Abatacept In Focus

摘要

There have been considerable advances in the treatment of rheumatoid arthritis. However, many patients are found to be refractory to traditional disease-modifying antirheumatic drugs and the newer anti-cytokine therapies. Agents such as abatacept and rituximab now offer exciting new options for patients, including those who, until recently, had limited treatment options. Randomized, multinational, double-blind, placebo-controlled trials have assessed the efficacy and safety of abatacept in patients with active RA, who are methotrexate (MTX) and tumor necrosis factor (TNF) antagonist inadequate responders. Results from these trials have shown that abatacept provides significant clinical and health-related quality of life benefits in both MTX and TNF antagonist inadequate responders. Abatacept also slowed the progression of structural damage compared with placebo/MTX alone. In addition to these clinical benefits, a fixed dose of abatacept has demonstrated a consistent safety and tolerability profile. Longer-term data will be necessary to confirm the observations seen to date. Introduction Rheumatoid arthritis (RA) treatment is entering a new era, targeting the immunopathology of the disease with increased specificity and selectivity beyond that observed with traditional disease-modifying antirheumatic drugs (DMARDs). Several new agents have proven to be effective in many patients who previously demonstrated an inadequate or failing response to traditional DMARDs, such as methotrexate (MTX). Of the currently approved biologic therapies, the majority target pro-inflammatory cytokines involved in the downstream processes of the RA immune cascade. These include the tumor necrosis factor (TNF) antagonists, etanercept,1 infliximab2 and adalimumab,3 and the interleukin (IL)-1 antagonist, anakinra.4 These agents, often used in combination with the non-biologic DMARD, MTX, have helped deliver improvements in signs and symptoms of the disease, including radiographic outcomes, as well as improvements in health-related quality of life (HRQoL).5 Despite the efficacy of agents such as TNF antagonists, approximately 20–40% of patients may not respond to anti-cytokine therapy.6 Other patients may lose their response to treatment over time; in some patients, this is due to the formation of antibodies against the biologic agent.7, 8 Patients who are refractory to MTX and/or anti-cytokine agents had limited options until recently. However, the investigation of earlier events in RA immunopathogenesis as potential therapeutic targets, has led to developments in the RA armamentarium.This review will give an overview of the two newest biologic agents approved for the treatment of RA, with focus on the first-in-class therapy, abatacept. New therapeutic targets Rheumatoid arthritis is a complex autoimmune disease, involving multiple immune pathways and cell types.9 The immunopathology of RA involves activated T cells, which mediate immune processes within the synovium, resulting in the release of cytokines, autoantibodies and other inflammatory mediators from macrophages, T cells and B cells.10 These, in turn, stimulate the downstream release of further inflammatory mediators resulting in the direct attack upon joint structures by macrophage- and fibroblast-like synoviocytes and other cells.10 In order to become fully activated, a T cell must not only recognize an antigen that has been processed and presented by an antigen presenting cell (APC), but also receive a co-stimulatory signal.11 One of the best characterized co-stimulatory pathways is the engagement of CD80/CD86 on APCs with CD28 on T cells.11 Another co-stimulatory pathway involves the CD40 ligand, in which T cells interact with B cells via the CD40:CD40L pathway, thereby facilitating B-cell activation and the production of autoantibodies.12 T-cell activation is also downregulated by co-stimulatory pathways. The CD28-mediated T-cell activation is downregulated by expression of endogenous cyto