Immunotherapeutic implication of IL-6 blockade

Immunotherapy

Volumn 4, Issue 1, 2012, Pages 87-105

  Tanaka, Toshio ^a   Kishimoto, Tadamitsu ^b,c  

^a OSAKA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b OSAKA UNIVERSITY   (Japan)

^c OSAKA UNIVERSITY   (Japan)

Author keywords

autoimmune; humanized anti IL 6 receptor antibody; IL 6; inflammation; tocilizumab

Indexed keywords

BLOOD CLOTTING FACTOR 8; CORTICOSTEROID; DISEASE MODIFYING ANTIRHEUMATIC DRUG; INTERLEUKIN 6; METHOTREXATE; PLACEBO; TOCILIZUMAB;

ADULT ONSET STILL DISEASE; AMYLOIDOSIS; ANGIOFOLLICULAR LYMPH NODE HYPERPLASIA; ANKYLOSING SPONDYLITIS; AORTA ARCH SYNDROME; BEHCET DISEASE; CROHN DISEASE; CYTOKINE PRODUCTION; DERMATOMYOSITIS; DIGESTIVE SYSTEM PERFORATION; DISEASE ACTIVITY; DIVERTICULITIS; DRUG DOSE ESCALATION; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; ENVIRONMENTAL STRESS; GIANT CELL ARTERITIS; GRAFT VERSUS HOST REACTION; HEART MYXOMA; HEMOPHILIA A; HOST RESISTANCE; HUMAN; IMMUNOTHERAPY; INCLUSION BODY MYOSITIS; INFECTION; JUVENILE RHEUMATOID ARTHRITIS; LEG EDEMA; MULTIPLE SCLEROSIS; MYELOOPTIC NEUROPATHY; NONHUMAN; OFF LABEL DRUG USE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PLEIOTROPY; POLYCHONDRITIS; POLYMYOSITIS; PRIORITY JOURNAL; RELAPSING POLYCHONDRITIS; REVIEW; RHEUMATIC POLYMYALGIA; RHEUMATOID ARTHRITIS; SPONDYLOARTHROPATHY; SYSTEMIC LUPUS ERYTHEMATOSUS; SYSTEMIC SCLEROSIS; UVEITIS;

ANTIBODIES, MONOCLONAL, HUMANIZED; ARTHRITIS, RHEUMATOID; AUTOIMMUNE DISEASES; GIANT LYMPH NODE HYPERPLASIA; HUMANS; INFLAMMATION; INTERLEUKIN-6; RECEPTORS, INTERLEUKIN-6; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

EID: 83655203256     PISSN: 1750743X     EISSN: 17507448     Source Type: Journal    
DOI: 10.2217/imt.11.147     Document Type: Review

References (228)

1. Hirano T, Yasukawa K, Harada H et al. Complementary DNA for a novel human interleukin (BSF 2) that induces B lymphocytes to produce immunoglobulin. Nature 324, 73-76 (1986). (Pubitemid 16008419)
2. Kishimoto T. The biology of interleukin 6. Blood 74, 1-10 (1989).
3. Akira S, Taga T, Kishimoto T. Interleukin 6 in biology and medicine. Adv. Immunol. 54, 1-78 (1993).
4. Kishimoto T. Interleukin 6: From basic science to medicine-40 years in immunology. Ann. Rev. Immunol. 23, 1-21 (2005). (Pubitemid 40563163)
5. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL 17 and Th17 cells. Ann. Rev. Immunol. 27, 485-517 (2009).
6. Kimura A, Kishimoto T. IL 6: Regulator of Treg/Th17 balance. Eur. J. Immunol. 40, 1830-1835 (2010).
7. Okada M, Kitahara M, Kishimoto S et al. IL 6/BSF 2 functions as a killer helper factor in the in vitro induction of cytotoxic T cells. J. Immunol. 141, 1543-1549 (1988).
8. Heinrich PC, Castell JV, Andus T. Interleukin 6 and the acute phase response. Biochem. J. 265, 621-636 (1990).
9. Siewert E, Bort R, Kluge R et al. Hepatic cytochrome p450 down-regulation during aseptic inflammation in the mouse is interleukin 6 dependent. Hepatology 32, 49-55 (2000). (Pubitemid 30432365)
10. Obici L, Perfetti V, Palladini G, Moratti R, Merlini G. Clinical aspects of systemic amyloid diseases. Biochim. Biophys. Acta 1753, 11-22 (2005). (Pubitemid 41597427)
11. Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102, 783-788 (2003). (Pubitemid 36917762)
12. Nemeth E, Rivera S, Gabayan V et al. IL 6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113, 1271-1276 (2004). (Pubitemid 39069926)
13. Kotake S, Sato K, Kim KJ et al. Interleukin 6 and soluble interleukin 6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J. Bone Miner. Res. 11, 88-95 (1996). (Pubitemid 26026748)
14. Palmqvist P, Persson E, Conaway HH, Lerner UH. IL 6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF k B ligand, osteoprotegerin, and receptor activation of NF kB in mouse calvariae. J. Immunol. 169, 3353-3362 (2002). (Pubitemid 35013185)
15. Hashizume M, Hayakawa N, Mihara M. IL 6 trans-signaling directly induces RANKL induction by TNF a and IL 17. Rheumatology (Oxf.) 47, 1635-1640 (2008).
16. Nakahara H, Song J, Sugimoto M et al. Anti-interleukin 6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum. 48, 1521-1529 (2003). (Pubitemid 36682359)
17. Grossman RM, Krueger J, Yourish D et al. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc. Natl Acad. Sci. USA 86, 6367-6371 (1989). (Pubitemid 19210653)
18. Duncan MR, Berman B. Stimulation of collagen and glycosaminoglycan production in cultured human adult dermal fibroblasts by recombinant human interleukin 6. J. Invest. Dermatol. 97, 686-692 (1991).
19. Yamasaki K, Taga T, Hirata Y et al. Cloning and expression of the human interleukin 6 (BSF 2/IFN b 2) receptor. Science 241, 825-828 (1988).
