Papp Kim A, Langley Richard G, Lebwohl Mark, Krueger Gerald G, Szapary Philippe, Yeilding Newman, Guzzo Cynthia, Hsu Ming-Chun, Wang Yuhua, Li Shu, Dooley Lisa T, Reich Kristian
Probity Medical Research, Waterloo and University of Western Ontario, London, ON, Canada.
Lancet. 2008 May 17;371(9625):1675-84. doi: 10.1016/S0140-6736(08)60726-6.
Ustekinumab, a human monoclonal antibody against interleukins 12 and 23, has shown therapeutic potential for psoriasis. This study assessed the efficacy and safety of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders.
In this multicentre, phase III, double-blind, placebo-controlled study, 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score > or =12, and at least 10% total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n=409) or 90 mg (n=411) at weeks 0 and 4, then every 12 weeks, or placebo (n=410). Partial responders (ie, patients achieving > or =50% but <75% improvement from baseline in PASI) were re-randomised at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. Both randomisations were done with a minimisation method via a centralised interactive voice response. The primary endpoint was the proportion of patients achieving at least 75% improvement in PASI (PASI 75) at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00307437.
All randomised patients were included in the efficacy analysis. 273 (66.7%) patients receiving ustekinumab 45 mg, 311 (75.7%) receiving ustekinumab 90 mg, and 15 (3.7%) receiving placebo achieved the primary endpoint (difference in response rate 63.1%, 95% CI 58.2-68.0, p<0.0001 for the 45 mg group vs placebo and 72.0%, 67.5-76.5, p<0.0001 for the 90 mg group vs placebo). More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68.8%] vs 11 [33.3%]; difference in response rate 35.4%, 95% CI 12.7-58.1, p=0.004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg. During the placebo-controlled phase, 217 (53.1%) patients in the 45 mg group, 197 (47.9%) in the 90 mg group, and 204 (49.8%) in the placebo group experienced adverse events; serious adverse events were seen in eight (2.0%) patients in the 45 mg group, five (1.2%) in the 90 mg group, and eight (2.0%) in the placebo group.
Although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.
优特克单抗是一种抗白细胞介素12和23的人源单克隆抗体，已显示出治疗银屑病的潜力。本研究评估了优特克单抗对银屑病患者的疗效和安全性，并评估了部分缓解者的剂量强化情况。
在这项多中心、III期、双盲、安慰剂对照研究中，1230例中度至重度银屑病患者（银屑病面积和严重程度指数[PASI]评分≥12，且全身表面积受累至少10%）被随机分配在第0周和第4周接受45mg（n = 409）或90mg（n = 411）优特克单抗治疗，然后每12周一次，或接受安慰剂（n = 410）治疗。部分缓解者（即PASI较基线改善≥50%但<75%的患者）在第28周重新随机分组，继续每12周给药一次或升级为每8周给药一次。两次随机分组均通过集中交互式语音应答的最小化方法进行。主要终点是在第12周时PASI改善至少75%（PASI 75）的患者比例。分析采用意向性治疗。本研究已在ClinicalTrials.gov注册，编号为NCT00307437。
所有随机分组的患者均纳入疗效分析。接受45mg优特克单抗治疗的273例（66.7%）患者、接受90mg优特克单抗治疗的311例（75.7%）患者和接受安慰剂治疗的15例（3.7%）患者达到主要终点（45mg组与安慰剂组的缓解率差异为63.1%，95%CI 58.2 - 68.0，p<0.0001；90mg组与安慰剂组的缓解率差异为72.0%，67.5 - 76.5，p<0.0001）。第28周接受每8周一次90mg优特克单抗治疗的部分缓解者在第52周达到PASI 75的比例高于那些继续每12周接受相同剂量治疗的患者（22例[68.8%]对11例[33.3%]；缓解率差异为35.4%，95%CI 12.7 - 58.1，p = 0.004）。接受45mg优特克单抗治疗的部分缓解者对剂量强度变化没有这样的反应。在安慰剂对照阶段，45mg组217例（53.1%）患者、90mg组197例（47.9%）患者和安慰剂组204例（49.8%）患者发生不良事件；45mg组8例（2.0%）患者、90mg组5例（1.2%）患者和安慰剂组8例（2.0%）患者出现严重不良事件。
虽然每12周使用优特克单抗治疗对大多数中度至重度银屑病患者有效，但对于那些对初始治疗方案仅部分缓解的患者，将剂量强化至每8周一次90mg优特克单抗可能有必要以获得完全缓解。
