Abstract
Systemic-onset juvenile idiopathic arthritis (sJIA) is a severe and steroid-dependent disease of unknown etiology that sometimes progresses to a fatal disease known as the macrophage activation syndrome. The investigation of inflammatory cytokines and receptor levels revealed an increase in interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R) in serum of patients with active sJIA. The clinical symptoms and signs of the disease are presumably attributable to the continuous elevation of IL-6 and sIL-6R levels in serum. The characteristic fever spikes parallel IL-6 levels. In children, a long-term exposure to high levels of IL-6 causes severe growth impairment, as suggested by recently established studies of IL-6 transgenic mice.
The biological functions of IL-6 are expressed through the binding of IL-6/IL-6R complex to gp130. The administration of tocilizumab (a recombinant humanized anti-IL-6R monoclonal antibody) exerts its action by preventing the binding of IL-6 to its receptor and, therefore, preventing the activation of gp130.
After a few cases of compassionate use of tocilizumab, phase I and II studies of tocilizumab were conducted in children with sJIA, revealing that tocilizumab abruptly reduced the typical symptoms of inflammation and improved laboratory abnormalities. This article describes the experience in Japan regarding the treatment of sJIA with tocilizumab and supports the hypothesis that high levels of IL-6 may play an important role in the pathogenesis and maintenance of this disease. A confirmation of the role of tocilizumab in the treatment of sJIA will be provided by the results of the ongoing phase III study in Japan.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Petty, R. E., Southwood, T. R., Baum, J., et al. (1998), J. Rheumatol. 25, 1991–1994.
Cassidy, J. T. and Petty, R. E. Textbook of Pediatric Rheumatology. 4th ed. Philadelphia: W.B. Saunders, 2001.
Sawhney, S., Woo, P., Murray, K. J. (2001), Arch. Dis. Child 85, 421–426.
Yokota, S. (2003), Curr. Opin. Rheumatol. 15, 581–586.
Packham, J. C., Hall, M. A., and Pimm, T. J. (2002), Rheumatology (Oxford) 41, 1444–1449.
Zak, M., Muller, J., and Karup Pedersen, F. (1999), Horm. Res. 52, 80–85.
De Benedetti, F. and Martini, A. (1998), J. Rheumatol. 25, 203–207.
Taga, T. and Kishimoto, T. (1997), Annu. Rev. Immunol. 15, 797–819.
Rooney, M., David, J., Symons, J., Di Giovine, F., Varsani, H., and Woo, P. (1995), Br. J. Rheumatol. 34, 454–460.
Lieskovska, J., Guo, D., and Derman, E. (2003), Growth Horm. IGF Res. 13, 26–35.
Nishimoto, N., Sasai, M., Shima, Y., et al. (2000), Blood 95, 56–61.
Iwamoto, M., Nara, H., Hirata, D., Minota, S., Nishimoto, N., and Yoshizaki, K. (2002), Arthritis Rheum. 46, 3388,3389.
Choy, E. H., Isenberg, D. A., Garrood, T., et al. (2002), Arthritis Rheum. 46, 3143–3150.
Nishimoto, N., Yoshizaki, K., Maeda, K., et al. (2003), J. Rheumatol. 30, 1426–1435.
Mouy, R., Stephan, J. L., Pillet, P., Haddad, E., Hubert, P., Prieur, A. M. (1996), J. Pediatr. 129, 750–754.
Taga, T. 1997, Annu. Rev. Immunol. 15, 797–819.
Ishihara, K. and Hirano, T. (2002), Cytokine Growth Rev. 13, 357–368.
Hirota, H., Yoshida, K., Kishimoto, T., and Taga, T. (1995), Proc. Natl. Acad. Sci. USA 92, 4862–4866.
Prieur, A. M., Roux-Lombard, P., Dayer, J. M. (1996), Rev. Rheum. 63, 163–170.
Harre, E. M., Roth, J., Pehl, U., Kueth, M., Gerstberger, R., and Hubschle, T. (2002), J. Appl. Physiol. 92, 2657–2666.
Jenkins, B. J., Quilici, C., Roberts, A. W., Grail, D., Dunn, A. R., and Ernst, M. (2002), Exp. Hematol. 30, 1248–1256.
De Benedetti, F., Massa, M., Robbioni, P., Ravelli, A., Burgio, G. R., and Martini, A. (1991), Arthritis Rheum. 34, 1158–1163.
De Benedetti, F., Massa, M., Pignatti, O., Albani, S., Novick, D., and Martini, A. (1994), J. Clin. Invest. 93, 2114–2119.
Woo, P. (2002), Curr. Rheumatol. Rep. 4, 452–457.
Rooney, M., David, J., Symons, J., Di Giovine, F., Varsani, H., and Woo P. (1995), Br. J. Rheumatol. 34, 454–460.
Keul, R., Heinrich, P. C., Muller-Newen, G., Muller, K., and Woo, P. A (1998), Cytokine 10, 729–734.
Lieskovska, J., Guo, D., and Derman, E. (2002), Growth Horm. IGF Res. 12, 388–398.
Lieskovska, J., Guo, D., and Derman, E. (2003), Growth Horm. IGF Res. 13, 26–35.
Sato, K., Tsuchiya, M., Saldanha, J., Koishihara, Y., Ohsugi, Y., and Kishimoto, T. (1993), Cancer Res. 53, 851–856.
Nishimoto, N., Yoshizaki, K., Miyasaka, N., et al. (2004), Arthritis Rheum. 50(6), 1761–1769.
Yokota, S. (2003), Curr. Opin. Rheumatol. 15, 581–586.
Yokota, S., Miyamae, T., Imagawa, T., et al. (2005), Arthritis Rheum. 52, 818–825.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yokota, S., Miyamae, T., Imagawa, T. et al. Clinical study of tocilizumab in children with systemic-onset juvenile idiopathic arthritis. Clinic Rev Allerg Immunol 28, 231–237 (2005). https://doi.org/10.1385/CRIAI:28:3:231
Issue Date:
DOI: https://doi.org/10.1385/CRIAI:28:3:231