Table of Contents Author Guidelines Submit a Manuscript
International Journal of Rheumatology
Volume 2012, Article ID 946048, 14 pages
http://dx.doi.org/10.1155/2012/946048
Review Article

Tocilizumab for the Treatment of Rheumatoid Arthritis and Other Systemic Autoimmune Diseases: Current Perspectives and Future Directions

Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita City, Osaka 565-0871, Japan

Received 23 September 2011; Accepted 5 October 2011

Academic Editor: Jozélio Freire de Carvalho

Copyright © 2012 Atsushi Ogata 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. 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
  2. T. Kishimoto, “The biology of interleukin-6,” Blood, vol. 74, no. 1, pp. 1–10, 1989. View at Google Scholar · View at Scopus
  3. 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
  4. 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 PubMed · View at Scopus
  5. 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 PubMed · View at Scopus
  6. 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 PubMed · View at Scopus
  7. 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
  8. 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. View at Google Scholar · View at Scopus
  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 · View at Scopus
  10. T. Hirano, T. Taga, and K. Yasukawa, “Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production,” Proceedings of the National Academy of Sciences of the United States of America, vol. 84, no. 1, pp. 228–231, 1987. View at Google Scholar · View at Scopus
  11. K. Yoshizaki, T. Matsuda, N. Nishimoto et al., “Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease,” Blood, vol. 74, no. 4, pp. 1360–1367, 1989. View at Google Scholar · View at Scopus
  12. 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
  13. N. Nishimoto and T. Kishimoto, “Interleukin 6: from bench to bedside,” Nature Clinical Practice Rheumatology, vol. 2, no. 11, pp. 619–626, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. 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 PubMed · View at Scopus
  15. 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 Google Scholar
  16. J. S. Smolen, D. Aletaha, M. Koeller, M. H. Weisman, and P. Emery, “New therapies for treatment of rheumatoid arthritis,” The Lancet, vol. 370, no. 9602, pp. 1861–1874, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. 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
  18. 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. View at Google Scholar · View at Scopus
  19. 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 · View at Scopus
  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 & Rheumatism, vol. 48, no. 6, pp. 1521–1529, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. F. A. Houssiau, J. P. Devogelaer, J. Van Damme, C. N. de Deuxchaisnes, and J. Van Snick, “Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides,” Arthritis & Rheumatism, vol. 31, no. 6, pp. 784–788, 1988. View at Google Scholar · View at Scopus
  22. 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
  23. T. Alonzi, E. Fattori, D. Lazzaro et al., “Interleukin 6 is required for the development of collagen-induced arthritis,” Journal of Experimental Medicine, vol. 187, no. 4, pp. 461–468, 1998. View at Publisher · View at Google Scholar · View at Scopus
  24. 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
  25. N. Takagi, M. Mihara, Y. Moriya et al., “Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis,” Arthritis & Rheumatism, vol. 41, no. 12, pp. 2117–2121, 1998. View at Publisher · View at Google Scholar · View at Scopus
  26. 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 Publisher · View at Google Scholar · View at Scopus
  27. M. Mihara, M. Kotoh, N. Nishimoto et al., “Humanized antibody to human interleukin-6 receptor inhibits the development of collagen arthritis in cynomolgus monkeys,” Clinical Immunology, vol. 98, no. 3, pp. 319–326, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. 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 & Pharmaceutical Bulletin, vol. 31, no. 6, pp. 1159–1163, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. 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 PubMed · View at Scopus
  30. 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 & Rheumatism, vol. 58, no. 3, pp. 754–763, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. T. Kagari, H. Doi, and T. Shimozato, “The importance of IL-1β and TNF-α, and the noninvolvement of IL-6, in the development of monoclonal antibody-induced arthritis,” Journal of Immunology, vol. 169, no. 3, pp. 1459–1466, 2002. View at Google Scholar · View at Scopus
  32. Y. Iwakura, S. Nakae, S. Saijo, and H. Ishigame, “The roles of IL-17A in inflammatory immune responses and host defense against pathogens,” Immunological Reviews, vol. 226, no. 1, pp. 57–79, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. A Ogata, N. Umegaki, I. Katayama, A. Kumanogoh, and T. Tanaka, “Psoriatic arthritis in two patients with an inadequate response to treatment with tocilizumab,” Joint Bone Spine. In press.
