Davis J C, Fessler B J, Tassiulas I O, McInnes I B, Yarboro C H, Pillemer S, Wilder R, Fleisher T A, Klippel J H, Boumpas D T
Clinical Investigation Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
J Rheumatol. 1998 Sep;25(9):1694-704.
Fludarabine, a nucleoside analog that targets both resting and proliferating lymphocytes, is a promising drug for the treatment of autoimmune diseases. We conducted a 2 dose, open label clinical trial to evaluate the toxicity/safety of the fludarabine treatment and its clinical and immunological effects.
Twenty-six patients with severe rheumatoid arthritis (RA) refractory to treatment with at least one slow acting antirheumatic drug were treated with intravenous fludarabine [20 mg/m2 body surface area (n=12) or 30 mg/m2 body surface area (n=14) per day for 3 consecutive days] given monthly for 6 months. Second line agents with the exception of glucocorticoids were discontinued at least 4 weeks before study entry. Measurements included toxicity and tolerability monitored at monthly intervals: efficacy, by both a 50% reduction in tender or swollen joint count and American College of Rheumatology (ACR) criteria for 20% response; and phenotypic analysis of peripheral blood mononuclear cells and T cell functional assays.
Using intention-to-treat analysis, 2 of 12 (17%) patients in the low dose and 7 of 14 (50%) in the high dose groups had 50% or greater reduction in tender and/or swollen joint count after 6 months of therapy compared to baseline (p=0.09). Two of 12 (17%) in the low dose group and 5 of 14 (36%) in the high dose group met ACR criteria for 20% improvement (p=0.28). No immediate toxicity was observed. Several infections occurred, including 4 episodes of limited Herpes zoster, which responded to standard therapy. Significant lymphopenia involving T and B cells was observed in all patients. Both naive (CD4+CD45RA+) and memory CD4+ T cells (CD4+CD45RO+) were reduced (naive > memory). No significant regeneration of naive T cells was observed, which may suggest limited thymic regenerative capacity. Fludarabine decreased the proliferative response of peripheral blood lymphocytes to mitogens, as well as the production of T cell (interleukin 2 and interferon-gamma) and monocyte derived (tumor necrosis factor-alpha and IL-10) cytokines.
Fludarabine treatment of patients with severe, refractory RA resulted in significant lymphopenia, suppression of lymphocyte function, and clinical improvement in the high dose group. There was no immediate toxicity; however, several infections occurred. Controlled trials are needed to substantiate the clinical improvement observed in this open label trial.
氟达拉滨是一种核苷类似物，可作用于静止和增殖的淋巴细胞，是一种有前景的治疗自身免疫性疾病的药物。我们进行了一项2剂量、开放标签的临床试验，以评估氟达拉滨治疗的毒性/安全性及其临床和免疫学效应。
26例对至少一种慢作用抗风湿药物治疗无效的重度类风湿关节炎（RA）患者接受静脉注射氟达拉滨治疗[每天20mg/m²体表面积（n = 12）或30mg/m²体表面积（n = 14），连续3天]，每月给药1次，共6个月。除糖皮质激素外，二线药物在研究入组前至少4周停用。测量指标包括每月监测的毒性和耐受性；疗效指标为压痛或肿胀关节计数减少50%以及达到美国风湿病学会（ACR）20%改善标准；对外周血单个核细胞进行表型分析以及进行T细胞功能检测。
采用意向性分析，低剂量组12例患者中有2例（17%）、高剂量组14例患者中有7例（50%）在治疗6个月后与基线相比压痛和/或肿胀关节计数减少50%或更多（p = 0.09）。低剂量组12例患者中有2例（17%）、高剂量组14例患者中有5例（36%）达到ACR 20%改善标准（p = 0.28）。未观察到即刻毒性。发生了几例感染，包括4例局限性带状疱疹，对标准治疗有反应。所有患者均观察到明显的淋巴细胞减少，累及T细胞和B细胞。初始（CD4⁺CD45RA⁺）和记忆性CD4⁺T细胞（CD4⁺CD45RO⁺）均减少（初始细胞>记忆细胞）。未观察到初始T细胞的显著再生，这可能提示胸腺再生能力有限。氟达拉滨降低了外周血淋巴细胞对有丝分裂原的增殖反应，以及T细胞（白细胞介素2和干扰素-γ）和单核细胞衍生（肿瘤坏死因子-α和IL-10）细胞因子的产生。
氟达拉滨治疗重度难治性RA患者导致高剂量组出现明显的淋巴细胞减少、淋巴细胞功能受抑制以及临床改善。未观察到即刻毒性；然而，发生了几例感染。需要进行对照试验以证实该开放标签试验中观察到的临床改善情况。
