Copyright © 2011 Misato Hashizume and Masahiko Mihara. 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. NICE, “Rheumatoid Arthritis Consultation Document,” http://www.nice.org.uk/nicemedia/pdf/scope_ra_consultation.pdf.
2. JL 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.
3. P. Garnero, E. Thompson, T. Woodworth, and J. S. Smolen, “Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone,” Arthritis and Rheumatism, vol. 62, no. 1, pp. 33–43, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
4. M. Romano, M. Sironi, C. Toniatti et al., “Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment,” Immunity, vol. 6, no. 3, pp. 315–325, 1997. View at Publisher · View at Google Scholar · View at Scopus
5. S. H. Yap, H. J. Moshage, B. P. C. Hazenberg et al., “Tumor necrosis factor (TNF) inhibits interleukin (IL)-1 and/or IL-6 stimulated synthesis of C-reactive protein (CRP) and serum amyloid A (SAA) in primary cultures of human hepatocytes,” Biochimica et Biophysica Acta, vol. 1091, no. 3, pp. 405–408, 1991. View at Publisher · View at Google Scholar · View at Scopus
6. T. Suwa, J. C. Hogg, D. English, and S. F. Van Eeden, “Interleukin-6 induces demargination of intravascular neutrophils and shortens their transit in marrow,” American Journal of Physiology, vol. 279, no. 6, pp. H2954–H2960, 2000. View at Scopus
7. Y. Uchiyama, N. Koike, and M. Mihara, “Anemia in monkey collagen-induced arthritis is correlated with serum IL-6, but not TNFα,” Rheumatology International, vol. 28, no. 9, pp. 879–883, 2008. View at Publisher · View at Google Scholar · View at PubMed
8. S. Rivera, E. Nemeth, V. Gabayan, M. A. Lopez, D. Farshidi, and T. Ganz, “Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs,” Blood, vol. 106, no. 6, pp. 2196–2199, 2005. View at Publisher · View at Google Scholar · View at PubMed
9. 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
10. S. Rose-John and M. F. Neurath, “IL-6 trans-signaling: the heat is on,” Immunity, vol. 20, no. 1, pp. 2–4, 2004. View at Publisher · View at Google Scholar
11. M. Mihara, K. Kasutani, M. Okazaki et al., “Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family,” International Immunopharmacology, vol. 5, no. 12, pp. 1731–1740, 2005. View at Publisher · View at Google Scholar · View at PubMed
12. M. Narazaki, K. Yasukawa, T. Saito et al., “Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130,” Blood, vol. 82, no. 4, pp. 1120–1126, 1993.
13. G. Müller-Newen, A. Küster, U. Hemmann et al., “Soluble IL-6 receptor potentiates the antagonistic activity of soluble gp130 on IL-6 responses,” Journal of Immunology, vol. 161, no. 11, pp. 6347–6355, 1998.
14. A. Mackiewicz, S. Rose-John, H. Schooltink, M. Laciak, A. Gorny, and P. C. Heinrich, “Soluble human interleukin-6-receptor modulates interleukin-6-dependent N-glycosylation of α-protease inhibitor secreted by HepG2 cells,” FEBS Letters, vol. 306, no. 2-3, pp. 257–261, 1992. View at Publisher · View at Google Scholar
15. M. Peters, S. Jacobs, M. Ehlers et al., “The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6,” Journal of Experimental Medicine, vol. 183, no. 4, pp. 1399–1406, 1996. View at Publisher · View at Google Scholar
16. F. A. Houssiau, J. P. Devogelaer, J. Van Damme, C. Nagant de Deuxchaisnes, and J. Van Snick, “Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides,” Arthritis and Rheumatism, vol. 31, no. 6, pp. 784–788, 1988.
17. 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.
18. 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.
19. N. Maruotti, F. P. Cantatore, E. Crivellato, A. Vacca, and D. Ribatti, “Angiogenesis in rheumatoid arthritis,” Histology and Histopathology, vol. 21, no. 4–6, pp. 557–566, 2006.