  34. 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 · View at Scopus
  35. 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 PubMed · View at Scopus
  36. 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 PubMed · View at Scopus
  37. 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 · View at Scopus
  38. 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 PubMed · View at Scopus
  39. 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 PubMed · View at Scopus
  40. 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 Google Scholar
  41. J. A. Singh, S. Beg, and M. A. Lopez-Olivo, “Tocilizumab for rheumatoid arthritis,” Cochrane Database of Systematic Reviews, vol. 7, p. CD008331, 2010. View at Google Scholar · View at Scopus
  42. N. Nishimoto and N. Takagi, “Assessment of the validity of the 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) as a disease activity index of rheumatoid arthritis in the efficacy evaluation of 24-week treatment with tocilizumab: subanalysis of the SATORI study,” Modern Rheumatology, vol. 20, no. 6, pp. 539–547, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. J. S. Smolen and D. Aletaha, “Interleukin-6 receptor inhibition with tocilizumab and attainment of disease remission in rheumatoid arthritis: the role of acute-phase reactants,” Arthritis & Rheumatism, vol. 63, no. 1, pp. 43–52, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. G. R. Burmester, E. Feist, H. Kellner, J. Braun, C. Iking-Konert, and A. Rubbert-Roth, “Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA),” Annals of the Rheumatic Diseases, vol. 70, no. 5, pp. 755–759, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. C. Iking-Konert, M. Aringer, J. Wollenhaupt et al., “Performance of the new 2011 ACR/EULAR remission criteria with tocilizumab using the phase IIIb study TAMARA as an example and their comparison with traditional remission criteria,” Annals of Rheumatic Diseases, vol. 70, no. 11, pp. 1986–1990, 2011. View at Google Scholar
  46. H. C. Leffers, M. Ostergaard, B. Glintborg et al., “Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry,” Annals of the Rheumatic Diseases, vol. 70, no. 7, pp. 1216–1222, 2011. View at Google Scholar
  47. 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, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. 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 Google Scholar
  49. N. Nishimoto, K. Ito, and N. Takagi, “Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions,” Modern Rheumatology, vol. 20, no. 3, pp. 222–232, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. L. Campbell, C. Chen, S. S. Bhagat, R. A. Parker, and A. J. Ostor, “Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systemic literature review and meta-analysis of randomized controlled trials,” Rheumatology, vol. 50, no. 3, pp. 552–562, 2011. View at Google Scholar
  51. T. Koike, M. Harigai, and S. Inokuma, “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 Google Scholar
  52. 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
  53. A. Ogata, A. Morishima, T. Hirano et al., “Improvement of HbA1c during treatment with humanised anti-interleukin 6 receptor antibody, tocilizumab,” Annals of the Rheumatic Diseases, vol. 70, no. 6, pp. 1164–1165, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. O. Schultz, F. Oberhauser, J. Saech et al., “Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (A) levels in human subjects with rheumatoid diseases,” PLoS One, vol. 5, no. 12, Article ID e14328, 2010. View at Publisher · View at Google Scholar · View at PubMed
  55. T. Gout, A.J. Ostör, 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 Google Scholar
  56. J. J. Gomez-Reino, L. Carmona, V. R. Valverde, E. M. Mola, and M. D. Montero, “Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report,” Arthritis & Rheumatism, vol. 48, no. 8, pp. 2122–2127, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. M. Okada, Y. Kita, N. Kanamaru et al., “Anti-IL-6 receptor antibody causes less promotion of tuberculosis infection than anti-TNF-α antibody in mice,” Clinical and Developmental Immunology, vol. 2011, Article ID 404929, 9 pages, 2011. View at Publisher · View at Google Scholar · View at PubMed
  58. A. Ogata, M. Mori, S. Hashimoto et al., “Minimal influence of tocilizumab on IFN-γ synthesis by tuberculosis antigens,” Modern Rheumatology, vol. 20, no. 2, pp. 130–133, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. F. Perfetto, A. Moggi-Pignone, R. Livi, A. Tempestini, F. Bergesio, and M. Matucci-Cerinic, “Systemic amyloidosis: a challenge for the rheumatologist,” Nature Reviews Rheumatology, vol. 6, no. 7, pp. 417–429, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. T. Tanaka, K. Hagihara, Y. Hishitani, and A. Ogata, in Amyloidosis—An Insight to Disease Systems and Novel Therapies, I. A. Guvenc, Ed., chapter 11, INTECH Open Access Publisher, Croatia, 2011.
  61. K. Hagihara, T. Nishikawa, T. Isobe, J. Song, Y. Sugamata, and K. Yoshizaki, “IL-6 plays a critical role in the synergistic induction of human serum amyloid a (SAA) gene when stimulated with proinflammatory cytokines as analyzed with an SAA isoform real-time quantitative RT-PCR assay system,” Biochemical and Biophysical Research Communications, vol. 314, no. 2, pp. 363–369, 2004. View at Publisher · View at Google Scholar · View at Scopus
  62. K. Hagihara, T. Nishikawa, Y. Sugamata et al., “Essential role of STAT3 in cytokine-driven NF-κB-mediated serum amyloid A gene expression,” Genes to Cells, vol. 10, no. 11, pp. 1051–1063, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  63. S. Nishida, K. Hagihara, Y. Shima et al., “Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment,” Annals of the Rheumatic Diseases, vol. 68, no. 7, pp. 1235–1236, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. H. Sato, T. Sakai, T. Sugaya et al., “Tocilizumab dramatically ameliorated life-threatening diarrhea due to secondary amyloidosis associated with rheumatoid arthritis,” Clinical Rheumatology, vol. 28, no. 9, pp. 1113–1116, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. D. Inoue, H. Arima, C. Kawanami et al., “Excellent therapeutic effect of tocilizumab on intestinal amyloid a deposition secondary to active rheumatoid arthritis,” Clinical Rheumatology, vol. 29, no. 10, pp. 1195–1197, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. M. van den Broek, T.W. Huizinga, B.A. Dijkmans, and C.F. Allaart, “Drug-free remission: is it already possible?” Current Opinion in Rheumatology, vol. 23, no. 3, pp. 266–272, 2011. View at Google Scholar
  67. N. Nishimoto and Japanese MRA study group for RA, “Drug free remission after cessation of actemra monotherapy (DREAM Study),” in Proceedings of the Annual European League Against Rheumatism Conference (EULAR '10), abstract OP0134, Rome, Italy.
