Abstract
Therapy of rheumatoid arthritis (RA) aims at interfering with the disease process, namely inflammation and destruction of the joints, and thus at preventing long-term disability. Proinflammatory cytokines play a decisive role in the generation of the inflammatory and destructive response. Aside from traditional disease-modifying anti-rheumatic drugs and tumor necrosis factor-blocking agents, a number of targeted therapies are currently in evaluation, such as abatacept (interfering with co-stimulation), rituximab (an anti-B-cell agent) and tocilizumab (an anti-interleukin-6 receptor antibody). In phase II trials, all these agents have resulted in significant clinical improvement, and phase III trials have been partly completed with similar results and are partly on the way. Because none of these agents lead to good clinical responses in all patients and many patients have only relatively low degrees of response, it will still be a challenge to find the best therapeutic paths to combat the “inflammatory house of cards” of RA.
Similar content being viewed by others
References
Smolen, J. S., Breedveld, F. C., Eberl, G., et al. (1995), Arthritis Rheum. 38(1), 38–43.
Weichselbaum, A. (1878), Arch. Pathol. Anat. Physiol. Klin. Med. (Virchow’s Arch.) 73, 461–475.
Felson, D. T., Anderson, J. J., Boers, M., et al. (1995), Arthritis Rheum. 38, 727–735.
Prevoo, M. L. L., van’t Hof, M. A., Kuper, H. H., van de Putte, L. B. A., and van Riel, P. L. C. M. (1995), Arthritis Rheum. 38, 44–48.
Smolen, J. S., Breedveld, F. C., Schiff, M. H., et al. (2003), Rheumatology 42, 244–257.
Aletaha, D., Nell, V. P. K., Stamm, T., et al. (2005), Arthritus Res. Ther. 7, R796-R806.
van der Heijde, D., Simon, L., Smolen, J., et al. (2002), Arthritis Rheum. 47(2), 215–218.
Fries, J. F., Spitz, P. W., Kraines, R. G., and Holman, H. R. (1980), Arthritis Rheum. 23, 137–145.
Drossaers-Bakker, K. W., de Buck, M., van Zeben, D., Zwinderman, A. H., Breedveld, F. C., and Hazes, J. M. (1999), Arthritis Rheum. 42, 1854–1860.
Smolen, J. S., and Aletaha, D. (2004), Ann. Rheum. Dis. 63, 221–225.
Welsing, P. M., van Gestel, A. M., Swinkels, H. L., Kiemeney, L. A., and van Riel, P. L. (2001), Arthritis Rheum. 44(9), 2009–2017.
Smolen, J. S. and Steiner, G. (2003), Nat. Rev. Drug Discov. 2, 473–488.
Firestein, G. S. (2003), Nature 423[356], 361.
Partsch, G., Steiner, G., Leeb, B. F., Dunky, A., Broll, H., and Smolen, J. S. (1997), J. Rheumatol. 24, 518–523.
Steiner, G., Tohidast-Akrad, M., Witzmann, G., et al. (1999), Rheumatology (Oxford) 38, 202–213.
Firestein, G. S., Alvaro-Gracia, J. M., and Maki, R. (1990), J. Immunol. 144, 3347–3353.
Gregersen, P. K., Silver, J., and Winchester, R. J. (1987), Arthritis Rheum. 30, 1205–1213.
Steiner, G. and Smolen, J. S. (2002), Arthritis Res. 4(Suppl. 2), S1-S5.
Mattey, D. L., Dawes, P. T., Clarke, S., et al. (2002), Arthritis Rheum. 47, 403–407.
Ishikawa, H., Smiley, J. D., and Ziff, M. (1975), Arthritis Rheum. 18(6), 563–576.
Neumann, E., Barnum, S. R., Tarner, I. H., et al. (2002), Arthritis Rheum. 46(4), 934–945.