20. H. Nakahara, J. Song, M. Sugimoto et al., “Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis,” Arthritis and Rheumatism, vol. 48, no. 6, pp. 1521–1529, 2003. View at Publisher · View at Google Scholar · View at PubMed
21. M. Hashizume, N. Hayakawa, M. Suzuki, and M. Mihara, “IL-6/sIL-6R trans-signalling, but not TNF-α induced angiogenesis in a HUVEC and synovial cell co-culture system,” Rheumatology International, vol. 29, no. 12, pp. 1449–1454, 2009. View at Publisher · View at Google Scholar · View at PubMed
22. Y. Uchiyama, K. Yorozu, M. Hashizume, Y. Moriya, and M. Mihara, “Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorates joint swelling in established monkey collagen-induced arthritis,” Biological and Pharmaceutical Bulletin, vol. 31, no. 6, pp. 1159–1163, 2008. View at Publisher · View at Google Scholar
23. 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 PubMed
24. M. Romano, M. Sironi, C. Toniatti et al., “Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment,” Immunity, vol. 6, no. 3, pp. 315–325, 1997. View at Publisher · View at Google Scholar
25. M. Mihara, Y. Moriya, T. Kishimoto, and Y. Ohsugi, “Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the presence of soluble IL-6 receptor,” British Journal of Rheumatology, vol. 34, no. 4, pp. 321–325, 1995.
26. M. Hashizume, N. Hayakawa, and M. Mihara, “IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-α and IL-17,” Rheumatology, vol. 47, no. 11, pp. 1635–1640, 2008. View at Publisher · View at Google Scholar · View at PubMed
27. A. Sagawa, “The effect of short term treatment of anti-IL-6 receptor antibody tocilizumab on signs and symptoms and synovial inflammation in patients with active rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 69, supplement 3, p. 539, 2010.
28. 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 PubMed
29. Y. Fujikawa, M. Shingu, T. Torisu, I. Itonaga, and S. Masumi, “Bone resorption by tartrate-resistant acid phosphatase-positive multinuclear cells isolated from rheumatoid synovium,” British Journal of Rheumatology, vol. 35, no. 3, pp. 213–217, 1996.
30. E. M. Gravallese, C. Manning, A. Tsay et al., “Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor,” Arthritis and Rheumatism, vol. 43, no. 2, pp. 250–258, 2000. View at Publisher · View at Google Scholar
31. D. L. Lacey, E. Timms, H. L. Tan et al., “Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation,” Cell, vol. 93, no. 2, pp. 165–176, 1998. View at Publisher · View at Google Scholar
32. Y. Y. Kong, H. Yoshida, I. Sarosi et al., “OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis,” Nature, vol. 397, no. 6717, pp. 315–323, 1999. View at Publisher · View at Google Scholar · View at PubMed
33. H. Takayanagi, H. Iizuka, T. Juji et al., “Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis,” Arthritis and Rheumatism, vol. 43, no. 2, pp. 259–269, 2000. View at Publisher · View at Google Scholar
34. 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,” Journal of Immunology, vol. 169, no. 6, pp. 3353–3362, 2002.
