Interleukin-1, rheumatoid arthritis

Kraan MC, Patel DD, Haringman JJ, et al. The development of clinical signs of rheumatoid synovial inflammation is associated with increased synthesis of the chemokine CXCL8 (interleukin-8). Arthritis Res 2001 3(1) 65-71. 

Nissinen R, Leirisalo-Repo M, Tiittanen M, et al. CCR3, CCR5, interleukin 4, and interferon-gamma expression on synovial and peripheral T cells and monocytes in patients with rheumatoid arthritis. J Rheumatol 2003 30(9) 1928-1934. 

Interleukin 1 (IL-1) is produced mainly by activated monocytes-macropha-ges, and its principal action is to stimulate thymocytes. A pleiotropic cytokine, IL-1 induces the expression of a large diversity of cytokines such as IL-6, leukaemia inhibitory factor (LIF), and other proinflammatory molecules (Di-marello 1994). IL-1 and TNF-a carry out as part of their function increasing the expression of NF-/cB and JNK (c-Jun N-terminal kinase). The importance of IL-1 in OCS is demonstrated because the IL-1-receptor-deficient mouse is resistant to ovariectomy (OVX)-induced bone loss (Lorenzo et al. 1998). The importance in pathological bone loss is also illustrated by the fact that treatment with IL-1 receptor antagonist slows down bone erosion for patients affected with rheumatoid arthritis (Kwan et al. 2004). IL-1 increases osteoclast differentiation rather than mature osteoclast activity, and infusion of IL-1 into mice induces hypercalcemia and bone resorption. Finally, IL-1 and TNF-a... 

Brennan, F. M., Zachariae, C. O. C., Chantry, D., Larsen, C. G., Turner, M., Maini, R. N., Matsushima, K., Feldmann, M. (1990). Detection of Interleukin 8 biological activity in synovial fluids from patients with rheumatoid arthritis and production of Interleukin 8 mRNA by isolated synovial cells. Eur. J. Immunol. 20,2141-4. 

Langner J Gene expression induced by interleukin-17 in fibroblast-like synoviocytes of patients with rheumatoid arthritis upregulation of hyaluronan-binding protein TSG-6. Arthritis Res Ther 2003 5 R186-R192. 

Chabaud M, Garnero P, Dayer JM, Guerne PA, Fossiez F, Miossec P Contribution of interleukin 17 to synovium matrix destruction in rheumatoid arthritis. Cytokine 2000 12 1092-1099. 

Barrera, P., Joosten, L. A., den Broeder, A. A., van de Putte, L. B., van Riel, P. L., and van den Berg, W. B. (2001) Effects of treatment with a fully human anti-tumour necrosis factor alpha monoclonal antibody on the local and systemic homeostasis of interleukin 1 and TNFalpha in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 60, 660-669. 

Anakinra is the first biologic drug that has been developed specifically as an interleukin (IL)-l receptor antagonist and is derived from an endogenous IL-IRa. The drug blocks the activity of IL-1 in synovial joints, reducing the infiammatory and joint destructive processes associated with rheumatoid arthritis. It is administered subcutaneously and is generally well tolerated. Injection-site reactions are the most commonly reported adverse event. 

Mechanism of Action An interleukin-1 (IL-1) receptor antagonistthatblocksthebind-ing of IL 1, a protein that is a major mediator of joint disease and is present in excess amounts inpatients with rheumatoid arthritis. Therapeutic Effect Inhibits the inflammatory response. 

Sulfasalazine is metabolized to sulfapyridine and 5-aminosalicylic acid, and it is thought that the sulfapyridine is probably the active moiety when treating rheumatoid arthritis (unlike inflammatory bowel disease, see Chapter 62). Some authorities believe that the parent compound, sulfasalazine, also has an effect. In treated arthritis patients, IgA and IgM rheumatoid factor production are decreased. Suppression ofT-cell responses to concanavalin and inhibition of in vitro -cell proliferation have also been documented. In vitro studies have shown that sulfasalazine or its metabolites inhibit the release of inflammatory cytokines, including those produced by monocytes or macrophages, eg, interleukins-1, -6, and -12, and TNF-a. These findings suggest a possible mechanism for the clinical efficacy of sulfasalazine in rheumatoid arthritis. 

