RA is a chronic inflammatory disease that affects the synovial tissue in multiple joints. In most patients the disease leads to joint destruction and disability. Inflammation in RA is believed to be mediated by activation of T cells, leading to activation of macrophages and fibroblast-like synoviocytes. The latter produce a variety of proinflammatory cytokines, which results in proliferation of synovial tissue associated with destruction of cartilage and bone. Tissue destruction in RA is closely related to the production of matrix metalloproteinases (MMPs) and other proteinases, which are able to degrade collagen and proteoglycans. Macrophages play a central role in the amplification of stimulatory signals and tissue destruction. Macrophages are found in the synovial lining layer, where they may be involved in protection against infection. In RA they are activated and mediate inflammation by the production of cytokines such as TNF-α, IL-1β, IL-6, IL-12, IL-15, IL-18, platelet derived growth factor and TGF. These cytokines activate fibroblast-like synoviocytes, which maintain macrophage activation by secretion of granulocyte–macrophage colony-stimulating factor, IL-8 and other soluble mediators. Fibroblast-like synoviocytes and osteoclasts invade bone and cartilage, where chondrocytes are activated to produce further proinflammatory cytokines. It is believed that TNF-α is a key cytokine controlling the production of other proinflammatory cytokines.
As a consequence various anticytokine therapies for RA have been tried in the clinic. IL-1 and TNF-α are present in relatively high amounts in synovial fluid and synovial tissue of RA patients [34
] and, as major contributors to the inflammatory and destructive manifestations of RA, they were the first cytokines to be targeted for treatment of RA. Although the natural inhibitors of IL-1 and TNF-α, namely IL-1 receptor antagonist and soluble TNF receptor, are present in rheumatoid synovium, there might not be enough to neutralize the proinflammatory actions of IL-1 and TNF-α. There appears to be an imbalance between proinflammatory and anti-inflammatory molecules in RA joints.
Following animal studies, two forms of TNF inhibitors have been used in clinical trials in RA: anti-TNF-α antibodies and soluble receptors, which bind with high affinity to TNF. A multicenter, placebo-controlled, double-blind trial in 73 patients was performed in 1994 [37
]. Patients were followed over 4 weeks. A single infusion of TNF inhibitor induced significant improvement in arthritis activity. All other clinical trials performed with agents that block TNF-α revealed significant improvement in arthritis and protection against joint destruction [38
The efficacy of recombinant human IL-1 receptor antagonist in RA patients was investigated in a 6-month, placebo-controlled, double-blind, randomized trial [43
]. A group of 472 patients with active RA received daily, subcutaneous injections of placebo or one of three doses of recombinant human IL-1 receptor antagonist. After 6 months, the patients who received the highest dose of the active treatment exhibited significant clinical improvement, and X-ray films from those patients showed fewer bone erosions as compared with patients who received placebo.
Other therapeutic targets in RA include MMPs, to prevent the destruction of cartilage and bone. Collagenase (MMP-1), stromelysin-1 (MMP-3) and MMP-13 play important roles in RA [44
]. Normal fibroblasts produce very low levels of MMP-1 and MMP-3. However, levels increase markedly in response to a variety of stimuli, such as cytokines, crystals and phagocytosis of debris [44
]. Increased amounts of MMPs are present in cartilage from patients with RA, and the level of enzyme activity correlates with the severity of the lesion. Similarly, synovial fluid from patients with RA exhibits an increase in MMP levels [48
]. Natural inhibitors that are specific for MMPs exist; they are produced locally by chondrocytes and fibroblast-like synoviocytes, and are termed 'tissue inhibitors of metalloproteinases' (TIMPs). It is likely that joint destruction is in part due to a local imbalance between activated MMPs and TIMPs [44
]. One study investigated intraperitoneal administration of TIMP-1 in the collagen-induced arthritis mouse model [51
] and showed a significant reduction in the severity of disease as compared with untreated control aminals. Several chemotherapeutic agents, antibiotics and synthetic peptides can inhibit the activity of MMPs. Despite promising preclinical data, MMP inhibitors have not been used extensively in the clinic [46
]. Minocycline – an antibiotic that can inhibit MMP activity – has been evaluated in three well controlled trials in RA [52
]. All trials showed some improvement in the patient groups treated with minocycline as compared with placebo.