35. R. K. Dore, S. B. Cohen, N. E. Lane et al., “Effects of denosumab on bone mineral density and bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or bisphosphonates,” Annals of the Rheumatic Diseases, vol. 69, no. 5, pp. 872–875, 2010. View at Publisher · View at Google Scholar · View at PubMed
36. M. Hashizume and M. Mihara, “Desirable effect of combination therapy with high molecular weight hyaluronate and NSAIDs on MMP production,” Osteoarthritis and Cartilage, vol. 17, no. 11, pp. 1513–1518, 2009. View at Publisher · View at Google Scholar · View at PubMed
37. 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 PubMed
38. P. Silacci, J. M. Dayer, A. Desgeorges, R. Peter, C. Manueddu, and P. A. Guernet, “Interleukin (IL)-6 and its soluble receptor induce TIMP-1 expression in synoviocytes and chondrocytes, and block IL-1-induced collagenolytic activity,” Journal of Biological Chemistry, vol. 273, no. 22, pp. 13625–13629, 1998. View at Publisher · View at Google Scholar
39. 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 PubMed
40. P. Garnero, E. Thompson, T. Woodworth, and J. S. Smolen, “Rapid and sustained improvement in bone and cartilage turnover markers with the anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone,” Arthritis and Rheumatism, vol. 62, no. 1, pp. 33–43, 2010. View at Publisher · View at Google Scholar · View at PubMed
41. S. Y. Kawashiri, A. Kawakami, N. Iwamoto et al., “Switching to the anti-interleukin-6 receptor antibody tocilizumab in rheumatoid arthritis patients refractory to antitumor necrosis factor biologics,” Modern Rheumatology, vol. 20, no. 1, pp. 40–45, 2010. View at Publisher · View at Google Scholar · View at PubMed
42. K. Funahashi, S. Koyano, T. Miura, T. Hagiwara, K. Okuda, and T. Matsubara, “Efficacy of tocilizumab and evaluation of clinical remission as determined by CDAI and MMP-3 level,” Modern Rheumatology, vol. 19, no. 5, pp. 507–512, 2009. View at Publisher · View at Google Scholar · View at PubMed
43. L. Zhou, I. I. Ivanov, R. Spolski et al., “IL-6 programs T-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways,” Nature Immunology, vol. 8, no. 9, pp. 967–974, 2007. View at Publisher · View at Google Scholar · View at PubMed
44. K. Iwanami, I. Matsumoto, Y. Tanaka-Watanabe et al., “Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase,” Arthritis and Rheumatism, vol. 58, no. 3, pp. 754–763, 2008. View at Publisher · View at Google Scholar · View at PubMed
45. M. Fujimoto, S. Serada, M. Mihara et al., “Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses,” Arthritis and Rheumatism, vol. 58, no. 12, pp. 3710–3719, 2008. View at Publisher · View at Google Scholar · View at PubMed
46. F. Annunziato, L. Cosmi, and S. Romagnani, “Human and murine Th17,” Current Opinion in HIV and AIDS, vol. 5, no. 2, pp. 114–119, 2010. View at Publisher · View at Google Scholar · View at PubMed
47. F. Annunziato, L. Cosmi, F. Liotta, E. Maggi, and S. Romagnani, “The phenotype of human T17 cells and their precursors, the cytokines that mediate their differentiation and the role of T17 cells in inflammation,” International Immunology, vol. 20, no. 11, pp. 1361–1368, 2008. View at Publisher · View at Google Scholar · View at PubMed
48. A. Muraguchi, T. Hirano, B. Tang et al., “The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells,” Journal of Experimental Medicine, vol. 167, no. 2, pp. 332–344, 1988.
49. G. Jego, R. Bataille, and C. Pellat-Deceunynck, “Interleukin-6 is a growth factor for nonmalignant human plasmablasts,” Blood, vol. 97, no. 6, pp. 1817–1822, 2001. View at Publisher · View at Google Scholar
50. 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,” Journal of Experimental Medicine, vol. 206, no. 1, pp. 69–78, 2009. View at Publisher · View at Google Scholar · View at PubMed
51. G. G. Illei, Y. Shirota, C. H. Yarboro et al., “Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study,” Arthritis and Rheumatism, vol. 62, no. 2, pp. 542–552, 2010. View at Publisher · View at Google Scholar · View at PubMed
52. A. N. Baer, E. N. Dessypris, E. Goldwasser, and S. B. Krantz, “Blunted erythropoietin response to anaemia in rheumatoid arthritis,” British Journal of Haematology, vol. 66, no. 4, pp. 559–564, 1987.
53. M. C. Hochberg, C. M. Arnold, B. B. Hogans, and J. L. Spivak, “Serum immunoreactive erythropoietin in rheumatoid arthritis: impaired response to anemia,” Arthritis and Rheumatism, vol. 31, no. 10, pp. 1318–1321, 1988.
54. M. Jongen-Lavrencic, H. R. M. Peeters, A. Wognum, G. Vreugdenhil, F. C. Breedveld, and A. J. G. Swaak, “Elevated levels of inflammatory cytokines in bone marrow of patients with rheumatoid arthritis and anemia of chronic disease,” Journal of Rheumatology, vol. 24, no. 8, pp. 1504–1509, 1997.
