Zintzaras Elias, Dahabreh Issa J, Giannouli Stavroula, Voulgarelis Michael, Moutsopoulos Haralampos M
Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
Clin Ther. 2008 Nov;30(11):1939-55. doi: 10.1016/j.clinthera.2008.11.007.
Because of its long-term effectiveness in clinical practice, methotrexate (MTX) is currently the preferred disease-modifying antirheumatic drug (DMARD) for patients with active rheumatoid arthritis (RRA). However, many patients do not experience remission and continue to have signs and symptoms of active disease while receiving a maximally tolerated dose.
The aims of this meta-analysis were to estimate the efficacy and tolerability of the various dosage schemes of infliximab versus MTX for the treatment of active RA, to eliminate size-related uncertainty of effects, and to identify subgroups of patients who benefit most from infliximab + MTX therapy.
Using the MEDLINE online database (inception through November 2006) and the Cochrane Database of Systematic Reviews (Issue 4, 2006), we identified English-language articles on randomized controlled clinical trials. Studies investigating infliximab + MTX regimens versus a control group receiving MTX alone to assess efficacy in active RA, using the American College of Rheumatology (ACR) criteria for 20% improvement (ACR20), 50% improvement (ACR50), and 70% improvement (ACR70), were considered eligible for the meta-analysis. Pooled odds ratios (ORs) and 95% CIs were calculated to compare the relative risks and benefits of adding infliximab to MTX.
From a total of 78 initially identified studies, 42 were considered potentially eligible for this review and 12 were considered eligible for the meta-analysis. Overall, 4899 patients were randomized to either infliximab + MTX (3919 patients) or MTX alone (980 patients). Mean patient age ranged from 44.6 to 56 years in the MTX-only arms and from 45.8 to 56 years in the infliximab + MTX arms. The proportion of female patients ranged from 66.6% to 100% in the MTX arms and from 68% to 100% in the infliximab arms. Infliximab 3 mg/kkg + MTX was more effective than MTX alone (OR = 3.52 [2.14-5.79] for reaching ACR20; 2.87 [2.228-3.61] for ACR50; and 2.42 [1.87-3.13] for ACR70). Infliximab 10 mg/kkg + MTX was also more effective than MTX alone (OR = 5.06 [3.88-6.59] for reaching ACR20; 5.72 [4.05-8.08] for ACR50; and 7.32 [2.28-23.50] for ACR70). Infliximab 10-mm/kg regimens appeared to be more effective than infliximab 3-mg/kg regimens (P = NS, P = 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), without being associated with an increased risk for adverse events. Infliximab 10 mg/kg appeared to be more effective in trials of longer duration (> or = 54 weeks) compared with those of shorter duration (P = 0.03, P = 0.02, and P = 0.01 for reaching ACR20, ACR50, and ACR70, respectively) and in those that enrolled patients with severe disease activity (P = 0.05, P = 0.05, and P = NS for reaching ACR20, ACR50, and ACR70, respectively). Steroid coadministration (P < 0.001, P < 0.001, and P = NS for reaching ACR20, ACR50, and ACR70, respectively), previous DMARD exposure (P < 0.001, P < 0.001, and P = 0.04 for reaching ACR20, ACR50, and ACR70, respectively), and MTX naivete (P = NS, P < 0.001, and P =0.013 for reaching ACR20, ACR50, and ACR70, respectively) correlated with higher infliximab efficacy.
Based on this meta-analysis, higher dose infliximab (10 mg/kg) in combination with MTX appeared to be more effective than the standard 3 mg/kg dose, particularly for patients with severe disease activity.The benefits of high-dose treatment appeared to accrue over time, and patients who received higher doses of infliximab did not experience a higher incidence of severe adverse events. The addition of oral low-dose steroids significantly enhanced infliximab efficacy.
由于甲氨蝶呤（MTX）在临床实践中具有长期有效性，目前它是活动性类风湿关节炎（RRA）患者首选的改善病情抗风湿药（DMARD）。然而，许多患者在接受最大耐受剂量治疗时并未实现缓解，仍有活动性疾病的体征和症状。
本荟萃分析的目的是评估英夫利昔单抗与MTX不同给药方案治疗活动性类风湿关节炎的疗效和耐受性，消除效应大小相关的不确定性，并确定最能从英夫利昔单抗+MTX治疗中获益的患者亚组。
利用MEDLINE在线数据库（建库至2006年11月）和Cochrane系统评价数据库（2006年第4期），我们检索了关于随机对照临床试验的英文文章。研究采用美国风湿病学会（ACR）20%改善标准（ACR20）、50%改善标准（ACR50）和70%改善标准（ACR70），调查英夫利昔单抗+MTX方案与单独接受MTX的对照组相比在活动性类风湿关节炎中的疗效，这些研究被认为符合荟萃分析的条件。计算合并比值比（OR）和95%可信区间（CI），以比较在MTX基础上加用英夫利昔单抗的相对风险和益处。
在最初识别的78项研究中，42项被认为可能符合本综述的条件，12项被认为符合荟萃分析的条件。总体而言，4899例患者被随机分为英夫利昔单抗+MTX组（3919例患者）或单独MTX组（980例患者）。仅接受MTX治疗组患者的平均年龄在44.6至56岁之间，英夫利昔单抗+MTX治疗组患者的平均年龄在45.8至56岁之间。MTX组女性患者比例在66.6%至100%之间，英夫利昔单抗组女性患者比例在68%至100%之间。英夫利昔单抗3mg/kg+MTX比单独使用MTX更有效（达到ACR20的OR = 3.52 [2.14 - 5.79]；达到ACR50的OR = 2.87 [2.228 - 3.61]；达到ACR70的OR = 2.42 [1.87 - 3.13]）。英夫利昔单抗10mg/kg+MTX也比单独使用MTX更有效（达到ACR20的OR = 5.06 [3.88 - 6.59]；达到ACR50的OR = 5.72 [4.05 - 8.08]；达到ACR70的OR = 7.32 [2.28 - 23.50]）。英夫利昔单抗10mg/kg方案似乎比3mg/kg方案更有效（达到ACR20、ACR50和ACR70时，P分别为无统计学意义、0.001和无统计学意义），且未增加不良事件风险。与疗程较短的试验相比，英夫利昔单抗10mg/kg在疗程较长（≥54周）的试验中似乎更有效（达到ACR20、ACR50和ACR70时，P分别为0.03、0.02和0.01），在纳入疾病活动度严重患者的试验中也是如此（达到ACR20、ACR50和ACR70时，P分别为0.05、0.05和无统计学意义）。联合使用类固醇（达到ACR20、ACR50和ACR70时，P分别为<0.001、<0.001和无统计学意义）以及既往使用过DMARD（达到ACR20、ACR50和ACR70时，P分别为<0.001、<0.001和0.04）与英夫利昔单抗疗效更高相关，而初治MTX（达到ACR20、ACR50和ACR70时，P分别为无统计学意义、<0.001和0.013）与英夫利昔单抗疗效更高也相关。
基于本荟萃分析，高剂量英夫利昔单抗（10mg/kg）联合MTX似乎比标准剂量3mg/kg更有效，尤其是对于疾病活动度严重的患者。高剂量治疗的益处似乎随时间增加，接受高剂量英夫利昔单抗治疗的患者严重不良事件发生率并未更高。加用口服低剂量类固醇显著提高了英夫利昔单抗的疗效。
