1376, 1998. View at Google Scholar · View at Scopus
  96. Y. H. Lee, S.-C. Bae, S. J. Choi, J. D. Ji, and G. G. Song, “Associations between TNFAIP3 gene polymorphisms and rheumatoid arthritis: a meta-analysis,” Inflammation Research, vol. 61, no. 7, pp. 665–671, 2012. View at Publisher · View at Google Scholar · View at Scopus
  97. T. Tanaka, M. Narazaki, K. Masuda, and T. Kishimoto, “Interleukin-6, pathogenesis and treatment of autoimmune inflammatory diseases,” Inflammation and Regeneration, vol. 33, no. 1, pp. 54–65, 2013. View at Google Scholar
  98. K. Matsushita, O. Takeuchi, D. M. Standley et al., “Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay,” Nature, vol. 458, no. 7242, pp. 1185–1190, 2009. View at Publisher · View at Google Scholar · View at Scopus
  99. H. Iwasaki, O. Takeuchi, S. Teraguchi et al., “The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1,” Nature Immunology, vol. 12, no. 12, pp. 1167–1175, 2011. View at Publisher · View at Google Scholar · View at Scopus
  100. K. Masuda, B. Ripley, R. Nishimura et al., “Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 23, pp. 9409–9414, 2013. View at Google Scholar