  68. N. Nishimoto and Japanese MRA study group for RA, “Retreatment efficacy and safety to tocilizumab in patients with rheumatoid arthritis at recurrence (RESTORE study),” in Proceedings of the Annual European League Against Rheumatism Conference (EULAR '10), abstract SAT0150, Rome, Italy.
  69. G. Ruiz-Irastorza, M. A. Khamashta, G. Castellino, and G. R. V. Hughes, “Systemic lupus erythematosus,” The Lancet, vol. 357, no. 9261, pp. 1027–1032, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. L. E. Munoz, K. Lauber, M. Schiller, A. A. Manfredi, and M. Herrmann, “The role of defective clearance of apoptotic cells in systemic autoimmunity,” Nature Reviews Rheumatology, vol. 6, no. 5, pp. 280–289, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. G. Obermoser and V. Pascual, “The interferon-α signature of systemic lupus erythematosus,” Lupus, vol. 19, no. 9, pp. 1012–1019, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. M. S. Shin, N. Lee, and I. Kang, “Effector T-cell subsets in systemic lupus erythematosus: update focusing on Th17 cells,” Current Opinion in Rheumatology, vol. 23, no. 5, pp. 444–448, 2011. View at Google Scholar
  73. B. Rhodes, B. G. Furnrohr, and T. J. Vyse, “C-reactive protein in rheumatology: biology and genetics,” Nature Reviews Rheumatology, vol. 7, no. 5, pp. 282–289, 2011. View at Google Scholar
  74. E. Tackey, P. E. Lipsky, and G. G. Illei, “Rationale for interleukin-6 blockade in systemic lupus erythematosus,” Lupus, vol. 13, no. 5, pp. 339–343, 2004. View at Publisher · View at Google Scholar · View at Scopus
  75. M. Linker-Israeli, R. J. Deans, D. J. Wallace, J. Prehn, T. Ozeri-Chen, and J. R. Klinenberg, “Elevated levels of endogenous IL-6 in systemic lupus erythematosus: a putative role in pathogenesis,” Journal of Immunology, vol. 147, no. 1, pp. 117–123, 1991. View at Google Scholar · View at Scopus
  76. E. Peterson, A. D. Robertson, and W. Emlen, “Serum and urinary interleukin-6 in systemic lupus erythematosus,” Lupus, vol. 5, no. 6, pp. 571–575, 1996. View at Google Scholar · View at Scopus
  77. G. Grondal, I. Gunnarsson, J. Ronnelid, S. Rogberg, L. Klareskog, and I. Lundberg, “Cytokine production, serum levels and disease activity in systemic lupus erythematosus,” Clinical and Experimental Rheumatology, vol. 18, no. 5, pp. 565–570, 2000. View at Google Scholar · View at Scopus
  78. M. Iwano, K. Dohi, E. Hirata et al., “Urinary levels of IL-6 in patients with active lupus nephritis,” Clinical Nephrology, vol. 40, no. 1, pp. 16–21, 1993. View at Google Scholar · View at Scopus
  79. D. Malide, P. Russo, and M. Bendayan, “Presence of tumor necrosis factor alpha and interleukin-6 in renal mesangial cells of lupus nephritis patients,” Human Pathology, vol. 26, no. 5, pp. 558–564, 1995. View at Google Scholar · View at Scopus
  80. R. Herrera-Esparza, O. Barbosa-Cisneros, R. Villalobos-Hurtado, and E. Avalos-Díaz, “Renal expression of IL-6 and TNFα genes in lupus nephritis,” Lupus, vol. 7, no. 3, pp. 154–158, 1998. View at Publisher · View at Google Scholar · View at Scopus
  81. C. Y. Tsai, T. H. Wu, C. L. Yu, J. Y. Lu, and Y. Y. Tsai, “Increased excretions of β2-microglobulin, IL-6, and IL-8 and decreased excretion of Tamm-Horsfall glycoprotein in urine of patients with active lupus nephritis,” Nephron, vol. 85, no. 3, pp. 207–214, 2000. View at Google Scholar · View at Scopus
  82. S. Hirohata and T. Miyamoto, “Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement,” Arthritis & Rheumatism, vol. 33, no. 5, pp. 644–649, 1990. View at Publisher · View at Google Scholar · View at Scopus
  83. E. Hagiwara, M. F. Gourley, S. Lee, and D. M. Klinman, “Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10: interferon-γ-secreting cells in the peripheral blood,” Arthritis & Rheumatism, vol. 39, no. 3, pp. 379–385, 1996. View at Publisher · View at Google Scholar · View at Scopus
  84. A. J. G. Swaak, H. G. van den Brink, and L. A. Aarden, “Cytokine production (IL-6 and TNFα) in whole blood cell cultures of patients with systemic lupus erythematosus,” Scandinavian Journal of Rheumatology, vol. 25, no. 4, pp. 233–238, 1996. View at Google Scholar · View at Scopus
  85. D. J. Klashman, R. A. Martin, O. Martinez-Maza, and R. H. Stevens, “In vitro regulation of B cell differentiation by interleukin-6 and soluble CD23 in systemic lupus erythematosus B cell subpopulations and antigen-induced normal B cells,” Arthritis & Rheumatism, vol. 34, no. 3, pp. 276–286, 1991. View at Google Scholar · View at Scopus
  86. A. Kitani, M. Hara, T. Hirose et al., “Autostimulatory effects of IL-6 on excessive B cell differentiation in patients with systemic lupus erythematosus: analysis of IL-6 production and IL-6R expression,” Clinical and Experimental Immunology, vol. 88, no. 1, pp. 75–83, 1992. View at Google Scholar · View at Scopus