20. Kishimoto T, Akira S, Taga T. Interleukin 6 and its receptor: A paradigm for cytokines. Science 258, 593-597 (1992).
21. Hibi M, Murakami M, Saito M et al. Molecular cloning and expression of an IL 6 signal transducer, gp130. Cell 63, 1149-1157 (1990). (Pubitemid 120035064)
22. Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin 6 family of cytokines and gp130. Blood 86, 1243-1254 (1995).
23. Taga T, Kishimoto T. Gp130 and the interleukin 6 family of cytokines. Ann. Rev. Immunol. 15, 797-819 (1997).
24. Murakami M, Hibi M, Nakagawa N et al. IL 6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science 260, 1808-1810 (1993). (Pubitemid 23244207)
25. Boulanger MJ, Chow DC, Brevnova EE, Garcia KC. Hexameric structure and assembly of the interleukin 6/IL 6 a-receptor/gp130 complex. Science 300, 2101-2104 (2003). (Pubitemid 36760138)
26. Narazaki M, Yasukawa K, Saito T 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 82, 1120-1126 (1993). (Pubitemid 23253984)
27. Pflanz S, Hibbert L, Mattson J et al. WSX 1 and glycoprotein 130 constitute a signal-transducing receptor for IL 27. J. Immunol. 172, 2225-2231 (2004). (Pubitemid 38182370)
28. Hirano T, Taga T, Yasukawa K et al. Human B cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production. Proc. Natl Acad. Sci. USA 84, 228-231 (1987). (Pubitemid 17013607)
29. Yoshizaki K, Matsuda T, Nishimoto N et al. Pathogenic significance of interleukin 6 (IL 6/BSF 2) in Castlemans disease. Blood 74, 1360-1367 (1989). (Pubitemid 19227448)
30. Hirano T, Matsuda T, Turner M et al. Excessive production of interleukin 6/B cell stimulatory factor 2 in rheumatoid arthritis. Eur. J. Immunol. 18, 1797-1801 (1988). (Pubitemid 19011590)
31. Kawano M, Hirano T, Matsuda T et al. Autocrine generation and requirement of BSF 2/IL 6 for human multiple myelomas. Nature 332, 83-85 (1988).
32. Nishimoto N, Kishimoto T. Interleukin 6: From bench to bedside. Nat. Clin. Pract. Rheumatol. 2, 619-626 (2006). (Pubitemid 44650950)
33. Tanaka T, Narazaki M, Kishimoto T. Anti-interleukin 6 receptor antibody, tocilizumab, for the treatment of autoimmune diseases. FEBS Lett. doi:10.1016/j. febslet.2011.03.023 (2011) (Epub ahead of print).
34. Nishimoto N, Terao K, Mima T et al. Mechanisms and pathologic significances in increase in serum interleukin 6 (IL 6) and soluble IL 6 receptor after administration of an anti-IL 6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 112, 3959-3964 (2008).
35. Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet 370, 1861-1874 (2007). (Pubitemid 350180008)
36. Houssiau FA, Devogelaer JP, Van Damme J, de Deuxchaisnes CN, Van Snick J. Interleukin 6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 31, 784-788 (1988).
37. Madhok R, Crilly A, Watson J, Capell HA. Serum interleukin 6 levels in rheumatoid arthritis: Correlations with clinical and laboratory indices of disease activity. Ann. Rheum. Dis. 52, 232-234 (1993). (Pubitemid 23094315)
38. Alonzi T, Fattori E, Lazzaro D et al. Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187, 461-468 (1998). (Pubitemid 28093348)
39. Ohshima S, Saeki Y, Mima T et al. Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc. Natl Acad. Sci. USA 95, 8222-8226 (1998). (Pubitemid 28326094)
40. Takagi N, Mihara M, Moriya Y et al. Blockade of interleukin 6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheum. 41, 2117-2121 (1998). (Pubitemid 29009369)
41. Sasai M, Saeki Y, Ohshima S et al. Delayed onset and reduced severity of collagen-induced arthritis in interleukin 6-deficient mice. Arthritis Rheum. 42, 1635-1643 (1999). (Pubitemid 30263631)
42. Mihara M, Kotoh M, Nishimoto N et al. Humanized antibody to human interleukin 6 receptor inhibits the development of collagen arthritis in cynomolgus monkeys. Clin. Immunol. 98, 319-326 (2001).
43. Uchiyama Y, Yorozu K, Hashizume M, Moriya Y, Mihara M. Tocilizumab, a humanized anti-interleukin 6 receptor antibody, ameliorates joint swelling in established monkey collagen-induced arthritis. Biol. Pharm. Bull. 31, 1159-1163 (2008). (Pubitemid 351871169)
44. Nishimoto N, Hashimoto J, Miyasaka N 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 randomized controlled trial of tocilizumab. Ann. Rheum. Dis. 66, 1162-1167 (2007). (Pubitemid 47309731)
45. Genovese MC, McKay JD, Nasonov EL 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 Rheum. 58, 2968-2980 (2008).
46. Emery P, Keystone E, Tony HP et al. IL 6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumor necrosis factor biologicals: Results from a 24 week multicentre randomized placebo controlled trial. Ann. Rheum. Dis. 67, 1516-1523 (2008).
47. Smolen JS, Beaulieu A, Rubbert-Roth A et al. Effect of interleukin 6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): A double-blind, placebo-controlled, randomized trial. Lancet 371, 987-997 (2008). (Pubitemid 351392039)
48. Nishimoto N, Miyasaka N, Yamamoto K 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. Mod. Rheumatol. 19, 12-19 (2009).
49. Kremer JM, Blanco R, Brzosko M 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 Rheum. 63, 609-621 (2011).
50. Jones G, Sebba A, Gu J et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study. Ann. Rheum. Dis. 69, 88-96 (2010).
51. Tanaka T, Ogata A, Narazaki M. Tocilizumab for the treatment of rheumatoid arthritis. Exp. Rev. Clin. Immunol. 6, 843-854 (2010).
52. Smolen JS, Aletaha D. Interleukin 6 receptor inhibition with tocilizumab and attainment of disease remission in rheumatoid arthritis: The role of acute-phase reactants. Arthritis Rheum. 63, 43-52 (2011).
