Targeting IL1

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Studies in animal models of arthritis have demonstrated the therapeutic potential of IL-1 blockade (van den Berg 2000). The dominance of IL-1P over IL-1a in the pathogenesis of collagen-induced arthritis has been demonstrated in studies of cytokine blockade (Joosten et al. 1996; Williams et al. 2000b) and confirmed by the finding that IL-1P gene knock-out mice show markedly reduced levels of inflammation following immunization with type II collagen. The use of genetically modified mice has also helped to confirm the physiological significance of IL-1ra as deletion of this gene in BALB/c mice results in the spontaneous development of arthritis (Horai et al. 2000).

Proof of principle for IL-1 blockade in rheumatoid arthritis has been established using once-daily, subcu-taneously administered IL-1 receptor antagonist (IL-1ra: anakinra), a naturally occurring inhibitor of IL-1 (Bresnihan et al. 1998). In a phase II placebo-controlled study, 472 patients received daily subcutaneous injections of placebo or one of three different doses of human IL-1ra; 30 mg, 75 mg, or 150 mg. Improvements were observed in all individual clinical parameters, including swollen and tender joint counts, pain score, duration of early morning stiffness, patient assessment of disease activity, and investigator assessment of disease activity, although no clear dose-response relationship was observed. At the end of the study period, significantly more patients on the higher dosage schedule achieved improvement at the ACR 20 % response level than placebo-treated patients. There were also significant reductions in ESR in all active treatment groups. However, the overall magnitude of clinical responses and changes in acute phase reactants were relatively modest, at 20-35% from baseline, as compared with those reported for TNF- blockade. These observations do not necessarily imply that IL-1 is not a good target for therapy in rheumatoid arthritis, but may reflect pharmacokinetic challenges for IL-1ra as a means to achieve IL-1 blockade. For example, the kidneys excrete IL-1ra rapidly and therapeutic levels persist for a few hours only. Furthermore, IL-1 receptors are ubiquitously expressed and have a rapid turnover. Nonetheless, daily administration of human IL-1ra is reported to have the benefit of disease modification, with a reduction in the rate of radiographic damage in patients receiving active drug as compared with those on placebo. However, the reduction only reached statistical significance in patients receiving the two lower doses.

The efficacy and safety of anakinra in combination with methotrexate has been tested in a multi-centre randomized double-blind placebo-controlled trial (Cohen et al. 2002). In this study, patients with moderate to severely active rheumatoid arthritis despite methotrexate therapy for six consecutive months, with stable doses for more than 3 months, were randomized to receive either single daily placebo injections or one of five different doses of anakinra. At week 12, the ACR 20 responses in the five active treatment plus metho-trexate groups demonstrated a statistically significant dose-response relationship over that in the placebo plus methotrexate group, and these responses were enduring through 24 weeks. The combination of anakinra and methotrexate was safe and well tolerated.

Although IL-1 blockade using anakinra in combination with methotrexate has been shown to be clinically superior to methotrexate therapy alone, the disappointing magnitude of clinical efficacy as compared with that seen with TNF inhibitors has prompted the exploration of alternative strategies for exploring IL-1. These include the use of monoclonal antibodies with specificity for IL-1 , and the IL-1 trap, an engineered protein comprising the two high-affinity signalling chains of the cell surface IL-1 receptor, linked by the Fc portion of IgG-1. Preliminary results presented at meetings demonstrate efficacy for the IL-1 trap at the higher dose tested.

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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