  87. H. Suzuki, K. Yasukawa, T. Saito et al., “Serum soluble interleukin-6 receptor in MRL/lpr mice is elevated with age and mediates the interleukin-6 signal,” European Journal of Immunology, vol. 23, no. 5, pp. 1078–1082, 1993. View at Google Scholar · View at Scopus
  88. B. Tang, T. Matsuda, S. Akira et al., “Age-associated increase in interleukin 6 in MRL/lpr mice,” International Immunology, vol. 3, no. 3, pp. 273–278, 1991. View at Google Scholar · View at Scopus
  89. M. E. Alarcon-Riquelme, G. Moller, and C. Fernandez, “Age-dependent responsiveness to interleukin-6 in B lymphocytes from a systemic lupus erythematosus-prone (NZB x NZW)F1 hybrid,” Clinical Immunology and Immunopathology, vol. 62, no. 3, pp. 264–269, 1992. View at Publisher · View at Google Scholar · View at Scopus
  90. M. Mihara, H. Fukui, Y. Koishihara, M. Saito, and Y. Ohsugi, “Immunologic abnormality in NZB/W F1 mice. Thymus-independent expansion of B cells responding to interleukin-6,” Clinical & Experimental Immunology, vol. 82, no. 3, pp. 533–537, 1990. View at Google Scholar · View at Scopus
  91. M. Mihara and Y. Ohsugi, “Possible role of IL-6 in pathogenesis of immune complex-mediated glomerulonephritis in NZB/W F1 mice: induction of IgG class anti-DNA autoantibody production,” International Archives of Allergy & Applied Immunology, vol. 93, no. 1, pp. 89–92, 1990. View at Google Scholar · View at Scopus
  92. B. Ryffel, B. D. Car, H. Gunn, D. Roman, P. Hiestand, and M. J. Mihatsch, “Interleukin-6 exacerbates glomerulonephritis in (NZBxNZW)F1 mice,” American Journal of Pathology, vol. 144, no. 5, pp. 927–937, 1994. View at Google Scholar · View at Scopus
  93. B. K. Finck, B. Chan, and D. Wofsy, “Interleukin 6 promotes murine lupus in NZB/NZW F1 mice,” Journal of Clinical Investigation, vol. 94, no. 2, pp. 585–591, 1994. View at Google Scholar · View at Scopus
  94. M. Mihara, N. Takagi, Y. Takeda, and Y. Ohsugi, “IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/WF1 mice,” Clinical and Experimental Immunology, vol. 112, no. 3, pp. 397–402, 1998. View at Publisher · View at Google Scholar · View at Scopus
  95. B. Liang, D. B. Gardner, D. E. Griswold, P. J. Bugelski, and X. Y. R. Song, “Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus,” Immunology, vol. 119, no. 3, pp. 296–305, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  96. P. Pflegerl, P. Vesely, B. Hantusch et al., “Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 48, pp. 20423–20428, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  97. 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 & Rheumatism, vol. 62, no. 2, pp. 542–552, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  98. A. Gabrielli, E. V. Avvedimento, and T. Krieg, “Mechanisms of disease: Scleroderma,” New England Journal of Medicine, vol. 360, no. 19, pp. 1989–2003, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  99. T. C. Barnes, M. E. Anderson, and R. J. Moots, “The many faces of interleukin-6 (IL-6): the role of IL-6 in inflammation, vasculopathy and fibrosis in systemic sclerosis,” International Journal of Rheumatology, vol. 2011, Article ID 721608, 6 pages, 2011. View at Publisher · View at Google Scholar · View at PubMed
  100. M. Hasegawa, S. Sato, M. Fujimoto, H. Ihn, K. Kikuchi, and K. Takehara, “Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis,” Journal of Rheumatology, vol. 25, no. 2, pp. 308–313, 1998. View at Google Scholar · View at Scopus
  101. S. Sato, M. Hasegawa, and K. Takehara, “Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis,” Journal of Dermatological Science, vol. 27, no. 2, pp. 140–146, 2001. View at Publisher · View at Google Scholar · View at Scopus
  102. E. Scala, S. Pallotta, A. Frezzolini et al., “Cytokine and chemokine levels in systemic sclerosis: relationship with cutaneous and internal organ involvement,” Clinical & Experimental Immunology, vol. 138, no. 3, pp. 540–546, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  103. T. Matsushita, M. Hasegawa, Y. Hamaguchi, K. Takehara, and S. Sato, “Longitudinal analysis of serum cytokine concentrations in systemic sclerosis: association of interleukin 12 elevation with spontaneous regression of skin sclerosis,” Journal of Rheumatology, vol. 33, no. 2, pp. 275–284, 2006. View at Google Scholar · View at Scopus
  104. P. Gourh, F. C. Arnett, S. Assassi et al., “Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations,” Arthritis Research & Therapy, vol. 11, no. 5, p. R147, 2009. View at Google Scholar · View at Scopus
