Boers M, Verhoeven A C, Markusse H M, van de Laar M A, Westhovens R, van Denderen J C, van Zeben D, Dijkmans B A, Peeters A J, Jacobs P, van den Brink H R, Schouten H J, van der Heijde D M, Boonen A, van der Linden S
University Hospital Maastricht, The Netherlands.
Lancet. 1997 Aug 2;350(9074):309-18. doi: 10.1016/S0140-6736(97)01300-7.
The value of intensive combination therapy in early rheumatoid arthritis is unproven. In a multicentre, double-blind, randomised trial (COBRA), we compared the combination of sulphasalazine (2 g/day), methotrexate (7.5 mg/week), and prednisolone (initially 60 mg/day, tapered in 6 weekly steps to 7.5 mg/day) with sulphasalazine alone.
155 patients with early rheumatoid arthritis (median duration 4 months) were randomly assigned combined treatment (76) or sulphasalazine alone (79). Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks, respectively. The main outcomes were the pooled index (a weighted change score of five disease activity measures) and the Sharp/Van der Heijde radiographic damage score in hands and feet. Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation.
At week 28, the mean pooled index was 1.4 (95% CI 1.2-1.6) in the combined treatment group and 0.8 (0.6-1.0) in the sulphasalazine group (p < 0.0001). At this time, 55 (72%) and 39 (49%) patients, respectively, were improved according to American College of Rheumatology criteria. The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped, and there were no further changes after methotrexate was stopped. At 28 weeks, the radiographic damage score had increased by a median of 1 (range 0-28) in the combined-therapy group and 4 (0-44) in the sulphasalazine group (p < 0.0001). The increases at week 56 (2 [0-43] vs 6 [0-54], p = 0.004), and at week 80 (4 [0-80] vs 12 [0-72], p = 0.01) were also significant. Further analysis suggests that combined therapy immediately suppressed damage progression, whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months. There were fewer withdrawals in the combined therapy than the sulphasalazine group (6 [8%] vs 23 [29%]), and they occurred later.
This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped. Although confirmatory studies and long-term follow-up are needed, this approach may prove useful in the treatment of early rheumatoid arthritis.
强化联合治疗在早期类风湿关节炎中的价值尚未得到证实。在一项多中心、双盲、随机试验（COBRA）中，我们比较了柳氮磺胺吡啶（2克/天）、甲氨蝶呤（7.5毫克/周）和泼尼松龙（初始剂量60毫克/天，每6周递减一次至7.5毫克/天）联合治疗与单用柳氮磺胺吡啶治疗的效果。
155例早期类风湿关节炎患者（中位病程4个月）被随机分配接受联合治疗（76例）或单用柳氮磺胺吡啶治疗（79例）。泼尼松龙和甲氨蝶呤分别在28周和40周后逐渐减量并停用。主要结局指标为综合指数（五项疾病活动度指标的加权变化评分）以及手和足的Sharp/van der Heijde放射学损伤评分。独立的医疗保健专业人员在不知道治疗分配情况的前提下评估主要结局指标。
在第28周时，联合治疗组的平均综合指数为1.4（95%置信区间1.2 - 1.6），柳氮磺胺吡啶组为0.8（0.6 - 1.0）（p < 0.0001）。此时，根据美国风湿病学会标准，联合治疗组和柳氮磺胺吡啶组分别有55例（72%）和39例（49%）患者病情改善。两组之间的临床差异在停用泼尼松龙后减小且不再显著，停用甲氨蝶呤后也未再有进一步变化。在第28周时，联合治疗组的放射学损伤评分中位数增加了1（范围0 - 28），柳氮磺胺吡啶组增加了4（0 - 44）（p < 0.0001）。在第56周（2 [0 - 43] 对比 6 [0 - 54]，p = 0.004）和第80周（4 [0 - 80] 对比12 [0 - 72]，p = 0.01）时的增加也具有显著性。进一步分析表明，联合治疗可立即抑制损伤进展，而柳氮磺胺吡啶的抑制效果较差且有6至12个月的延迟。联合治疗组的退出人数比柳氮磺胺吡啶组少（6例 [8%] 对比23例 [29%]），且退出时间较晚。
这种联合治疗方案比单用柳氮磺胺吡啶能提供更好的疾病控制，且在停用糖皮质激素后长达一年仍持续有效。尽管需要进行验证性研究和长期随访，但这种方法可能对早期类风湿关节炎的治疗有用。