Cytokines and antagonists (2—4), intercellular proteins produced by immune cells, play an important role in the regulation of immune responses. Cytokines are present in a variety of tissues under normal conditions. Through insufficient or excessive production, these macromolecules can mediate chronic inflammatory diseases. An inability to respond to cytokines, eg, interleukin 1 (IL-1) or interleukin 2 (IL-2), may lead to an immunosuppressive state, whereas over-production can result in severe shock, autoimmune disease, or immunopathological conditions, such as leukemia and rheumatoid arthritis (RA). Specific communications between immune cells are constantly modulated by naturally occurring inhibitors. 

In addition to direct effects on genes regulating inflammation, glucocorticoids also inhibit the transcription factors that initiate synthesis of pro-inflammatory cytokines (e.g., interleukin-1, tumor necrosis factor), enzymes (e.g., COX-2, nitric oxide synthase), and receptor proteins (e.g., natural killer receptors).17,87,89 Glucocorticoids may also exert some of their effects via a membrane-bound receptor that regulates activity of macrophages, eosinophils, T lymphocytes, and several other types of cells involved in the inflammatory response.89 Consequently, glucocorticoids affect many aspects of inflammation, and their powerful anti-inflammatory effects in rheumatoid arthritis result from their ability to blunt various cellular and chemical components of the inflammatory response. 

Anakinra (Kineret) blocks the effects of interleukin-1 on joint tissues. Like TNF-a, interleukin-1 is a cytokine that promotes inflammation and joint destruction in rheumatoid arthritis.23,36 By blocking interleukin-1 receptors on joint tissues, anakinra prevents the destructive events mediated by this cytokine. This drug appears to be moderately effective in limiting the progression of rheumatoid arthritis, and it is generally well tolerated.36 Hence, anakinra is another option that can be used alone or in combination with other DMARDs such as methotrexate.23... 

Cohen SB. The use of anakinra, an interleukin-1 receptor antagonist, in the treatment of rheumatoid arthritis. Rheum Dis Clin North Am. 2004 30 365-380. 

Furst DE. Anakinra review of recombinant human interleukin-I receptor antagonist in the treatment of rheumatoid arthritis. Clin Ther. 2004 26 1960-1975. 

Young, D. A., Hegen, M., Ma, H. L., Whitters, M. J., Albert, L. M., Lowe, L., et al. (2007) Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum 56, 1152-1163. 

Arend, W. P., and Dayer, J. M. (1995). Inhibition of the production and effects of interleukin-1 and tumor necrosis factor a in rheumatoid arthritis. Arthritis Rheum. 38, 151-160. 

Bresnihan, B., Alvaro-Gracia, J. M., Cobby, M., Doherty, M., Domljan, Z., Emery, P., Nuki, G., Pavelka, K, Rau, R., Rozman, B., Watt, I., Williams, B., Aitchison, R., McCabe, D., and Musikic, P. (1998). Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 41, 2196-2204. 

Wendling, D., Racadot, E., and Widenes, J. (1993). Treatment of severe rheumatoid arthritis by anti-interleukin 6 monoclonal antibody. / Rheumatol. 20, 259-262. 

Tosyliminothiochromone-2-carboxylates 585 are inhibitors of interleukin-1 and are thus useful for the treatment of rheumatoid arthritis, multiple sclerosis, diabetes mellitus, atherosclerosis and septic shock <1995WO9514670>, and thiochromones possessing a sulfamoyloxy side chain at either C-6 or C-7 behave as steroid sulfatase inhibitors < 1999W O9952890>. 

Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN. Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum 1998 41 1258-1265. 

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