  105. C. A. Feghali, K. L. Bost, D. W. Boulware, and L. S. Levy, “Mechanisms of pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts cultured from affected skin sites of patients with scleroderma,” Journal of Rheumatology, vol. 19, no. 8, pp. 1207–1211, 1992. View at Google Scholar · View at Scopus
  106. A. E. Koch, L. B. Kronfeld-Harrington, Z. Szekanecz et al., “In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis. Their role in early and late disease,” Pathobiology, vol. 61, no. 5-6, pp. 239–246, 1993. View at Google Scholar · View at Scopus
  107. M. Gurram, S. Pahwa, and M. Frieri, “Augmented interleukin-6 secretion in collagen-stimulated peripheral blood mononuclear cells from patients with systemic sclerosis,” Annals of Allergy Asthma & Immunology, vol. 73, no. 6, pp. 493–496, 1994. View at Google Scholar
  108. C. S. Zurita-Salinas, Y. Richaud-Patin, E. Krotzsch-Gomez et al., “Spontaneous cytokine gene expression by cultured skin fibroblasts of systemic sclerosis. Correlation with collagen synthesis,” Revista de Investigacion Clinics, vol. 50, no. 2, pp. 97–104, 1998. View at Google Scholar
  109. T. Kadono, K. Kikuchi, H. Ihn, K. Takehara, and K. Tamaki, “Increased production of interleukin 6 and interleukin 8 in scleroderma fibroblasts,” Journal of Rheumatology, vol. 25, no. 2, pp. 296–301, 1998. View at Google Scholar · View at Scopus
  110. M. R. Duncan and B. Berman, “Stimulation of collagen and glycosaminoglycan production in cultured human adult dermal fibroblasts by recombinant human interleukin 6,” Journal of Investigative Dermatology, vol. 97, no. 4, pp. 686–692, 1991. View at Google Scholar · View at Scopus
  111. R. M. Gallucci, E. G. Lee, and J. J. Tomasek, “IL-6 modulates alpha-smooth muscle actin expression in dermal fibroblasts from IL-6-deficient mice,” Journal of Investigative Dermatology, vol. 126, no. 3, pp. 561–568, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  112. Y. Kawaguchi, M. Hara, and T. M. Wright, “Endogenous IL-1α from systemic sclerosis fibroblasts induces IL-6 and PDGF-A,” Journal of Clinical Investigation, vol. 103, no. 9, pp. 1253–1260, 1999. View at Google Scholar · View at Scopus
  113. T. C. Barnes, D. G. Spiller, M. E. Anderson, S. W. Edwards, and R. J. Moots, “Endothelial activation and apoptosis mediated by neutrophil-dependent interleukin 6 trans-signalling: a novel target for systemic sclerosis?” Annals of the Rheumatic Diseases, vol. 70, no. 2, pp. 366–372, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  114. A. Yoshizaki, K. Yanaba, A. Ogawa, Y. Asano, T. Kadono, and S. Sato, “Immunization with DNA topoisomerase I and complete Freund’s adjuvant induces skin and lung fibrosis and autoimmunity via interleukin-6 signaling,” Arthritis & Rheumatism, vol. 63, no. 11, pp. 3575–3585, 2011. View at Publisher · View at Google Scholar · View at PubMed
  115. Y. Shima, Y. Kuwahara, H. Murota et al., “The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab,” Rheumatology, vol. 49, no. 12, pp. 2408–2412, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  116. Y. Kuwahara, Y. Shima, D. Shirayama et al., “Quantification of hardness, elasticity and viscosity of the skin of patients with systemic sclerosis using a novel sensing device (Vesmeter): a proposal for a new outcome measurement procedure,” Rheumatology, vol. 47, no. 7, pp. 1018–1024, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  117. O. Kowal-Bielecka, R. Landewe, S. Chwiesko et al., “EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR scleroderma trials and research group (EUSTAR),” Annals of the Rheumatic Diseases, vol. 68, no. 5, pp. 620–628, 2009. View at Google Scholar
  118. M. C. Dalakas, “Immunotherapy of myositis: issues, concerns and future prospects,” Nature Reviews Rheumatology, vol. 6, no. 3, pp. 129–137, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  119. B. K. Pedersen and M. A. Febbraio, “Muscle as an endocrine organ: focus on muscle-derived interleukin-6,” Physiological Reviews, vol. 88, no. 4, pp. 1379–1406, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  120. J. A. Carson and K. A. Baltgalvis, “Interleukin 6 as a key regulator of muscle mass during cachexia,” Exercise and Sport Sciences Reviews, vol. 38, no. 4, pp. 168–176, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  121. C. Gabay, F. Gay-Croisier, P. Roux-Lombard et al., “Elevated serum levels of interleukin-1 receptor antagonist in polymyositis/dermatomyositis: a biologic marker of disease activity with a possible role in the lack of acute-phase protein response,” Arthritis & Rheumatism, vol. 37, no. 12, pp. 1744–1751, 1994. View at Publisher · View at Google Scholar · View at Scopus
