When anti-CCR2 treatment for arthritis strikes out.
When anti-CCR2 treatment for arthritis strikes out.
复制标题
当针对关节炎的抗 CCR2 治疗开始发挥作用时。
DOI：
10.1002/art.30104
复制
发表时间：
2011
影响因子：
--
通讯作者：
Lolis,Elias
中科院分区：
文献类型：
--
作者：
Cho,Yoonsang;Lolis,Elias
About 1% of the general population has rheumatoid arthritis (RA) or another form of arthritis. Although there are many medications available for treating the symptoms of arthritis, including nonsteroidal antiinflammatory drugs, glucocorticoids, disease-modifying antirheumatic drugs (DMARDs), biologic agents, and various combinations of these categories, there is no cure. The medications that have a significant impact in the most severe cases are biologic therapies, such as tumor necrosis factor α (TNFα) blockers (infliximab, etanercept, and adalimumab) and a variety of other agents, including anakinra (recombinant interleukin-1 receptor antagonist [IL-1Ra]), abatacept (CTLA-4 fused to the CH2 and CH3 domains of IgG1), and rituximab (a chimeric anti-CD20 monoclonal antibody). There is a clear protocol that rheumatologists follow to provide individualized therapy for each patient that provides the maximum therapeutic effect while minimizing the adverse effects of the treatments, particularly with DMARDs and biologic therapies. It is not uncommon for patients with severe RA to receive a combination of a glucocorticoid, a DMARD, and a biologic agent. Rituximab was first approved for the treatment of non-Hodgkin’s lymphoma in 1997, and it is a newcomer to treating RA (approved by the Food and Drug Administration in 2006). CD20 is a cell surface protein expressed by mature B cells but not by pro–B cells or antibody-producing plasma cells. A randomized, doubleblind, controlled study demonstrated that this anti-CD20 therapy in combination with methotrexate or cyclophosphamide was a more effective treatment for RA than rituximab or methotrexate alone (1). It was later shown that anti-CD20 treatment (rituximab or ofatumumab) was effective even after one or more anti-TNF therapies failed (2, 3). A number of studies have correlated the effectiveness of rituximab in RA with the depletion of B cells (4, 5), although studies with a larger group of RA cases indicated a lack of response in approximately one-third of the patients with depleted B cells (6). The effectiveness of anti-CD20 was surprising, given the belief that various T cell lymphocytes and the macrophage, which secretes the inflammatory cytokines TNFα, IL-1α, and IL-1ß, are most associated with RA. Evidently, multiple activated cell types contribute to the symptoms of RA.Due to the debilitating suffering caused by severe RA (and other forms of arthritis) and the large number of patients whose disease does not respond effectively to currently available treatments, there continues to be a concerted effort to better understand the pathophysiology of RA and to develop additional treatments. Mouse models are excellent tools for studying the mechanism of disease, but many of these models can be double-edged swords, precisely because the homogeneous genetic backgrounds of the mouse populations provide such clear-cut results validating a specific drug target. Initially, this was the case with the role of the chemokine receptor CCR2 and its agonists in RA. CCR2 and CCL2 (one of the chemokine agonists for CCR2) were thought to be valid targets based on their enhanced levels in arthritic joints, their chemotactic function on macrophages, and the effectiveness of monoclonal antibodies to CCR2 or CCL2 in many rodent models of arthritis. However, not all models showed that this chemokine receptor and its agonist were appropriate targets for RA (7). In a study using a murine collagen-induced arthritis model, treatment with an anti-CCR2 monoclonal antibody within the induction phase of the disease (days 0–15) ameliorated symptoms, but treatment during the progressive phase (days 21–36) led to …
