重度ANCA相关性血管炎的两种治疗方案疗效相等

据8月1日发表于《新英格兰医学杂志》上的一篇报道，对于重度抗中性粒细胞胞浆抗体（ANCA）相关性血管炎患者，4周的利妥昔单抗单疗程治疗在诱导并维持缓解的疗效上不劣于传统的18周持续免疫抑制治疗，另外，除了接受利妥昔单抗单疗程治疗的患者白细胞减少症和肺炎的发生率低于接受标准治疗的患者外，两种治疗方案在总体不良事件上无其他差异(N. Engl. J. Med. 2013 Aug. 1 [doi: 10.1056/NEJMoa1213277])。

罗彻斯特市梅奥医院基金会的Ulrich Specks医生及其RAVE-ITN（Rituximab in ANCA-Associated Vasculitis–Immune Tolerance Network）利妥昔单抗研究组的合作者们之前发表的是这项随机、双盲、多中心研究的短期（6个月）结果，本次报告的是该研究中197例患者的长期（18个月）结果。在此研究中，他们对99例患者采用375 mg/m²体表面积、每周1次、持续4周的利妥昔单抗输注+1种环磷酰胺安慰剂序贯以17个月的安慰剂治疗方案，对98例患者采用2 mg/kg环磷酰胺每日1次（根据肾功能不全进行调整）+一种利妥昔单抗安慰剂输注、持续3~6个月（具体长短视是否及何时获得缓解而定）序贯硫唑嘌呤2 mg/kg以平衡18个月治疗期的治疗方案。如果处于缓解期，则在5.5个月后停用泼尼松。

结果显示，利妥昔单抗治疗组共有64%的患者到6个月时获得完全缓解，48%到12个月时仍维持缓解，而传统免疫抑制组到6个月时相应的百分比为53%，12个月时相应的百分比为39%。在18个月时，利妥昔单抗治疗组有39%的患者仍维持着完全缓解，而环磷酰胺-硫唑嘌呤治疗组为33%，满足非劣效标准，但不满足优效性标准。两个研究组在任何疗效指标上都无显著差异，其中包括缓解持续时间，复发的例数、发生率及严重度，以及血管炎损伤和生活质量指标的评分。

此外，在入组时病情复发而不是新发的101例患者亚组中，利妥昔单抗治疗优于传统的免疫抑制治疗，而且，接受利妥昔单抗治疗的患者6个月时的完全缓解率为67%，在12个月时为49%，在18个月时为37%，相比之下，环磷酰胺-硫唑嘌呤治疗组相应的发生率均显著降低，分别为42%、24%和20%。在102例基线时有严重肾病的患者亚组中，利妥昔单抗的效能与传统的免疫抑制治疗相当，利妥昔单抗治疗组18个月前在某个时间点的缓解率为75%，而环磷酰胺-硫唑嘌呤治疗组为76%，两组平均估计的肌酐清除率的改善程度相当。

同样在18个月时，两组在总体不良事件、严重不良事件或非疾病相关性不良事件的发生例数或发生率上均无显著差异，均有2例患者死亡。尤其值得关注的是，这两个试验组3级或3级以上感染的发生率和血清IgG、IgA及IgM的水平相近。在随访期间，两组患者均无新增癌症。不过，接受利妥昔单抗治疗的患者中、重度白细胞减少症的发作次数减少（5例 vs. 23例），需要做剂量调整或中断用药的次数也较少。

研究者表示，所有患者使用利妥昔单抗均能有效诱导B细胞清除，但到18个月时几乎所有患者都显示外周血B细胞重建，这反映了这种疾病的现实情况，即当免疫抑制治疗的作用逐渐消失时往往又出现复发，不过，本研究的结果提示通过间断性再治疗或可更有效地长期控制病情。

本研究得到美国国立过敏与传染病研究所、青少年糖尿病研究基金会、基因泰克公司、Biogen公司、美国国家研究资源中心、美国国立关节炎、骨骼肌病及皮肤病研究所、关节炎基金会的支持。Specks医生报告称获得了罗氏提供的酬金和差旅费报销（基因泰克公司是罗氏集团的成员），部分合作者报告与基因泰克、Biogen及其他公司有联系。

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By: MARY ANN MOON, Internal Medicine News Digital Network

For patients with severe antineutrophil cytoplasmic antibody–associated vasculitis, a single 4-week course of rituximab proved to be noninferior to conventional continuous immunosuppression at inducing and maintaining remission for 18 months, according to a report published Aug. 1 in the New England Journal of Medicine.

