Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, , Leeds, UK.
Ann Rheum Dis. 2014 May;73(5):909-12. doi: 10.1136/annrheumdis-2013-204417. Epub 2014 Jan 2.
To evaluate the efficacy and safety of two different targeted approaches-abatacept or tocilizumab-after rituximab therapy in rheumatoid arthritis, and to explain observed difference in efficacy using blood and synovial studies of interleukin 6 (IL-6) and B cells in patients receiving rituximab therapy.
Consecutive series of patients who had discontinued rituximab therapy owing to inefficacy or toxicity were treated with abatacept (n=16) or tocilizumab (n=35). Clinical response and reasons for discontinuation were evaluated. Serial blood and synovial samples were obtained from a group of 57 and 25 rituximab-treated patients, respectively, and were analysed for B cells and IL-6 using flow cytometry, immunohistochemistry and quantitative real-time PCR.
In the abatacept group, mean (SEM) Disease Activity Score in 28 joints calculated using the erythrocyte sedimentation rate (DAS28-ESR) reduced from 5.69 (0.42) at baseline to 4.94 (0.44) at 6 months (p=0.12). In the tocilizumab group: mean (SEM) DAS28- ESR reduced from 5.75 (0.21) at baseline to 3.28 (0.26) at 6 months (p<0.001). This was paralleled by a significant swollen joint count reduction in the tocilizumab (5.47 (0.70) to 2.70 (0.61), p=0.033), but not abatacept (6.23 (1.3) to 4.15 (1.2), p=0.26), group. In the synovium, despite complete depletion of B cells in 19/22 patients, IL-6 mRNA expression was not significantly reduced after rituximab. Blood B cell numbers remained low 12 months after rituximab. Serum IL-6 was raised at baseline and significantly higher in rituximab clinical non-responders (p=0.035) than responders. A significant reduction in serum IL-6 was seen in rituximab clinical responders (p=0.005) but not in non-responders (p=0.237).
In patients with rheumatoid arthritis for whom rituximab therapy failed despite adequate B cell depletion, IL-6-directed therapy might be a more logical and effective treatment choice than T cell costimulation blockade. Further controlled studies investigating other possible mechanisms are needed to validate these initial findings.
评估两种不同靶向方法——阿巴西普或托珠单抗——在利妥昔单抗治疗类风湿关节炎中的疗效和安全性，并通过接受利妥昔单抗治疗的患者的白细胞介素 6（IL-6）和 B 细胞的血液和滑膜研究来解释观察到的疗效差异。
因疗效不佳或毒性而停止利妥昔单抗治疗的连续系列患者接受阿巴西普（n=16）或托珠单抗（n=35）治疗。评估临床反应和停药原因。分别从 57 名和 25 名接受利妥昔单抗治疗的患者中获得一组连续的血液和滑膜样本，并使用流式细胞术、免疫组织化学和定量实时 PCR 分析 B 细胞和 IL-6。
在阿巴西普组中，使用红细胞沉降率（ESR）计算的 28 个关节疾病活动评分（DAS28-ESR）从基线时的 5.69（0.42）降至 6 个月时的 4.94（0.44）（p=0.12）。在托珠单抗组中：DAS28-ESR 从基线时的 5.75（0.21）降至 6 个月时的 3.28（0.26）（p<0.001）。这与托珠单抗组（5.47（0.70）至 2.70（0.61），p=0.033）关节肿胀计数的显著减少相平行，但阿巴西普组（6.23（1.3）至 4.15（1.2），p=0.26）则没有。在滑膜中，尽管 22 名患者中有 19 名的 B 细胞完全耗尽，但利妥昔单抗后 IL-6mRNA 的表达并未显著降低。利妥昔单抗治疗 12 个月后，血液 B 细胞数量仍保持较低水平。基线时血清 IL-6 升高，利妥昔单抗临床无反应者（p=0.035）明显高于反应者。利妥昔单抗临床反应者的血清 IL-6 显著降低（p=0.005），而非无反应者（p=0.237）则无。
在因 B 细胞耗竭充分但利妥昔单抗治疗失败的类风湿关节炎患者中，IL-6 靶向治疗可能是比 T 细胞共刺激阻断更合理、更有效的治疗选择。需要进一步的对照研究来验证这些初步发现，以调查其他可能的机制。
