Kavanaugh A, Rosengren S, Lee S J, Hammaker D, Firestein G S, Kalunian K, Wei N, Boyle D L
University of California, San Diego, Division of Rheumatology, Allergy, and Immunology, 9500 Gilman Drive, Mail Code 0943, La Jolla, CA 92093-0943, USA.
Ann Rheum Dis. 2008 Mar;67(3):402-8. doi: 10.1136/ard.2007.074229. Epub 2007 Jul 20.
Treatment with the anti-CD20 monoclonal antibody (mAb) rituximab is effective in rheumatoid arthritis (RA). Marked depletion of circulating B cells, seen in almost all patients, does not correlate with efficacy. The potential synovial immunomodulatory effects of rituximab have not been fully defined.
The ARISE trial is an open label, serial synovial biopsy (pre-treatment and 8 weeks) study of rituximab, given 1 g intravenously on days 0 and 14 without peri-infusional steroids, in active RA patients on concomitant methotrexate (MTX). Synovial tissue was analysed by immunohistochemistry with digital image analysis and gene expression by real-time PCR.
The mean (SD) baseline DAS28 score was 6.5 (0.4), and mean MTX dose 17.3 mg/week. Of 13 patients, 11 had failed prior tumour necrosis factor (TNF) inhibitor therapy. With treatment, all patients experienced near complete depletion of circulating B cell numbers. During the 6 months after treatment, 7/13 patients achieved an American College of Rheumatology (ACR) 20% improvement (ACR20) response, 3/13 an ACR50 response and 2/13 an ACR70 response. There was a significant decrease in synovial B cells after treatment, but only a small trend towards greater reduction among clinical responders. Among the three patients with ACR50 responses there was a significant decrease in synovial immunoglobulin synthesis.
These data suggest that unlike those in circulation, synovial B cells are decreased but are not eliminated by rituximab therapy. Patients with higher levels of response may have more consistent depletion of synovial B cells, and may also have an alteration in synovial B cell function, as indicated by decreases in synovial immunoglobulin synthesis. Thus, effects on synovial B cells may be necessary but not sufficient for inducing clinical efficacy. Other effects, such as on primary lymph organ B cell antigen presentation or cytokine production, may be operative.
抗CD20单克隆抗体（mAb）利妥昔单抗治疗类风湿性关节炎（RA）有效。几乎所有患者循环B细胞均显著减少，但这与疗效无关。利妥昔单抗潜在的滑膜免疫调节作用尚未完全明确。
ARISE试验是一项开放标签、系列滑膜活检（治疗前和治疗8周）研究，在接受甲氨蝶呤（MTX）治疗的活动性RA患者中，于第0天和第14天静脉注射1g利妥昔单抗，不使用输注期类固醇。通过免疫组织化学和数字图像分析对滑膜组织进行分析，并通过实时PCR分析基因表达。
平均（标准差）基线DAS28评分为6.5（0.4），平均MTX剂量为17.3mg/周。13例患者中，11例先前肿瘤坏死因子（TNF）抑制剂治疗失败。治疗后，所有患者循环B细胞数量几乎完全减少。治疗后6个月内，13例患者中有7例达到美国风湿病学会（ACR）20%改善（ACR20）反应，13例中有3例达到ACR50反应，13例中有2例达到ACR70反应。治疗后滑膜B细胞显著减少，但临床反应者中仅有轻微的更大程度减少趋势。在3例达到ACR50反应的患者中，滑膜免疫球蛋白合成显著减少。
这些数据表明，与循环中的B细胞不同，滑膜B细胞数量减少但未被利妥昔单抗治疗消除。反应水平较高的患者滑膜B细胞可能更持续减少，并且滑膜B细胞功能可能也有改变，如滑膜免疫球蛋白合成减少所示。因此，对滑膜B细胞的作用可能是诱导临床疗效所必需的，但并不充分。其他作用，如对初级淋巴器官B细胞抗原呈递或细胞因子产生的作用，可能也在起作用。