There were no differences between the two regimens in overall adverse events, except that patients who received rituximab for 1 month had fewer cases of leukopenia and pneumonia than did those who received a standard regimen of cyclophosphamide and azathioprine for 18 months, said Dr. Ulrich Specks of the Mayo Clinic Foundation, Rochester, Minn., and his associates in the RAVE-ITN (Rituximab in ANCA-Associated Vasculitis–Immune Tolerance Network) Research Group.

"Rituximab effectively induced B-cell depletion in all patients, but nearly all the patients showed reconstitution of peripheral-blood B cells by 18 months," the researchers noted.

This reflects "the reality of this disease, which is that relapses are common when the effects of immunosuppressive therapy wear off." However, the results also "point the way to more effective, long-term disease control through intermittent retreatment," they said.

The researchers previously published the short-term (6-month) results of their randomized, double-blind, multicenter RAVE study (N. Engl. J. Med. 2010;363:221-32) and now report the long-term (18-month) results for the 197 patients in the study. They assigned 99 patients to receive an infusion of rituximab at 375 mg/m2 of body surface area once a week for 4 weeks and a cyclophosphamide placebo followed by 17 months of a placebo, and 98 patients to receive cyclophosphamide at 2 mg/kg daily (adjusted for renal insufficiency) and infusions of a rituximab placebo for 3-6 months, depending on if and when remission was achieved, followed by azathioprine at 2 mg/kg for the balance of the 18-month treatment period. Patients stopped taking prednisone after 5.5 months if they were in remission.

A total of 64% of the rituximab group had a complete remission by 6 months, which was maintained in 48% at 12 months. The corresponding percentages for conventional immunosuppression were slightly lower at 53% at 6 months and 39% at 12 months.

At 18 months, complete remission was maintained in 39% of patients who had received rituximab and 33% of those who had received cyclophosphamide-azathioprine, which met the criterion for noninferiority but not for superiority, the investigators reported (N. Engl. J. Med. 2013 Aug. 1 [doi: 10.1056/NEJMoa1213277]).

There were no significant differences between the two study groups in any efficacy measure, including the duration of remission; the number, rate, and severity of relapses; or scores on measures of vasculitis damage and quality of life.

Rituximab was found superior to conventional immunosuppression in the subgroup of 101 patients who had relapsing rather than new-onset disease at enrollment in the study. In that subgroup, patients who received rituximab showed complete remission rates of 67% at 6 months, 49% at 12 months, and 37% at 18 months. The corresponding rates were significantly lower with cyclophosphamide-azathioprine at 42%, 24%, and 20%, respectively.

Rituximab’s efficacy was comparable to that of conventional immunosuppression in another important subgroup of patients: those who had major renal disease at baseline. Among the 102 patients with major renal disease at baseline, remission occurred at some point before 18 months in 75% with rituximab and 76% with cyclophosphamide-azathioprine, and the magnitude of improvement in mean estimated creatinine clearance levels was judged to be comparable between the groups.

Also at 18 months, there were no significant differences between the two study groups in the numbers or rates of total adverse events, serious adverse events, or non–disease-related adverse events. There were two deaths in each group.

In particular, the study groups had similar rates of infections of grade 3 or higher and similar serum levels of IgG, IgA, and IgM. No additional cancers developed during follow-up in either group.

However, patients who received rituximab had fewer episodes of moderate or severe leukopenia (5 vs. 23 cases) and required fewer dose adjustments or interruptions.

This study was supported by the National Institute of Allergy and Infectious Diseases, the Juvenile Diabetes Research Foundation, Genentech, Biogen Idec, the National Center for Research Resources, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Arthritis Foundation. Dr. Specks reported receiving an honorarium and travel reimbursement from Roche (Genentech is a member of the Roche Group), and some of his associates reported ties to Genentech, Biogen Idec, and other companies.