  122. I. Lundberg, A. K. Ulfgren, P. Nyberg, U. Andersson, and L. Klareskog, “Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies,” Arthritis & Rheumatism, vol. 40, no. 5, pp. 865–874, 1997. View at Google Scholar · View at Scopus
  123. H. Lepidi, V. Frances, D. Figarella-Branger, C. Bartoli, A. Machado-Baeta, and J. F. Pellissier, “Local expression of cytokines in idiopathic inflammatory myopathies,” Neuropathology and Applied Neurobiology, vol. 24, no. 1, pp. 73–79, 1998. View at Publisher · View at Google Scholar · View at Scopus
  124. M. Okada, M. Kitahara, S. Kishimoto, T. Matsuda, T. Hirano, and T. Kishimoto, “IL-6/BSF-2 functions as a killer helper factor in the in vitro induction of cytotoxic T cells,” Journal of Immunology, vol. 141, no. 5, pp. 1543–1549, 1988. View at Google Scholar · View at Scopus
  125. F. Scuderi, F. Mannella, M. Marino, C. Provenzano, and E. Bartoccioni, “IL-6-deficient mice show impaired inflammatory response in a model of myosin-induced experimental myositis,” Journal of Neuroimmunology, vol. 176, no. 1-2, pp. 9–15, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  126. N. Okiyama, T. Sugihara, Y. Iwakura, H. Yokozeki, N. Miyasaka, and H. Kohsaka, “Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17A,” Arthritis & Rheumatism, vol. 60, no. 8, pp. 2505–2512, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  127. M. Narazaki, K. Hagihara, Y. Shima et al., “Therapeutic effect of tocilizumab on two patients with polymyositis,” Rheumatology, vol. 50, no. 7, pp. 1344–1346, 2011. View at Google Scholar
  128. H. Bilgic, S. R. Ytterberg, S. Amin et al., “Interleukin-6 and type I interferon-regulated genes and chemokines Mark disease activity in dermatomyositis,” Arthritis & Rheumatism, vol. 60, no. 11, pp. 3436–3446, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  129. J. C. Mason, “Takayasu arteritis—advances in diagnosis and management,” Nature Reviews Rheumatology, vol. 6, no. 7, pp. 406–415, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  130. C. Salvarani, F. Cantini, and G. G. Hunder, “Polymyalgia rheumatica and giant-cell arteritis,” The Lancet, vol. 372, no. 9634, pp. 234–245, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  131. Y. Seko, O. Sato, and A. Takag, “Restricted usage of T-cell receptor Valpha-Vbeta genes in infiltrating cells in aortic tissue of patients with Takayasu’s arteritis,” Circulation, vol. 93, no. 10, pp. 1788–1790, 1996. View at Google Scholar
  132. M. Noris, E. Daina, S. Gamba, S. Bonazzola, and G. Remuzzi, “Interleukin-6 and RANTES in Takayasu arteritis a guide for therapeutic decisions?” Circulation, vol. 100, no. 1, pp. 55–60, 1999. View at Google Scholar · View at Scopus
  133. M. C. Park, S. W. Lee, Y. B. Park, and S. K. Lee, “Serum cytokine profiles and their correlations with disease activity in Takayasu's arteritis,” Rheumatology, vol. 45, no. 5, pp. 545–548, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  134. N. Nishimoto, H. Nakahara, N. Yoshio-Hoshino, and T. Mima, “Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody,” Arthritis & Rheumatism, vol. 58, no. 4, pp. 1197–1200, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  135. M. Seitz, S. Reichenbach, H. M. Bonel et al., “Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series,” Swiss Medical Weekly, vol. 141, Article ID w13156, 2011. View at Google Scholar
  136. C. Beyer, R. Axmann, and E. Sahinbegovic, “Anti-interleukin 6 receptor therapy as rescue treatment for giant cell arteritis,” Annals of the Rheumatic Diseases, vol. 70, no. 10, pp. 1874–1875, 2011. View at Google Scholar
  137. M. C. Cid, J. Hernandez-Rodriquez, M. J. Esteban et al., “Tissue and serum angiogenic activity is associated with low prevalence of ischemic complications in patients with giant-cell arteritis,” Circulation, vol. 106, no. 13, pp. 1664–1671, 2002. View at Publisher · View at Google Scholar · View at Scopus
  138. J. Hernandez-Rodriquez, M. Segarra, C. Vilardell et al., “Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant-cell arteritis: angiogenic activity of interleukin-6 as a potential protective mechanism,” Circulation, vol. 107, no. 19, pp. 2428–2434, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  139. H. Nakahama, M. Okada, M. Miyazaki, N. Imai, T. Yokokawa, and S. Kubori, “Distinct responses of interleukin-6 and other laboratory parameters to treatment in a patient with polyarteritis nodosa: a case report,” Angiology, vol. 43, no. 6, pp. 512–516, 1992. View at Google Scholar · View at Scopus
  140. A. C. Muller Kobold, R. T. Van Wijk, C. F. M. Franssen, G. Molema, C. G. M. Kallenberg, and J. W. Cohen Tervaert, “In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener's granulomatosis and microscopic polyangiitis,” Clinical and Experimental Rheumatology, vol. 17, no. 4, pp. 433–440, 1999. View at Google Scholar · View at Scopus
