Anti-cytokine therapy in chronic destructive arthritis

Abstract

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are considered to be master cytokines in chronic, destructive arthritis. Therapeutic approaches in rheumatoid arthritis (RA) patients have so far focused mainly on TNF, which is a major inflammatory mediator in RA and a potent inducer of IL-1; anti-TNF therapy shows great efficacy in RA patients. However, it is not effective in all patients, nor does it fully control the arthritic process in affected joints of good responders. Directed therapy for IL-1, with IL-1 receptor antagonist, mainly reduces erosions and is marginally anti-inflammatory. It is as yet unclear whether the limited effect is akin to the RA process or linked to suboptimal blocking of IL-1. Analysis of cytokine patterns in early synovial biopsies of RA patients reveals a marked heterogeneity, with variable staining of TNF and IL-1 beta, indicative of TNF-independent IL-1 production in at least some patients. Evidence for this pathway emerged from experimental arthritises in rodents, and is summarized in this review. If elements of the models apply to the arthritic process in RA patients, it is necessary to block IL-1 beta in addition to TNF.

Figure 1

Simplified view of potential pathways of TNF overproduction. Deranged synoviocyte-mediated TNF production might initiate a TNF–IL-1 cascade. Note that general triggering of T cells or macrophages, as studied in arthritis models, gives rise to both TNF and IL-1, with considerable TNF-independent IL-1 production, and skewing to IL-1 when immune complexes are used as the stimulus.

Figure 2

Amplifying elements in erosive processes. Immune complexes (IC's) generate high levels of IL-1 and, through Fc interaction, also provide additional mediators to activate pro-metalloproteinases (MMPs). T cells might be involved in enhanced bone erosion through TNF, IL-17 and the direct production of osteoprotegerin ligand (OPG-L). T cells come close to the bone at erosion sites. IL-17 also promotes cartilage erosion; a role for OPG-L in this remains to be determined. Fc Rec, Fc receptor; LT, lymphotoxin; PMN, polymorphonuclear cell.