Moreland Larry W, O'Dell James R, Paulus Harold E, Curtis Jeffrey R, Bathon Joan M, St Clair E William, Bridges S Louis, Zhang Jie, McVie Theresa, Howard George, van der Heijde Désirée, Cofield Stacey S
University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Arthritis Rheum. 2012 Sep;64(9):2824-35. doi: 10.1002/art.34498.
To assess whether it is better to intensively treat all patients with early rheumatoid arthritis (RA) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response (as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] of ≥ 3.2 at week 24) to methotrexate (MTX) monotherapy, and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine.
The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study is a 2-year, randomized, double-blind trial. A 2 × 2 factorial design was used to randomly assign subjects to 1 of 4 treatment arms: immediate treatment with MTX plus etanercept, immediate oral triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or step-up from MTX monotherapy to one of the combination therapies (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine) at week 24 if the DAS28-ESR was ≥ 3.2. All treatment arms included matching placebos. The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102.
At week 24 (beginning of the step-up period), subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups (3.6 versus 4.2; P < 0.0001); no differences between the combination-therapy regimens were observed. Between week 48 and week 102, subjects randomized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy, regardless of the treatment arm. There was no significant difference in the DAS28-ESR between subjects randomized to oral triple therapy and those randomized to receive MTX plus etanercept. By week 102, there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy (0.64 versus 1.69; P = 0.047).
There were no differences in the mean DAS28-ESR during weeks 48-102 between subjects randomized to receive MTX plus etanercept and those randomized to triple therapy, regardless of whether they received immediate combination treatment or step-up from MTX monotherapy. At 102 weeks, immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy. Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine (or etanercept, if necessary, after 6 months) is a reasonable therapeutic strategy for patients with early RA. Treatment with the combination of MTX plus etanercept resulted in a statistically significant radiographic benefit compared with oral triple therapy.
评估对所有早期类风湿关节炎（RA）患者使用联合药物进行强化治疗，还是仅对那些对甲氨蝶呤（MTX）单药治疗无适当反应（根据第24周时28个关节的疾病活动评分[DAS28-ESR]，使用红细胞沉降率，≥3.2来确定）的患者采用这种方法更好，并评估MTX联合依那西普的联合疗法是否优于MTX联合柳氮磺胺吡啶加羟氯喹的联合疗法。
早期侵袭性类风湿关节炎治疗（TEAR）研究是一项为期2年的随机双盲试验。采用2×2析因设计将受试者随机分配到4个治疗组之一：立即接受MTX联合依那西普治疗、立即接受口服三联疗法（MTX联合柳氮磺胺吡啶加羟氯喹），或者如果DAS28-ESR≥3.2，则在第24周从MTX单药治疗逐步升级为联合疗法之一（MTX联合依那西普或MTX联合柳氮磺胺吡啶加羟氯喹）。所有治疗组均包括匹配的安慰剂。主要结局是对第48周至第102周DAS28-ESR值进行观察组分析。
在第24周（逐步升级期开始时），两个立即治疗组的受试者DAS28-ESR的降低幅度大于两个逐步升级组（分别为3.6与4.2；P<0.0001）；联合治疗方案之间未观察到差异。在第48周和第102周之间，随机分配到逐步升级组的受试者的DAS28-ESR临床反应与最初接受联合治疗的受试者无异，无论治疗组如何。随机接受口服三联疗法的受试者与随机接受MTX联合依那西普治疗的受试者之间，DAS28-ESR无显著差异。到第102周时，接受MTX联合依那西普治疗组与接受口服三联疗法组相比，影像学测量值从基线的变化存在统计学显著差异（分别为0.64与1.69；P = 0.047）。
在第48 - 102周期间，随机接受MTX联合依那西普治疗的受试者与随机接受三联疗法的受试者之间，DAS28-ESR均值无差异，无论他们是接受立即联合治疗还是从MTX单药治疗逐步升级。在第102周时，两种策略的立即联合治疗均比逐步升级治疗开始前的MTX单药治疗更有效。对于早期RA患者，初始使用MTX单药治疗并加用柳氮磺胺吡啶加羟氯喹（或必要时6个月后加用依那西普）是一种合理的治疗策略。与口服三联疗法相比，MTX联合依那西普治疗在影像学方面具有统计学显著益处。