53. Burmester GR, Feist E, Kellner H, Braun J, Iking-Konert C, Rubbert-Roth A. Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: The first Phase 3b real-life study (TAMARA). Ann. Rheum. Dis. 70, 755-759 (2011).
54. Bykerk VP, Alvaro-Gracia J, Ivora JAR et al. Tocilizumab treatment in patients with rheumatoid arthritis and an inadequate response to DMARDs and/or TNF inhibitors: ACT SURE preliminary results. Arthritis Rheum. 62, S1840 (2010).
55. Leffers HC, Ostergaard M, Glintborg B et al. Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: Results from the nationwide Danish DANBIO registry. Ann. Rheum. Dis. 70, 1216-1222 (2011).
56. Yamanaka H, Tanaka Y, Inoue E 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). Mod. Rheumatol. 21, 122-133 (2011).
57. Nishimoto N, Ito K, Takagi N. Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: Meta-analysis of six initial trials and five long-term extensions. Mod. Rheumatol. 20, 222-232 (2010).
58. Hashizume M, Yoshida H, Koike N, Suzuki M, Mihara M. Overproduced IL 6 decreases blood lipid levels via upregulation of very-low-density lipoprotein receptor. Ann. Rheum. Dis. 69, 741-746 (2010).
59. Campbell L, Chen C, Bhagat SS, Parker RA, Ostor AJ. 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 (Oxf.) 50, 552-562 (2011).
60. Fujiwara H, Nishimoto N, Hamano Y et al. Masked early symptoms of pneumonia in patients with rheumatid arthritis during tocilizumab treatment: A report of two cases. Mod. Rheumatol. 19, 64-68 (2009).
61. Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD. Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: A multicenter active-surveillance report. Arthritis Rheum. 48, 2122-2127 (2003). (Pubitemid 36959191)
62. Okada M, Kita Y, Kanamaru N et al. Anti-IL 6 receptor antibody causes less promotion of tuberculosis infection than anti-TNF a antibody in mice. Clin. Dev. Immunol. doi:10.1155/2011/404929 (2011) (Epub ahead of print).tocilizumab, for the treatment of autoimmune diseases. FEBS Lett. doi:10.1016/j. febslet.2011.03.023 (2011) (Epub ahead of print).
63. Ogata A, Mori M, Hashimoto S et al. Minimal influence of tocilizumab on IFN g synthesis by tuberculosis antigens. Mod. Rheumatol. 20, 130-133 (2010).
64. Gout T, Ostor AJ, Nisar MK. Lower gastrointestinal perforation in rheumatoid arthritis patients with conventional DMARDs or tocilizumab: A systemic literature review. Clin. Rheumatol. 30(11), 1471-1474 (2011).
65. Palestro G, Turrini F, Pagano M, Chiusa L. Castlemans disease. Adv. Clin. Path. 3, 11-22 (1999).
66. Brandt SJ, Bodine DM, Dunbar CE, Nienhuis AW. Dysregulated interleukin 6 expression produces a syndrome resembling Castlemans disease in mice. J. Clin. Invest. 86, 592-599 (1990). (Pubitemid 20271895)
67. Katsume A, Saito H, Yamada Y et al. Anti-interleukin 6 (IL 6) receptor antibody suppresses Castlemans disease like symptoms emerged in IL 6 transgenic mice. Cytokine 20, 304-311 (2002). (Pubitemid 36299051)
68. Soulier J, Grollet L, Oksenhendler E et al. Kaposi's sarcoma-associated herpes virus-like DNA sequences in multicentric Castlemans disease. Blood 86, 1276-1280 (1995).
69. Aoki Y, Narazaki M, Kishimoto T, Tosato G. Receptor engagement by viral interleukin 6 encoded by Kaposi sarcoma-associated herpes virus. Blood 98, 3042-3049 (2001).
70. Beck JT, Hsu SM, Wijdenes J et al. Brief report: Alleviation of systemic manifestations of Castlemans disease by monoclonal anti-interleukin 6 antibody. N. Engl. J. Med. 330, 602-605 (1994). (Pubitemid 24065794)
71. Nishimoto N, Sasai M, Shima Y et al. Improvement in Castlemans disease by humanized anti-interleukin 6 receptor antibody therapy. Blood 95, 56-61 (2000). (Pubitemid 30017224)
72. Nishimoto N, Kanakura Y, Aozasa K et al. Humanized anti-interleukin 6 receptor antibody treatment of multicentric Castleman disease. Blood 106, 2627-2632 (2005). (Pubitemid 41510733)
73. Yokota S, Kishimoto T. Tocilizumab: Molecular intervention therapy in children with systemic juvenile idiopathic arthritis. Exp. Rev. Clin. Immunol. 6, 735-743 (2010).
74. De Benedetti F, Pignatti P, Gerloni V et al. Differences in synovial fluid cytokine levels between juvenile and adult rheumatoid arthritis. J. Rheumatol. 24, 1403-1409 (1997). (Pubitemid 27353389)
75. Yokota S, Miyamae T, Imagawa T et al. Therapeutic efficacy of humanized recombinant anti-interleukin 6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 52, 818-825 (2005). (Pubitemid 40365104)
76. Yokota S, Imagawa T, Mori M et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: A randomized, double-blind, placebo-controlled, withdrawal Phase 3 trial. Lancet 371, 998-1006 (2008). (Pubitemid 351389534)
77. Inaba Y, Ozawa R, Imagawa T et al. Radiographic improvement of damaged large joints in children with systemic juvenile idiopathic arthritis following tocilizumab treatment. Ann. Rheum. Dis. 70, 1693-1695 (2011).
78. Yokota S, Imagawa T, Takei S et al. Guideline on using tocilizumab for juvenile idiopathic arthritis. Mod. Rheumatol. doi:10.1007/ s10165-011-0464-1 (2011) (Epub ahead of print).
79. De Benedetti F, Brunner H, Ruperto N et al. From biology to classification and targeted therapy in juvenile idiopathic arthritis. Ann. Rheum. Dis. 69(Suppl. 3), S146 (2010).
80. Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140, 1756-1767 (2011).
81. Ito H. Novel therapy for Crohn's disease targeting IL 6 signaling. Exp. Opin. Ther. Targets 8, 287-294 (2004). (Pubitemid 39117694)
82. Mitsuyama K, Toyonaga A, Sasaki E et al. Soluble interleukin 6 receptors in inflammatory bowel disease: Relation to circulating interleukin 6. Gut 36, 45-49 (1995).
83. Hosokawa T, Kusugami K, Ina K et al. Interleukin 6 and soluble interleukin 6 receptor in the colonic mucosa of inflammatory bowel disease. J. Gastroenterol. Hepatol. 14, 987-996 (1999). (Pubitemid 29487295)
84. Yamamoto M, Yoshizaki K, Kishimoto T, Ito H. IL 6 is required for the development of Th1 cell-mediated murine colitis. J. Immunol. 164, 4878-4882 (2000). (Pubitemid 30238092)
85. Ito H, Takazoe M, Fukuda Y et al. A pilot randomized trial of a human anti-interleukin 6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology 126, 989-996 (2004). (Pubitemid 38451170)
86. Becker C, Fantini MC, Schramm C et al. TGF b suppresses tumor progression in colon cancer by inhibition of IL 6 trans-signaling. Immunity 21, 491-501 (2004). (Pubitemid 39370505)
87. Grivennikov S, Karin E, Terzic J et al. IL 6 and STAT3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103-113 (2009).
88. Ruiz-Irastorza G, Khamashta MA, Castellino G, Hughes GR. Systemic lupus erythematosus. Lancet 357, 1027-1032 (2001). (Pubitemid 32285401)
89. Rhodes B, Furnrohr BG, Vyse TJ. C reactive protein in rheumatology: biology and genetics. Nat. Rev. Rheumatol. 7, 282-289 (2011).
90. Tackey E, Lipsky PE, Illei GG. Rationale for interleukin 6 blockade in systemic lupus erythematosus. Lupus 13, 339-343 (2004). (Pubitemid 38788493)
91. Linker-Israeli M, Deans RJ, Wallace DJ et al. Elevated levels of endogenous IL 6 in systemic lupus erythematosus: A putative role in pathogenesis. J. Immunol. 147, 117-123 (1991).
92. Peterson E, Robertson AD, Emlen W. Serum and urinary interleukin 6 in systemic lupus erythematosus. Lupus 5, 571-575 (1996). (Pubitemid 27035726)
93. Grondal G, Gunnarsson I, Ronnelid J, Rodberg S, Klareskog L, Lunderg I. Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin. Exp. Rheumatol. 18, 565-570 (2000).
94. Iwano M, Dohi K, Hirata E et al. Urinary levels of IL 6 in patients with active lupus nephritis. Clin. Nephrol. 40, 16-21 (1993). (Pubitemid 23221728)
95. Hirohata S, Miyamoto T. Elevated levels of interleukin 6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthritis Rheum. 33, 644-649 (1990). (Pubitemid 20166565)
96. Hagiwara E, Gourley MF, Lee S, Klinman DK. Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin 10: Interferon g-secreting cells in the peripheral blood. Arthritis Rheum. 39, 379-385 (1996). (Pubitemid 26085213)
97. Klashman DJ, Martin RA, Martinez-Maza O, Stevens RH. 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 Rheum. 34, 276-286 (1991).
98. Kitani A, Hara M, Hirose T 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. Clin. Exp. Immunol. 88, 75-83 (1992).
99. Pflegerl P, Vesely P, Hantusch B et al. Epidermal loss of JunB leads to a SLE phenotype due to hyper IL 6 signaling. Proc. Natl Acad. Sci. USA 106, 20423-20428 (2009).
100. Ryffel B, Car BD, Gunn H, Roman D, Hiestand P, Mihatsch MJ. Interleukin 6 exacerbates glomerulonephritis in (NZB . NZW)F1 mice. Am. J. Pathol. 144, 927-937 (1994).
101. Finck BK, Chan B, Wofsy D. Interleukin 6 promotes murine lupus in NZB/NZW F1 mice. J. Clin. Invest. 94, 585-591 (1994). (Pubitemid 24250987)
102. Mihara M, Takagi N, Takeda Y, Ohsugi Y. IL 6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. Clin. Exp. Immunol. 112, 397-402 (1998). (Pubitemid 28267419)
103. Liang B, Gardner DB, Griswold DE, Bugelski PJ, Song XY. Anti-interleukin 6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology 119, 296-305 (2006). (Pubitemid 44571047)
104. Illei GG, Shirota Y, Yarboro CH et al. Tocilizumab in systemic lupus erythematosus: Data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label Phase 1 dosage-escalation study. Arthritis Rheum. 62, 542-552 (2010).
105. Fautrel B. Adult-onset Still disease. Best Pract. Res. Clin. Rheumatol. 22, 773-792 (2008).
106. Iwamoto M, Nara H, Hirata D et al. Humanized monoclonal anti-interleukin 6 receptor antibody for treatment of intractable adult-onset Still's disease. Arthritis Rheum. 46, 3388-3389 (2002). (Pubitemid 35453552)
107. Nakahara H, Mima T, Yoshino-Hoshino N et al. A case report of a patient with refractory adult-onset Still's disease who was successfully treated with tocilizumab over 6 years. Mod. Rheumatol. 19, 69-72 (2009).
108. De Bandt M, Saint-Marcoux B. Tocilizumab for multirefractory adult-onset Still's disease. Ann. Rheum. Dis. 68, 153-154 (2009).
109. Matsumoto K, Nagashima T, Takatori S et al. Glucocorticoid and cyclosporine refractory adult onset Still's disease successfully treated with tocilizumab. Clin. Rheumatol. 28, 485-487 (2009).
110. Cunha ML, Wagner J, Osawa A, Scheinberg M. The effect of tocilizumab on the uptake of 18FDG PET imaging in patients with adult-onset Still's disease. Rheumatology (Oxf.) 49, 1014-1016 (2010).
111. Sumida K, Ubara Y, Hoshino J et al. Etanercept-refractory adult-onset Still's disease with thrombotic thrombocytopenic purpura successfully treated with tocilizumab. Clin. Rheumatol. 29, 1191-1194 (2010).
112. Yoshimura M, Makiyama J, Koga T et al. Successful treatment with tocilizumab in a patient with refractory adult-onset Still's disease (AOSD). Clin. Exp. Rheumatol. 28, 141-142 (2010).
113. Perdan-Pirkmajer K, Praprotnik S, Tomsic M. A case of refractory adult-onset Still's disease successfully controlled with tocilizumab and a review of the literature. Clin. Rheumatol. 29, 1465-1467 (2010).
114. Naniwa T, Ito R, Watanabe M et al. Case report: Successful use of short-term add-on tocilizumab for multirefractory systemic flare of adult-onset Still's disease. Clin. Rheumatol. doi:10.1007/s10067-010-1562-8 (2010) (Epub ahead of print).
115. Kishida D, Okuda Y, Onishi M et al. Successful tocilizumab treatment in a patient with adult-onset Still's disease complicated by chronic active hepatitis B and amyloid A amyloidosis. Mod. Rheumatol. 21, 215-218 (2011).
116. Thonhofer R, Hiller M, Just H, Trummer M, Siegel C, Dejaco C. Treatment of refractory adult-onset Still's disease with tocilizumab: Report of two cases and review of the literature. Rheumatol. Int. doi:10.1007/ s00296-010-1631-y (2011) (Epub ahead of print).
117. Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet 372, 234-245 (2008). (Pubitemid 351997438)
118. Mason JC. Takayasu arteritis - advances in diagnosis and management. Nat. Rev. Rheumatol. 6, 405-415 (2010).
119. Seko Y, Sato O, Takagi A et al. Restricted usage of T cell receptor Va Vb genes in infiltrating cells in aortic tissue of patients with Takayasu's arteritis. Circulation 93, 1788-1790 (1996). (Pubitemid 26154028)
120. Noris M, Daina E, Gamba S, Bonazzola S, Remuzzi G. Interleukin 6 and RANTES in Takayasu arteritis: A guide for therapeutic decisions? Circulation 100, 55-60 (1999). (Pubitemid 29297940)
121. Park MC, Lee SW, Park YB, Lee SK. Serum cytokine profiles and their correlations with disease activity in Takayasu's arteritis. Rheumatology (Oxf.) 45, 545-548 (2006).
122. Nishimoto N, Nakahara H, Yoshio-Hoshino N, Mima T. Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin 6 receptor antibody. Arthritis Rheum. 58, 1197-1200 (2008). (Pubitemid 351564023)
123. Seitz M, Reichenbach S, Bonel HM et al. Rapid induction of remission in large vessel vasculitis by IL 6 blockade. A case series. Swiss Med. Wkly 141, W13156 (2011).
124. Beyer C, Axmann R, Sahinbegovic E et al. Anti-interleukin 6 receptor therapy as rescue treatment for giant cell arteritis. Ann. Rheum. Dis. 70, 1874-1875 (2011).
125. Cid MC, Hernandez-Rodriquez J, Esteban MJ et al. Tissue and serum angiogenic activity is associated with low prevalence of ischemic complications in patients with giant-cell arteritis. Circulation 106, 1664-1671 (2002).
126. Hernandez-Rodriquez J, Segarra M, Vilardell C 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 107, 2428-2434 (2003). (Pubitemid 36605224)
127. Nakahama H, Okada M, Miyazaki M, Imai N, Yokokawa T, Kubori S. Distinct responses of interleukin 6 and other laboratory parameters to treatment in a patient with polyarteritis nodosa: A case report. Angiology 43, 512-516 (1992).
128. Muller Kobold AC, van Wijk RT, Franssen CF, Molema G, Kallenberg CG, Tervaert JW. In vitro up-regulation of E selectin and induction of interleukin 6 in endothelial cells by autoantibodies in Wegener's granulomatosis and microscopic polyangitis. Clin. Exp. Rheumatol. 17, 433-440 (1999). (Pubitemid 29343627)
129. Popa ER, Franssen CF, Limburg PC, Huitema MG, Kallenberg CG, Tervaert JW. 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 Rheum. 46, 1894-1904 (2002). (Pubitemid 34774522)
130. Ohlsson S, Bakoush O, Tencer J, Torffvit O, Segelmark M. Monocyte chemoattractant protein 1 is a prognostic marker in ANCA-associated small vessel vasculitis. Mediators Inflamm. 584916 (2009).
131. Salvarani C, Gabriel SE, O'Fallon WM, Hunder GG. Epidemiology of polymyalgia rheumatica in Olmsted county, Minnesota, 1970-1991. Arthritis Rheum. 38, 369-373 (1995).
132. Bernatsky S, Loseph L, Pineau CA et al. Polymyalgia rheumatica prevalence in a population-based sample. Arthritis Rheum. 61, 1264-1267 (2009).
133. Alvarez-Rodriguez L, Lopez-Hoyos M, Mata C et al. Circulating cytokines in active polymyalgia rheumatica. Ann. Rheum. Dis. 69, 263-269 (2010).
134. Gabriel SE, Sunku J, Salvarani C, O'Fallon WM, Hunder GG. Adverse outcomes of antiinflammatory therapy among patients with polymyalgia rheumatica. Arthritis Rheum. 40, 1873-1878 (1997). (Pubitemid 27452540)
135. Cimmino MA, Salvarani C, Macchioni P et al. Long-term follow-up of polymyalgia rheumatica patients treated with methotrexate and steroids. Clin. Exp. Rheumatol. 26, 395-400 (2008). (Pubitemid 352003206)
136. Hagihara K, Kawase I, Tanaka T, Kishimoto T. Tocilizumab ameliorates clinical symptoms in polymyalgia rheumatica. J. Rheumatol. 37, 1075-1076 (2010).
137. Gergis U, Arnason J, Yantiss R et al. Effectiveness and safety of tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, in a patient with refractory GI graft-versus-host disease. J. Clin. Onocol. 28, E602-E604 (2010).
138. Drobyski WR, Pasquini M, Kovatovic K et al. Tocilizumab for the treatment of steroid refractory graft versus host disease. Biol. Blood Marrow Transplant. 17(12), 1862-1868 (2011).
139. Tawara I, Koyama M, Liu C et al. Interleukin 6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin. Cancer Res. 17, 77-88 (2011).
140. McCarty DJ, O'Duffy JD, Pearson L, Hunter JB. Remitting seronegative symmetrical synovitis with pitting edema. RS3PE syndrome. JAMA 254, 2763-2767 (1985). (Pubitemid 16243296)
141. Oide T, Ohara S, Oguchi K et al. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome in Nagano, Japan: Clinical, radiological, and cytokine studies of 13 patients. Clin. Exp. Rheumatol. 22, 91-98 (2004). (Pubitemid 38232814)
142. Arima K, Origuchi T, Tamai M et al. RS3PE syndrome presenting as vascular endothelial growth factor associated disorder. Ann. Rheum. Dis. 64, 1653-1655 (2005). (Pubitemid 41532054)
143. Kawashiro S, Nakano M, Kawakami A, Eguchi K. Monitoring of therapeutic efficacy in a patient with RS3PE syndromes by serologic and radiographic methods. Rheumatol. Int. 30, 1677-1680 (2010).
144. Tanaka T, Hagihara K, Shima Y et al. Treatment of a patient with remitting seronegative, symmetrical synovitis with pitting oedema with a humanized anti-interleukin 6 receptor antibody, tocilizumab. Rheumatology (Oxf.) 49, 824-826 (2010).
145. Perfetto F, Moggi-Pignone A, Livi R, Tempestini A, Bergesio F, Matucci-Cerinic M. Systemic amyloidosis: A challenge for the rheumatologist. Nat. Rev. Rheumatol. 6, 417-429 (2010).
146. Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 358, 24-29 (2001). (Pubitemid 32709735)
147. Lachmann HJ, Goodman HJ, Gilbertson JA et al. Natural history and outcome in systemic AA amyloidosis. N. Engl. J. Med. 356, 2361-2371 (2007). (Pubitemid 46883770)
148. Hagihara K, Nishikawa T, Isobe T et al. 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. Biochem. Biophys. Res. Comm. 314, 363-369 (2004). (Pubitemid 38084725)
149. Hagihara K, Nishikawa T, Sugamata Y et al. Essential role of STAT3 in cytokine-driven NF kB-mediated serum amyloid A gene expression. Genes Cells 10, 1051-1063 (2005). (Pubitemid 41556074)
150. Nishimoto N, Yoshizaki K, Miyasaka N et al. Treatment of rheumatoid arthritis with humanized anti-interleukin 6 receptor antibody: A multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 50, 1761-1769 (2004). (Pubitemid 38725087)
151. Okuda Y, Takasugi K. Successful use of a humanized anti-interleukin 6 receptor antibody, tocilizumab, to treat amyloid A amyloidosis complicating
152. Nishida S, Hagihara K, Shima Y et al. Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment. Ann. Rheum. Dis. 68, 1235-1236 (2009).
153. Sato H, Sakai T, Sugaya T et al. Tocilizumab dramatically ameliorated life-threatening diarrhea due to secondary amyloidosis associated with rheumatoid arthritis. Clin. Rheumatol. 28, 1113-1116 (2009).
154. Inoue D, Arima H, Kawanami C et al. Excellent therapeutic effect of tocilizumab on intestinal amyloid a deposition secondary to active rheumatoid arthritis. Clin. Rheumatol. 29, 1195-1197 (2010).
155. Reveille JD, Arnett FC. Spondyloarthritis: update on pathogenesis and management. Am. J. Med. 118, 592-603 (2005). (Pubitemid 40732696)
156. Wu IB, Schwartz RA. Reiter's syndrome: The classic triad and more. J. Am. Acad. Dermatol. 59, 113-121 (2008).
157. Metsarinne KP, Nordstrom DC, Konttinen YT, Teppo AM, Fyhrquist FY. Plasma interleukin 6 and renin substrate in reactive arthritis, rheumatoid arthritis, and systemic lupus erythematosus. Rheumatol. Int. 12, 93-96 (1992).
158. Straub RH, Paimela L, Peltomaa R et al. Inadequate low serum levels of steroid hormones in relation to interleukin 6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis. Arthritis Rheum. 46, 3436-3446 (2002).
159. Singh R, Aggarwal A, Misra R. Th1/Th17 cytokine profiles in patients with reactive arthritis/undifferentiated spondyloarthropathy. J. Rheumatol. 34, 2285-2290 (2007). (Pubitemid 350076892)
160. Tanaka T, Kuwahara Y, Shima Y et al. Successful treatment of reactive arthritis with a humanized anti-interleukin 6 receptor antibody, tocilizumab. Arthritis Rheum. 61, 1762-1764 (2009).
161. Wendling D, Racadot E, Toussirot E, Wijdenes J. Combination therapy of anti-CD4 and anti-IL6 monoclonal antibodies in a case of severe spondylarthropathy. Br. J. Rheumatol. 35, 1330 (1996). (Pubitemid 27032963)
162. Henes JC, Horger M, Guenaydin I, Kanz L, Koetter I. Mixed response to tocilizumab for ankylosing spondylitis. Ann. Rheum. Dis. 69, 2217-2218 (2010).
163. Wendling D, Bossert M, Prati C. Short-term effect of IL 6 inhibition in spondylarthritis. Joint Bone Spine 77, 624-625 (2010).
164. Brulhart L, Nissen MJ, Chevallier P, Gabay C. Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists. Joint Bone Spine 77, 625-626 (2010).
165. Shima Y, Tomita T, Ishii T et al. Tocilizumab, a humanized anti-interleukin 6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis. Mod. Rheumatol. 21, 436-439 (2011).
166. Cohen JD, Ferreira R, Jorgensen C. Ankylosing spondylitis refractory to tumor necrosis factor blockade responds to tocilizumab. J. Rheumatol. 38, 1527 (2011).
167. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N. Engl. J. Med. 360, 1989-2003 (2009).
168. Hasegawa M, Sato S, Fujimoto M et al. Serum levels of interleukin 6 (IL 6), oncostatin M, soluble IL 6 receptor, and soluble gp130 in patients with systemic sclerosis. J. Rheumatol. 25, 308-313 (1998). (Pubitemid 28088260)
169. Sato S, Hasegawa M, Takehara K. Serum levels of interleukin 6 and interleukin 10 correlate with total skin thickness score in patients with systemic sclerosis. J. Dermatol. Sci. 27, 140-146 (2001). (Pubitemid 32781022)
170. Gourh P, Arnett FC, Assassi S et al. Plasma cytokine profiles in systemic sclerosis: Associations with autoantibody subsets and clinical manifestation. Arthrit. Res. Ther. 11, R147 (2009).
171. Radstake TR, van Bon L, Broen J et al. The pronounced Th17 profiles in systemic sclerosis (SSc) together with intracellular expression of TGFb and IFNg distinguishes SSc phenotype. PLoS ONE 4, E5903 (2009).
172. Feghali CA, Bost KL, Boulware DW, Levy LS. Mechanisms of pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts cultured from affected skin sites of patients with scleroderma. J. Rheumatol. 19, 1207-1211 (1992).
173. Koch AE, Kronfeld-Harrington LB, Szekanecz Z 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 61, 239-246 (1993). (Pubitemid 24007481)
174. Gurram M, Pahwa S, Frieri M. Augmented interleukin 6 secretion in collagen-stimulated peripheral blood mononuclear cells from patients with systemic sclerosis. Ann. Allergy 73, 493-496 (1994).
175. Gallucci RM, Lee EG, Tomasek JJ. IL 6 modulates a-smooth muscle actin expression in dermal fibroblasts from IL 6-deficient mice. J. Invest. Dermatol. 126, 561-568 (2006). (Pubitemid 43255642)
176. Kawaguchi Y, Hara M, Wright TM. Endogenous IL 1a from systemic sclerosis fibroblasts induces IL 6 and PDGF A. J. Clin. Invest. 102, 1253-1260 (1999). (Pubitemid 29218295)
177. Barnes TC, Spiller DG, Anderson ME, Edwards SW, Moots RJ. Endothelial activation and apoptosis mediated by neutrophil-dependent interleukin 6 trans-signaling: A novel target for systemic sclerosis? Ann. Rheum. Dis. 70, 368-372 (2011).
178. Shima Y, Kuwahara Y, Murota H et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL 6 receptor antibody tocilizumab. Rheumatology (Oxf.) 49, 2408-2412 (2010).
179. Kuwahara Y, Shima Y, Shirayama D 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 (Oxf.) 47, 1018-1024 (2008). (Pubitemid 351865926)
180. Kowal-Bielecka O, Landewe R, Avouac J et al. EULAR recommendations for the treatment of systemic sclerosis: A report from the EULAR scleroderma trials and research group (EUSTAR). Ann. Rheum. Dis. 68, 620-628 (2009).
181. Dalakas MC. Immunotherapy of myositis: Issues, concerns and future prospects. Nat. Rev. Rheumatol. 6, 129-137 (2010).
182. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: Focus on muscle-derived interleukin 6. Physiol. Rev. 88, 1379-1406 (2008).
183. Carson JA, Baltgalvis KA. Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc. Sport Sci. Rev. 38, 168-176 (2010).
184. Gabay C, Gay-Croisier F, Roux-Lombard P et al. Elevated serum levels of interleukin 1 receptor anatagonist in polymyositis/ dermatomyositis. A biologic marker of disease activity with a possible role in the lack of acute-phase protein response. Arthritis Rheum. 37, 1744-1751 (1994). (Pubitemid 24371875)
185. Lundberg I, Ulfgren AK, Nyberg P, Andersson U, Klareskog L. Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies. Arthritis Rheum. 40, 865-874 (1997). (Pubitemid 27200003)
186. Lepidi H, Frances V, Figarella-Branger D et al. Local expression of cytokines in idiopathic inflammatory myopathies. Neuropathol. Appl. Neurobiol. 24, 73-79 (1998). (Pubitemid 28105417)
187. Scuderi F, Mannella F, Marino M, Provenzano C, Bartoccioni E. IL 6-deficient mice show impaired inflammatory response in a model of myosin-induced experimental myositis. J. Neuroimmunol. 176, 9-15 (2006). (Pubitemid 44080332)
188. Okiyama N, Sugihara T, Iwakura Y et al. Therapeutic effects of interleukin 6 blockade in a murine model of polymyositis that does not require interleukin 17A. Arthritis Rheum. 60, 2505-2512 (2009).
189. Narazaki M, Hagihara K, Shima Y et al. Therapeutic effect of tocilizumab on two patients with polymyositis. Rheumatology (Oxf.) 50, 1344-1346 (2011).
190. Bilgic H, Ytterberg SR, Amin S et al. Interleukin 6 and type 1 interferon regulated genes and chemokines mark disease activity in dermatomyositis. Arthritis Rheum. 60, 3436-3446 (2009).
191. Rapini RP, Warner NB. Relapsing polychondritis. Clin. Dermatol. 24, 482-485 (2006). (Pubitemid 44750558)
192. Stabler T, Piette JC, Chevalier X, Marini-Portugal A, Kraus VB. Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation. Arthritis Rheum. 50, 3663-3667 (2004). (Pubitemid 39488695)
193. Kawai M, Hagihara K, Hirano T et al. Sustained response to tocilizumab, anti-interleukin 6 receptor antibody, in two patients with refractory relapsing polychondritis. Rheumatology (Oxf.) 48, 318-319 (2009).
194. Collins PW, Percy CL. Advances in the understanding of acquired haemophilia A: Implications for clinical practice. Br. J. Haematol. 148, 183-194 (2010).
195. Miao CH. Immunomodulation for inhibitors in hemophilia A: The important role of Treg cells. Exp. Rev. Hematol. 3, 469-483 (2010).
196. Nishida S, Kawasaki T, Kashiwagi H et al. Successful treatment of acquired hemophilia A, complicated by chronic GVHD, with tocilizumab. Mod. Rheumatol. 21, 420-422 (2011).
197. Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood 112, 250-255 (2008).
198. Mendes D, Correia M, Barbedo M, Vaio T, Mota M. Behcet's disease - a contemporary review. J. Autoimmun. 32, 178-188 (2009).
199. Hirohata S, Oka H, Mizushima Y. Streptococcal-related antigens stimulate production of IL 6 and interferon g by T cells from patients with Behcet's disease. Cell Immunol. 140, 410-419 (1992).
200. Mege JL, Dilsen N, Sanguedolce V et al. Overproduction of monocyte derived tumor necrosis factor a, interleukin (IL) 6, IL 8 and increased neutrophil superoxide generation in Behcet's disease. A comparative study with familial Mediterranean fever and healthy subjects. J. Rheumatol. 20, 1544-1549 (1993). (Pubitemid 24027329)
201. Hirohata S, Isshi K, Oguchi H et al. Cerebrospinal fluid interleukin 6 in progressive Neuro-Behcet's syndrome. Clin. Immunol. Immunopathol. 82, 12-17 (1997). (Pubitemid 27049067)
202. Kulaber A, Tugal-Tutkun I, Sibel P et al. Pro-inflammatory cellular immune response in Behcet's disease. Rheumatol. Int. 27, 1113-1118 (2007). (Pubitemid 47373949)
203. Hirano T, Ohguro N, Hohki S et al. A case of Behcet's disease treated with a humanized anti-interleukin 6 receptor antibody, tocilizumab. Mod. Rheumatol. doi:10.1007/ s10165-011-0497-5 (2011) (Epub ahead of print).
204. Caspi RR. A look at autoimmunity and inflammation in the eye. J. Clin. Invest. 120, 3073-3083 (2010).
205. Perez VL, Papaliodis GN, Chu D, Anzaar F, Christen W, Foster CS. Elevated levels of interleukin 6 in the vitreous fluid of patients with pars planitis and posterior uveitis: The Massachusetts eye and ear experience and review of previous studies. Ocul. Immunol. Inflamm. 12, 193-201 (2004). (Pubitemid 39424882)
206. Yoshimura T, Sonoda K, Ohguro N et al. Involvement of Th17 cells and the effect of anti-IL 6 therapy in autoimmune uveitis. Rheumatology (Oxf.) 48, 347-354 (2009).
207. Hohki S, Ohguro N, Haruta H et al. Blockade of interleukin 6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses. Exp. Eye Res. 91, 162-170 (2010).
208. Haruta H, Ohguro N, Fujimoto M et al. Blockade of interleukin 6 signaling suppresses not only Th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis. Invest. Ophthalmol. Vis. Sci. 52, 3264-3271 (2011).
209. McDermott MF, Aksentijevick I, Galon J et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133-144 (1999). (Pubitemid 29165896)
210. Vaitla PM, Radford PM, Tighe PJ 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 Rheum. 63, 1151-1155 (2011).
211. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918-934 (2010).
212. Steinman L. Nuanced roles of cytokines in three major human brain disorders. J. Clin. Invest. 118, 3557-3563 (2008).
213. Maimone D, Gregory S, Arnason BG, Reder AT. Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J. Neuroimmunol. 32, 67-74 (1991).
214. Navikas V, Matusevicius D, Soderstrom M et al. Increased interleukin 6 mRNA expression in blood and cerebrospinal fluid mononuclear cells in multiple sclerosis. J. Neuroimmunol. 64, 63-69 (1996). (Pubitemid 26052075)
215. Lock C, Hermans G, Pedotti R et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500-508 (2002). (Pubitemid 34546753)
216. Gijbels K, Van Damme J, Proost P et al. Interleukin 6 production in the central nervous system during experimental autoimmune encephalomyelitis. Eur. J. Immunol. 20, 233-235 (1990). (Pubitemid 20087053)
217. Serada S, Fujimoto M, Mihara M et al. IL 6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 105, 9041-9046 (2008).
218. Codarri L, Gyulveszi G, Tosevski V et al. RORgt drives production of the cytokine GM CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat. Immunol. 12, 560-567 (2011).
219. El-Behi M, Ciric B, Dai H et al. The encephalitogenicity of TH17 cells is dependent on IL 1-and IL 23-induced production of the cytokine GM CSF. Nat. Immunol. 12, 568-575 (2011).
220. Jarius S, Wildemann B. AQP4 antibodies in neuromyelitis optica: Diagnostic and pathogenetic relevance. Nat. Rev. Neurol. 6, 383-392 (2010).
221. Uzawa A, Mori M, Arai K et al. Cytokine and chemokine profiles in neuromyelitis optica: Significance of interleukin 6. Mult. Scler. 16, 1443-1452 (2010).
222. Icoz S, Tuzun E, Kurtuncu M et al. Enhanced IL 6 production in aquaporin 4 antibody positive neuromyelitis optica patients. Int. J. Neurosci. 120, 71-75 (2010).
223. Chihara N, Aranami T, Sato W et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc. Natl Acad. Sci. USA 108, 3701-3706 (2011).
224. Van Vollenhoven RF. Unresolved issues in biologic therapy for rheumatoid arthritis. Nat. Rev. Rheumatol. 7, 205-215 (2011).
225. Iwanami K, Matsumoto I, Tanaka-Watanabe Y et al. Crucial role of the interleukin 6/ interleukin 17 cytokine axis in the induction of arthritis by glucose 6 phosphate isomerase. Arthritis Rheum. 58, 754-763 (2008). (Pubitemid 351364873)
226. Fujimoto M, Serada S, Mihara M et al. Interleukin 6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses. Arthritis Rheum. 58, 3710-3719 (2008).
227. Roll P, Muhammad K, Schumann M et al. In vivo effect of the anti-interleukin 6 receptor inhibitor tocilizumab on the B cell compartment. Arthritis Rheum. 63, 1255-1264 (2011).
228. Muhammad K, Roll P, Seibold T et al. Impact of IL 6 receptor inhibition on human memory B cells in vivo: Impaired somatic hypermutation in preswitch memory B cells and modulation of mutational targeting in memory B cells. Ann. Rheum. Dis. 70(8), 1507-1510 (2011).