55. P. V. Voulgari, G. Kolios, G. K. Papadopoulos, A. Katsaraki, K. Seferiadis, and A. A. Drosos, “Role of cytokines in the pathogenesis of anemia of chronic disease in rheumatoid arthritis,” Clinical Immunology, vol. 92, no. 2, pp. 153–160, 1999. View at Publisher · View at Google Scholar · View at PubMed
56. T. Ganz, “Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation,” Blood, vol. 102, no. 3, pp. 783–788, 2003. View at Publisher · View at Google Scholar · View at PubMed
57. G. Nicolas, M. Bennoun, A. Porteu et al., “Severe iron deficiency anemia in transgenic mice expressing liver hepcidin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 7, pp. 4596–4601, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
58. E. Nemeth, S. Rivera, V. Gabayan et al., “IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin,” Journal of Clinical Investigation, vol. 113, no. 9, pp. 1271–1276, 2004. View at Publisher · View at Google Scholar · View at Scopus
59. M. Hashizume, Y. Uchiyama, N. Horai, N. Tomosugi, and M. Mihara, “Tocilizumab, a humanized anti-interleukin-6 receptor antibody, improved anemia in monkey arthritis by suppressing IL-6-induced hepcidin production,” Rheumatology International, vol. 30, no. 7, pp. 917–923, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
60. E. Myasoedova, C. S. Crowson, H. M. Kremers, P. D. Fitz-Gibbon, T. M. Therneau, and S. E. Gabriel, “Total cholesterol and LDL levels decrease before rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 69, no. 7, pp. 1310–1314, 2010. View at Publisher · View at Google Scholar · View at PubMed
61. 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 PubMed · View at Scopus
62. V. R. Sopasakis, M. Sandqvist, B. Gustafson et al., “High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator,” Obesity Research, vol. 12, no. 3, pp. 454–460, 2004. View at Scopus
63. M. E. Trujillo, S. Sullivan, I. Harten, S. H. Schneider, A. S. Greenberg, and S. K. Fried, “Interleukin-6 regulates human adipose tissue lipid metabolism and leptin production in vitro,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 11, pp. 5577–5582, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
64. E. W. Petersen, A. L. Carey, M. Sacchetti et al., “Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro,” American Journal of Physiology, vol. 288, no. 1, pp. E155–E162, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
65. G. Van Hall, A. Steensberg, M. Sacchetti et al., “Interleukin-6 stimulates lipolysis and fat oxidation in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 7, pp. 3005–3010, 2003. View at Publisher · View at Google Scholar · View at Scopus
66. N. Nishimoto, K. Yoshizaki, N. Miyasaka et al., “Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial,” Arthritis and Rheumatism, vol. 50, no. 6, pp. 1761–1769, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
67. O. Saiki, R. Takao, Y. Naruse, M. Kuhara, S. Imai, and H. Uda, “Infliximab but not methotrexate induces extra-high levels of VLDL-triglyceride in patients with rheumatoid arthritis,” Journal of Rheumatology, vol. 34, no. 10, pp. 1997–2004, 2007. View at Scopus
68. H. K. Choi and J. D. Seeger, “Lipid profiles among US elderly with untreated rheumatoid arthritis—the Third National Health and Nutrition Examination Survey,” Journal of Rheumatology, vol. 32, no. 12, pp. 2311–2316, 2005. View at Scopus
69. Y. B. Park, H. K. Choi, M. Y. Kim et al., “Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study,” American Journal of Medicine, vol. 113, no. 3, pp. 188–193, 2002. View at Publisher · View at Google Scholar · View at Scopus
70. B. Seriolo, S. Paolino, A. Sulli, D. Fasciolo, and M. Cutolo, “Effects of anti-TNF-α treatment on lipid profile in patients with active rheumatoid arthritis,” Annals of the New York Academy of Sciences, vol. 1069, pp. 414–419, 2006. View at Publisher · View at Google Scholar · View at PubMed
71. S. Y. Kawashiri, A. Kawakami, S. Yamasaki et al., “Effects of the anti-interleukin-6 receptor antibody, tocilizumab, on serum lipid levels in patients with rheumatoid arthritis,” Rheumatology International, vol. 31, no. 4, pp. 451–456, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus