title: 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.
abstract: Interleukin-6 (IL-6) plays pathologic roles in immune-inflammatory diseases such as rheumatoid arthritis (RA) and Castleman disease. By inhibiting IL-6 receptors (IL-6Rs), tocilizumab (a humanized anti-IL-6R antibody) ameliorates the symptoms of these diseases and normalizes acute-phase proteins, including C-reactive protein (CRP). We found that tocilizumab treatment increased serum levels of IL-6 and soluble IL-6R (sIL-6R). To investigate the pathologic significance of these increases, we analyzed the kinetics of serum IL-6 and sIL-6R and the proportion of sIL-6R saturated with tocilizumab after tocilizumab administration in patients with RA and Castleman disease and then compared the results with the CRP values. Serum IL-6 and sIL-6R markedly increased after tocilizumab administration in both RA and Castleman disease. As long as free tocilizumab was detectable, sIL-6R was saturated with tocilizumab and IL-6 signaling was completely inhibited. We concluded that it is likely that sIL-6R increased because its elimination half-life was prolonged by the formation of tocilizumab/sIL-6R immune complex, and that free serum IL-6 increased because IL-6R-mediated consumption of IL-6 was inhibited by the unavailability of tocilizumab-free IL-6R. We also concluded that the increased level of free IL-6 during tocilizumab treatment closely reflects the actual endogenous IL-6 production and true disease activity.
authors.affiliation: Laboratory of Immune Regulation, Graduate School of Frontier Bioscience, Osaka University, Osaka, Japan. norihiro@fbs.osaka-u.ac.jp
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nishimoto
authors.forename: Kimio
authors.initials: K
authors.lastname: Terao
authors.forename: Toru
authors.initials: T
authors.lastname: Mima
authors.forename: Hideko
authors.initials: H
authors.lastname: Nakahara
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Takagi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kakehi
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy; D002097:C-Reactive Protein / Q000032:analysis; D005871:Castleman Disease / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006207:Half-Life; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D007700:Kinetics; D008297:Male; D019947:Receptors, Interleukin-6 / Q000097:blood*; D015398:Signal Transduction / Q000187:drug effects; D016037:Single-Blind Method
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000936:Antigen-Antibody Complex; C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D002097:C-Reactive Protein; C502936:tocilizumab