Interleukin (IL)-6 is a cytokine featuring redundancy and pleiotropic activity. While IL-6, when transiently produced, contributes to host defense against acute environmental stress, continuous dysregulated IL-6 production plays a significant pathological role in several systemic autoimmune diseases. In response to the expectation that IL-6 blockade would constitute a novel therapeutic strategy for the treatment of these diseases, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Clinical trials have verified the efficacy and the safety of tocilizumab for patients with rheumatoid arthritis, resulting in approval of this innovative biologic for the treatment of rheumatoid arthritis in more than 90 countries worldwide. Pathological analyses of the effect of IL-6 on the development of autoimmune diseases and a considerable number of case reports and pilot studies have also indicated the beneficial effects of this antibody on other systemic autoimmune diseases, including systemic lupus erythematosus, systemic sclerosis, polymyositis, and large-vessel vasculitis. 1. Introduction Interleukin (IL)-6 is a cytokine featuring redundancy and pleiotropic activity. It was successfully cloned in 1996 as a B-cell differentiation factor, which promotes B-cell differentiation into antibody-producing cells [1]. Subsequent in vitro studies and analysis of IL-6 transgenic mice have shown that IL-6 acts not only on B cells but also on T cells, hepatocytes, hematopoietic progenitor cells, and various other cells [2–4]. One of the important functions of IL-6 is the differentiation of CD4positive na？ve T cells into effector cells. IL-6 in the presence of TGF-β promotes na？ve T-cell differentiation into Th17 cells, while IL-6 inhibits TGF-β-induced regulatory T-cell (Treg) differentiation [5], causing imbalance between Th17 and Treg, which is a primary pathogenic factor in several autoimmune diseases [6]. IL-6 transmits its signal through its binding to transmembrane receptors or the soluble IL-6 receptor (IL-6R) [7, 8]. After binding of IL-6 to IL-6R, the resultant IL-6/IL-6R complex associates with gp130 and induces homodimerization of gp130, which triggers signal transduction system [9]. The pathological significance of IL-6 for diseases was first demonstrated in a case of cardiac myxoma [10]. The culture fluid obtained from the myxoma tissues of a patient who presented with fever, arthritis with positivity for antinuclear factor, increased C-reactive protein (CRP) levels and hypergammaglobulinemia and was diagnosed with undifferentiated connective tissue
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.
[2]
T. Kishimoto, “The biology of interleukin-6,” Blood, vol. 74, no. 1, pp. 1–10, 1989.
[3]
S. Akira, T. Taga, and T. Kishimoto, “Interleukin-6 in biology and medicine,” Advances in Immunology, vol. 54, pp. 1–78, 1993.
[4]
T. Kishimoto, “Interleukin-6: from basic science to medicine-40 Years in immunology,” Annual Review of Immunology, vol. 23, pp. 1–21, 2005.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[13]
N. Nishimoto and T. Kishimoto, “Interleukin 6: from bench to bedside,” Nature Clinical Practice Rheumatology, vol. 2, no. 11, pp. 619–626, 2006.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[55]
T. Gout, A.J. Ost？r, 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[71]
G. Obermoser and V. Pascual, “The interferon-α signature of systemic lupus erythematosus,” Lupus, vol. 19, no. 9, pp. 1012–1019, 2010.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[118]
M. C. Dalakas, “Immunotherapy of myositis: issues, concerns and future prospects,” Nature Reviews Rheumatology, vol. 6, no. 3, pp. 129–137, 2010.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[129]
J. C. Mason, “Takayasu arteritis—advances in diagnosis and management,” Nature Reviews Rheumatology, vol. 6, no. 7, pp. 406–415, 2010.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[158]
K. Perdan-Pirkmajer, S. Praprotnik, and M. Tom？i？, “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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
