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 Blood, 15 November 2008, Vol. 112, No. 10, pp. 3959-3964.
Prepublished online as a Blood First Edition Paper on September 10, 2008; DOI 10.1182/blood-2008-05-155846.

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CHEMOKINES, CYTOKINES, AND INTERLEUKINS

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

Norihiro Nishimoto1, Kimio Terao2, Toru Mima1, Hideko Nakahara1,3, Nobuhiro Takagi2, and Takahiro Kakehi2

1 Laboratory of Immune Regulation, Graduate School of Frontier Bioscience, Osaka University, Osaka; 2 Chugai Pharmaceutical Company, Tokyo; and 3 NTT West Osaka Hospital, Osaka, Japan

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.


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