Rituximab was found to be effective at inducing remission in two separate studies of severe antineutrophil cytoplasmic antibody–associated vasculitis reported in the July 15 issue of the New England Journal of Medicine.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a multisystem autoimmune disorder characterized by vasculitis predominantly affecting small- to medium-size vessels, particularly in the kidneys and respiratory tract. Remission induction therapy using cyclophosphamide and glucocorticoids has been the standard treatment for decades, but it is associated with severe toxicity including infertility, cytopenias, infection, bladder injury, and cancer. Researchers hoped that a regimen of rituximab plus glucocorticoids might prove effective and avert some of the adverse affects of standard treatment.

In one study, Dr. Rachel B. Jones of the vasculitis and lupus clinic at Addenbrooke’s Hospital, Cambridge, England, and her associates compared rituximab with standard treatment in 44 patients with newly diagnosed ANCA-associated vasculitis who were seen at eight medical centers in Europe and Australia. A total of 33 patients were randomly assigned to receive standard glucocorticoid therapy plus 4 weeks of rituximab and 2 intravenous pulses of cyclophosphamide, while 11 were assigned to receive standard glucocorticoid therapy plus IV cyclophosphamide for 3-6 months.

Six patients in the rituximab group and 1 in the control group died during 1 year of follow-up, a mortality of 18% for both groups.

The primary efficacy end point, sustained remission at 12 months, was achieved by 93% of patients in the rituximab group and 90% of those in the control group. Median time to remission was similar, at 90 days with rituximab and 94 days with cyclophosphamide. Only 2 of the 27 survivors taking rituximab failed to achieve sustained remission.

Severe adverse events occurred in 14 of 33 patients in the rituximab group (42%) and in 4 of 11 patients in the control group (36%). Changes in quality of life scores on two different measures did not differ significantly between the two groups.

Rituximab therefore was no safer than cyclophosphamide, although use of rituximab meant less exposure to cyclophosphamide, and patients were able to avoid taking maintenance immunosuppression. “Larger trials are needed to confirm our findings, and it is important to determine whether the potential benefits of rituximab translate into improvements in efficacy and safety over the long term,” Dr. Jones and her colleagues said (New Engl. M. Med. 2010;363:211-20).

In the other study, Dr. John H. Stone of Massachusetts General Hospital, Boston, and his associates compared rituximab with oral cyclophosphamide in 197 patients treated at nine clinical sites. A total of 99 patients were randomly assigned to rituximab and 98 to standard treatment. Approximately half of the subjects in this study had newly diagnosed ANCA-associated vasculitis and half were experiencing a relapse.

The primary efficacy end point, a result of 0 on the Birmingham Vasculitis Activity Score plus the successful tapering of prednisone therapy at 6 months, was achieved by 64% of patients taking rituximab and 53% of those taking cyclophosphamide. The rituximab-based regimen thus demonstrated noninferiority to standard treatment.

Rituximab was significantly more effective that cyclophosphamide in the subgroup of patients with relapsing disease. In that population, 34 of 51 patients taking rituximab (67%) achieved the primary end point, compared with only 21 of 50 (42%) in the control group.

There were no significant differences between the two groups in the number of adverse events or of serious adverse events. However, significantly more patients in the control group developed leukopenia.

Thus, as in Dr. Jones’ study, rituximab did not deliver the anticipated reduction in adverse events. However, the 6-month follow-up in this study “may have been too short a period in which to detect some of the cyclophosphamide-associated adverse events,” Dr. Stone and his colleagues noted (N. Engl. J. Med. 2010;363:221-32).

There also was no significant difference between the two groups in the number of severe or limited disease flares. As with Dr. Jones’ study, changes in scores on two measures of quality of life did not differ significantly between the two groups.

An unexpected finding was that 5% of patients exposed to rituximab developed solid malignant tumors, compared with only 1% of those not exposed to rituximab. All but two patients who developed malignancy had histories of exposure to at least two drugs known to raise the risk of cancer, such as cyclophosphamide, azathioprine, or methotrexate, Dr. Stone and his associates said.

According to Dr. Ronald J. Falk and Dr. J. Charles Jennette, who wrote in an accompanying editorial, both of these studies showed that rituximab is efficacious in inducing remission, but they also raised the specter of substantial complications from the use of rituximab and other immunomodulating agents (N. Engl. J. Med. 2010;363:285-6).

Both research groups anticipated that fewer adverse events would occur in patients given rituximab than in those given cyclophosphamide. Unfortunately, in Dr. Stone’s study the rates of adverse events were equivalent, and there was an unexpectedly high number of malignant conditions detected over a relatively short treatment period.

Similarly, in Dr. Jones’ study the rates of adverse events were not significantly different, and mortality was equally high (18%) in both treatment groups. “This high rate of death early in the course of disease is of great concern,” they noted.

“These adverse events challenge us to decrease the cumulative exposure to immunosuppressive agents in patients with relapsing and remitting disease.”

Dr. Jones’ study was supported by Cambridge University Hospitals NHS Foundation Trust, Hoffmann-La Roche, the Canadian Institutes of Health Research, the Kidney Foundation of Canada, the Canadian Society of Nephrology, and the Alberta Heritage Foundation for Medical Research. Dr. Jones and her associates reported financial ties to Hoffmann-La Roche, Schering-Plough, Wyeth, Abbott Laboratories, Biogen Idec Inc., GlaxoSmithKline, Biovitrum, and Talecris Biotherapeutics. Dr. Stone’s study was supported by the U.S. National Institute of Allergy and Infectious Diseases, Genentech Inc., Biogen, the U.S. National Center for Research Resources, the U.S. National Institutes of Health, the Arthritis Foundation, and Euroimmun AG. Dr. Falk and Dr. Jennette are at the University of North Carolina at Chapel Hill. Neither reports having any financial conflict of interest relevant to this study or their editorial.