  141. E. R. Popa, C. F. M. Franssen, P. C. Limburg, M. G. Huitema, C. G. M. Kallenberg, and J. W. Cohen Tervaert, “In vitro cytokine production and proliferation of T cells from patients with anti-proteinase 3- and antimyeloperoxidase-associated vasculitis, in response to proteinase 3 and myeloperoxidase,” Arthritis & Rheumatism, vol. 46, no. 7, pp. 1894–1904, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  142. S. Ohlsson, O. Bakoush, J. Tencer, O. Torffvit, and M. Segelmark, “Monocyte chemoattractant protein 1 is a prognostic marker in ANCA-associated small vessel vasculitis,” Mediators of Inflammation, vol. 2009, Article ID 584916, 2009. View at Publisher · View at Google Scholar · View at PubMed
  143. 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
  144. 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 PubMed · View at Scopus
  145. S. Yokota, T. Miyamae, T. Imagawa et al., “Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis,” Arthritis & Rheumatism, vol. 52, no. 3, pp. 818–825, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  146. S. Yokota, T. Imagawa, M. Mori et al., “Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial,” The Lancet, vol. 371, no. 9617, pp. 998–1006, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  147. F. De Benedetti, H. Brunner, N. Ruperto et al., “From biology to classification and targeted therapy in juvenile idiopathic arthritis,” Annals of the Rheumatic Diseases, vol. 69, supplement 3, p. 146, 2010. View at Google Scholar
  148. M. Kawai, K. Hagihara, T. Hirano et al., “Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis,” Rheumatology, vol. 48, no. 3, pp. 318–319, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  149. S. Nishida, T. Kawasaki, H. Kashiwagi et al., “Successful treatment of acquired hemophilia A, complicated by chronic GVHD, with tocilizumab,” Modern Rheumatology, vol. 21, no. 4, pp. 420–422, 2011. View at Google Scholar
  150. A. Yuzuriha, T. Saitoh, H. Koiso et al., “Successful treatment of autoimmune hemolytic anemia associated with multicentric Castleman disease by anti-interleukin-6 receptor antibody (tocilizumab) therapy,” Acta Haematologica, vol. 126, no. 3, pp. 147–150, 2011. View at Google Scholar
  151. M. Iwamoto, H. Nara, D. Hirata, S. Minota, N. Nishimoto, and K. Yoshizaki, “Humanized monoclonal anti-interleukin-6 receptor antibody for treatment of intractable adult-onset Still's disease,” Arthritis & Rheumatism, vol. 46, no. 12, pp. 3388–3389, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  152. H. Nakahara, T. Mima, N. Yoshio-Hoshino, M. Matsushita, J. Hashimoto, and N. Nishimoto, “A case report of a patient with refractory adult-onset Still's disease who was successfully treated with tocilizumab over 6 years,” Modern Rheumatology, vol. 19, no. 1, pp. 69–72, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  153. M. De Bandt and B. Saint-Marcoux, “Tocilizumab for multirefractory adult-onset Still's disease,” Annals of the Rheumatic Diseases, vol. 68, no. 1, pp. 153–154, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  154. K. Matsumoto, T. Nagashima, S. Takatori et al., “Glucocorticoid and cyclosporine refractory adult onset Still's disease successfully treated with tocilizumab,” Clinical Rheumatology, vol. 28, no. 4, pp. 485–487, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  155. M. L. Cunha, J. Wagner, A. Osawa, and M. Scheinberg, “The effect of tocilizumab on the uptake of 18FDG-PET imaging in patients with adult-onset Still’s disease,” Rheumatology, vol. 49, no. 5, pp. 1014–1016, 2010. View at Google Scholar
  156. K. Sumida, Y. Ubara, J. Hoshino et al., “Etanercept-refractory adult-onset Still's disease with thrombotic thrombocytopenic purpura successfully treated with tocilizumab,” Clinical Rheumatology, vol. 29, no. 10, pp. 1191–1194, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  157. M. Yoshimura, J. Makiyama, T. Koga et al., “Successful treatment with tocilizumab in a patient with refractory adult-onset Still's disease (AOSD),” Clinical and Experimental Rheumatology, vol. 28, no. 1, pp. 141–142, 2010. View at Google Scholar · View at Scopus
  158. K. Perdan-Pirkmajer, S. Praprotnik, and M. Tomšič, “A case of refractory adult-onset Still's disease successfully controlled with tocilizumab and a review of the literature,” Clinical Rheumatology, vol. 29, no. 12, pp. 1465–1467, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  159. T. Naniwa, R. Ito, M. Watanabe et al., “Case report: successful use of short-term add-on tocilizumab for multirefractory systemic flare of adult-onset Still’s disease,” Clinical Rheumatology. In press.