Debets, J. M., Van der Linden, C. J., Dieteren, I. E., Leeuwenberg, J. F., and Buurman, W. A. (1988), J. Immunol. 141, 1197–1201.
Keffer, J., Probert, L., Cazlaris, H., et al. (1991), EMBO J. 10, 4025–4031.
Horai, R., Saijo, S., Tanioka, H., et al. (2000), J. Exp. Med. 191(2), 313–320.
Takagi, N., Mihara, M., Moriya, Y., et al. (1998), Arthritis Rheum. 41, 2117–2121.
Brennan, F. M., Chantry, D., Jackson, A., Maini, R., and Feldmann, M. (1989), Lancet 2, 244–247.
Abramson, S. B. and Amin, A. (2002), Rheumatology (Oxford) 41(9), 972–980.
McInnes, I. B., Leung, B. P., Sturrock, R. D., Field, M., and Liew, F. Y. (1997), Nat. Med. 3, 189–195.
Phillip, R. and Epstein, L. B. (1986), Nature 323, 86–89.
Gravallese, E. M., Harada, Y., Wang, J. T., Gorn, A. H., Thornhill, T. S., and Goldring, S. R. (1998), Am. J. Pathol. 152, 943–951.
Redlich, K., Hayer, S., Ricci, R., et al. (2002), J. Clin. Invest. 110(10), 1419–1427.
Pettit, A. R., Ji, H., von Stechow, D., et al. (2001), Am. J. Pathol. 159(5), 1689–1699.
Redlich, K., Hayer, S., Maier, A., et al. (2002), Arthritis Rheum. 46, 785–792.
Teitelbaum, S. L. (2000), Science 289, 1504–1508.
Kong, Y. Y., Feige, U., Sarosi, I., et al. (1999), Nature 402(6759), 304–309.
Abu-Amer, Y., Ross, F. P., Edwards, J., and Teitelbaum, S. L. (1997), J. Clin. Invest. 100, 1557–1565.
Kobayashi, K., Takahashi, N., Jimi, E., et al. (2000), J. Exp. Med. 191, 275–286.
Kotake, S., Sato, K., Kim, K. J., et al. (1996), J. Bone Miner. Res. 11, 88–95.
Lam, J., Takeshita, S., Barker, J. E., Kanagawa, O., Ross, F. P., and Teitelbaum, S. L. (2000), J. Clin. Invest. 106, 1481–1488.
Ma, T., Miyanishi, K., Suen, A., et al. (2004), Cytokine 26, 138–144.
Udagawa, N. (2002), Biogerontology 3, 79–83.
Goldring, S. R. (2003), Rheumatology 42(Suppl. 2), 11–16.
Lee, Z. H., Lee, S. E., Kim, C. W., et al. (2002), J. Biochem. (Tokyo) 131, 161–166.
Kudo, O., Sabokbar, A., Pocock, A., Itonaga, I., Fujikawa, Y., and Athanasou, N. A. (2003), Blood 32, 1–7.
Devlin, R. D., Reddy, S. V., Savino, R., Ciliberto, G., and Roodman, G. D. (1998), J. Bone Miner. Res. 13, 393–399.
Ragab, A. A., Nalepka, J. L., Bi, Y., and Greenfield, E. M. (2002), Am. J. Physiol. Cell Physiol. 283, C679-C687.
Bathon, J. M., Martin, R. W., Fleischmann, R. M., et al. (2000), N. Engl. J. Med. 343(22), 1586–1593.
Elliott, M. J., Maini, R. N., Feldmann, M., et al. (1994), Lancet 344(8930), 1105–1110.
Keystone, E., Kavanaugh, A. F., Sharp, J., et al. (2002), Arthritis Rheum. 46(Suppl.), S205.
Lipsky, P. E., Van der Heijde, D. M., St. Clair, E. W., et al. (2000), N. Engl. J. Med. 343(22), 1594–1602.
Maini, R. N., Breedveld, F. C., Kalden, J. R., et al. (1998), Arthritis Rheum. 41(9), 1552–1563.
Moreland, L. W., Baumgartner, S. W., Schiff, M. H., et al. (1997), N. Engl. J. Med. 337(3), 141–147.
St. Clair, E.W., van der Heijde, D. M., Smolen, J. S., et al. (2004), Arthritis Rheum. 50, 3432–3443.
Weinblatt, M. E., Kremer, J. M., Bankhurst, A. D., et al. (1999), N. Engl. J. Med. 340(4), 253–259.
Zwerina, J., Redlich, K., Kollias, G., Smolen, J. S., and Schett, G. (2004), Arthritis Rheum. 50, 177–190.
Smolen, J. S., Han, C., Bala, M., et al. (2005), Arthritis Rheum. 52, 1020–1030.
Bresnihan, B., Alvaro-Gracia, J. M., Cobby, M., et al. (1998), Arthritis Rheum. 41(12), 2196–2204.
Burger, D., Chicheportiche, R., Giri, J. G., and Dayer, J. M. (1995), J. Clin. Invest. 96(1), 38–41.
Pavelka, K., Kuba, V., Moeller Rasmussen, J., et al. (2002), American College of Rheumatology 66th Annual Scientific Meeting, Late breaking Abstract.
Seitz, M., Zwicker, M., and Loetscher, P. (1998), Arthritis Rheum. 41(11), 2032–2038.
Klareskog, L., van der Heijde, D., de Jager, J. P., et al. (2004), Lancet 363, 675–681.
Hawkins, P. N., Lachmann, H. J., and McDermott, M. F. (2003), N. Engl. J. Med. 348, 2583–2584.
Naka, T., Nishimoto, N., and Kishimoto, T. (2002), Arthritis Res. 4(Suppl. 3), S233-S242.
Nishimoto, N., Yoshizaki, K., and Kishimoto, T. (2003), Interleukin-6. In: Smolen, J. S. and Lipsky, P. E., eds. Targeted Therapies in Rheumatology. London-New York: Martin Dunitz, 231–241.
Wendling, D., Racadot, E., and Wijdenes, J. (1993), J. Rheumatol. 20(2), 259–262.
Choy, E. H., Isenberg, D. A., Garrood, T., et al. (2002), Arthritis Rheum. 46(12), 3143–3150.
Nishimoto, N., Yoshizaki, K., Maeda, K., et al. (2003), J. Rheumatol. 30, 1426–1435.
Nishimoto, N., Yoshizaki, K., Miyasaka, N., et al. (2004), Arthritis Rheum. 50, 1761–1769.
Maini, R. and The Charisma Study group. (2003), Ann. Rheum. Dis. 62(Suppl. 1), OP002 (Abstract).
Redlich, K., Schett, G., Steiner, G., Hayer, S., Wagner, E. F., and Smolen, J. S. (2003), Arthritis Rheum. 48, 3308–3319.
Edwards, J. C., Szczepanski, L., Szechinski, J., et al. (2004), N. Engl. J. Med. 350, 2572–2581.
Kremer, J. M., Westhovens, R., Leon, M., et al. (2003), N. Engl. J. Med. 349, 1907–1915.
Redlich, K., Görtz, B., Hayer, S., et al. (2004), Am. J. Pathol. 164, 543–555.
Aletaha, D. and Smolen, J. S. (2004), Ann. Rheum. Dis. 63, 221–225.
Smolen, J. S., Sokka, T., Pincus, T., and Breedveld, F. C. (2003), Clin. Exp. Rheumatol. 21(Suppl. 31), S209, S210.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Smolen, J.S., Redlich, K., Zwerina, J. et al. Pro-inflammatory cytokines in rheumatoid arthritis. Clinic Rev Allerg Immunol 28, 239–248 (2005). https://doi.org/10.1385/CRIAI:28:3:239
Issue Date:
DOI: https://doi.org/10.1385/CRIAI:28:3:239