  160. D. Kishida, Y. Okuda, M. Onishi et al., “Successful tocilizumab treatment in a patient with adult-onset Still's disease complicated by chronic active hepatitis B and amyloid A amyloidosis,” Modern Rheumatology, vol. 21, no. 2, pp. 215–218, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  161. R. Thonhofer, M. Hiller, H. Just, M. Trummer, C. Siegel, and C. Dejaco, “Treatment of refractory adult-onset Still’s disease with tocilizumab: report of two cases and review of the literature,” Rheumatology International, vol. 31, no. 12, pp. 1653–1656, 2011. View at Google Scholar
  162. M. Kobayashi, Y. Takahashi, H. Yamashita, H. Kaneko, and A. Mimori, “Benefit and a possible risk of tocilizumab therapy for adult-onset Still's disease accompanied by macrophage-activation syndrome,” Modern Rheumatology, vol. 21, no. 1, pp. 92–96, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  163. X. Pechal, M. DeBandt, and J. M. Berthelot, “Tocilizumab in refractory adult Still’s disease,” Arthritis Care & Research, vol. 63, no. 1, pp. 155–159, 2011. View at Google Scholar
  164. G. R. Sabnis, Y. A. Gokhale, and U. P. Kulkarni, “Tocilizumab in refractory adult-onset Still’s disease with aseptic meningitis-efficacy of interleukin-6 blockade and review of the literature,” Seminars in Arthritis & Rheumatism, vol. 40, no. 4, pp. 365–368, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  165. J. Rech, M. Ronneberger, M. Englbrecht et al., “Successful treatment of adult-onset Still’s disease refractory to TNF and IL-1 blockade by IL-6 receptor blockade,” Annals of the Rheumatic Diseases, vol. 70, no. 2, pp. 390–392, 2011. View at Google Scholar
  166. H. Ito, M. Takazoe, Y. Fukuda et al., “A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease,” Gastroenterology, vol. 126, no. 4, pp. 989–996, 2004. View at Publisher · View at Google Scholar · View at Scopus
  167. T. Hirano, N. Ohguro, S. Hohki et al., “A case of Behcet’s disease treated with a humanized anti-interleukin-6 receptor antibody, tocilizumab,” Modern Rheumatology. In press.
  168. K. Hagihara, I. Kawase, T. Tanaka, and T. Kishimoto, “Tocilizumab ameliorates clinical symptoms in polymyalgia rheumatica,” Journal of Rheumatology, vol. 37, no. 5, pp. 1075–1076, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  169. T. Tanaka, K. Hagihara, Y. Shima et al., “Treatment of a patient with remitting seronegative, symmetrical synovitis with pitting oedema with a humanized anti-interleukin-6 receptor antibody, tocilizumab,” Rheumatology, vol. 49, no. 4, pp. 824–826, 2010. View at Google Scholar
  170. T. Tanaka, Y. Kuwahara, Y. Shima et al., “Successful treatment of reactive arthritis with a humanized anti-interleukin-6 receptor antibody, tocilizumab,” Arthritis Care & Research, vol. 61, no. 12, pp. 1762–1764, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  171. J. C. Henes, M. Horger, I. Guenaydin, L. Kanz, and I. Koetter, “Mixed response to tocilizumab for ankylosing spondylitis,” Annals of the Rheumatic Diseases, vol. 69, no. 12, pp. 2217–2218, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  172. D. Wendling, M. Bossert, and C. Prati, “Short-term effect of IL-6 inhibition in spondylarthritis,” Joint Bone Spine, vol. 77, no. 6, pp. 624–625, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  173. L. Brulhart, M. J. Nissen, P. Chevallier, and C. Gabay, “Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists,” Joint Bone Spine, vol. 77, no. 6, pp. 625–626, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  174. Y. Shima, T. Tomita, T. Ishii et al., “Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis,” Modern Rheumatology, vol. 21, no. 4, pp. 436–439, 2011. View at Google Scholar
  175. J. D. Cohen, R. Ferreira, and C. Jorgensen, “Ankylosing spondylitis refractory to tumor necrosis factor blockade responds to tocilizumab,” The Journal of Rheumatology, vol. 38, no. 7, p. 1527, 2011. View at Google Scholar
  176. U. Gergis, J. Arnason, R. Yantiss et al., “Effectiveness and safety of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in a patient with refractory GI graft-versus-host disease,” Journal of Clinical Oncology, vol. 28, no. 30, pp. e602–e604, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  177. W. R. Drobyski, M. Pasquini, K. Kovatovic et al., “Tocilizumab for the treatment of steroid refractory graft versus host disease,” Biology of Blood and Marrow Transplantation, vol. 17, no. 12, pp. 1862–1868, 2011. View at Google Scholar
  178. P. M. Vaitla, P. M. Radford, P. J. Tighe et al., “Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab,” Arthritis & Rheumatism, vol. 63, no. 4, pp. 1151–1155, 2011. View at Google Scholar
  179. K. Taniguchi, C. Shimazaki, Y. Fujimoto et al., “Tocilizumab is effective for pulmonary hypertension associated with multicentric Castleman's disease,” International Journal of Hematology, vol. 90, no. 1, pp. 99–102, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  180. Y. Arita, Y. Sakata, T. Sudo et al., “The efficacy of tocilizumab in a patient with pulmonary arterial hypertension associated with Castleman's disease,” Heart and Vessels, vol. 25, no. 5, pp. 444–447, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  181. Y. Furuya, T. Satoh, and M. Kuwana, “Interelukin-6 as a potential therapeutic target for pulmonary arterial hypertension,” International Journal of Rheumatology, vol. 2010, Article ID 720305, 8 pages, 2010. View at Publisher · View at Google Scholar · View at PubMed