 

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

抗中性粒细胞胞浆抗体(ANCA)相关性血管炎是一种累及多系统的自身免疫性疾病，其特征表现为血管炎，主要累及中小血管，尤其是肾脏和呼吸道。数十年来，一直采用环磷酰胺和糖皮质激素作为标准的缓解诱导治疗方案，但此方案可并发重度毒性作用，其中包括不育、细胞减少、感染、膀胱损伤以及癌症。研究者希望利妥昔单抗配伍糖皮质激素治疗方案能被证实有效，并能预防标准治疗的某些不良反应的发生。

 

在一项研究中，英格兰剑桥Addenbrooke医院血管炎和狼疮门诊的Rachel B. Jones博士及其合作者对利妥昔单抗与标准治疗进行了比较，受试者为44例初诊为ANCA相关性血管炎、已在欧洲和澳大利亚的8个医学中心就诊的患者。共有33例患者被随机分配接受标准的糖皮质激素治疗加4周利妥昔单抗和2次环磷酰胺静脉冲击治疗，同时有11例患者被分配接受糖皮质激素加环磷酰胺静脉用药的标准治疗，疗程为3~6个月。

 

利妥昔单抗治疗组和对照组分别有6例和1例患者在1年随访中死亡，两组的病死率均为18%。

 

主要疗效终点为12个月持续缓解，利妥昔单抗治疗组患者中有93%达到此终点，而对照组有90%。中位缓解时间相近，利妥昔单抗治疗组为90天，而环磷酰胺治疗组为94天。服用利妥昔单抗的27名生存者中仅2名未达到持续缓解。

 

利妥昔单抗治疗组33例患者中有14例(42%)、对照组11例中有4例(36%)发生了重度不良事件。对两个不同指标所作的生活质量评分的变化无显著组间差异。

 

因此，尽管使用利妥昔单抗意味着环磷酰胺的暴露量较少，并且患者能够避免服用免疫抑制维持治疗药，但利妥昔单抗的安全性仍与环磷酰胺相当。Jones博士及其同事说：“本研究的结果尚有待于通过较大型临床试验加以证实，另外，确定长期利妥昔单抗治疗能否提高疗效和安全性(即有潜在收益)非常重要。”  (New Engl. M. Med. 2010;363:211-20)

 

在另一项研究中，波士顿马萨诸塞州综合医院的John H. Stone博士及其同事在197例曾在9家临床单位接收过治疗的患者中比较了利妥昔单抗与环磷酰胺口服药的疗效。共有99例患者被随机分配接受利妥昔单抗治疗，有98例被随机分配接受标准治疗。这项研究中近半数受试者初诊为ANCA相关性血管炎，半数处于复发期。

 

主要疗效终点为伯明翰血管炎活动性评分结果为0以及6个月时成功实现泼尼松剂量递减。本研究结果为，服用利妥昔单抗和的服用环磷酰胺患者中分别有64%和53%达到主要疗效终点。因此，以利妥昔单抗为基础的治疗方案显示出不劣于标准治疗。

 

病情复发的亚组患者应用利妥昔单抗的疗效明显优于环磷酰胺治疗。在这个患者群中，接受利妥昔单抗治疗的51例患者中有34例(67%)达到主要终点，而对照组的50例患者中仅有21例(42%)。

 

不良事件数或严重不良事件数无显著组间差异，但对照组患者中白细胞减少的发生率明显偏多。

 

因此，正如Jones博士的研究，利妥昔单抗在减少不良事件的发生方面未能达到预期。不过，本研究的6个月随访期“可能过短，尚不足以发现环磷酰胺相关的某些不良事件”Stone博士及其同事指出(N. Engl. J. Med. 2010;363:221-32)。

 

两个治疗组之间在重度或轻度疾病突发例数上亦无显著差异。正如Jones博士的研究，生活质量的两个指标评分的变化无显著组间差异。

 

一个意外的研究结果为，利妥昔单抗治疗组有5%的患者发生了恶性实体瘤，而在未接受此药治疗的患者中发生率仅为1%。Stone博士及其合作者称，除2例发生恶性肿瘤的患者外，其余患者均有至少两种已知可增加癌症风险的药物接触史，诸如环磷酰胺、巯唑嘌呤或氨甲蝶呤。

 

Ronald J. Falk博士和J. Charles Jennette博士在随刊编者按中写道，上述两项研究均表明利妥昔单抗可有效诱导缓解，但同时也引起人们对使用利妥昔单抗及其他免疫调节药物引发的大量并发症产生恐慌(N. Engl. J. Med. 2010;363:285-6)。

 

两个研究组均预测利妥昔单抗治疗组患者不良事件的发生少于环磷酰胺治疗组。遗憾的是，在Stone博士的研究中，两治疗组的不良事件发生率相等，而且在相对较短的治疗期内恶性肿瘤的发现例数远超出预期。

 

同样，在Jones博士的研究中，不良事件的发生率亦无明显的组间差异，两治疗组的病死率相同(18%)。他们指出，“在病程早期死亡率如此之高着实令人担忧”。

 

“这些不良事件促使我们减少对复发及缓解期患者所应用的免疫抑制剂的累计接触量。”

 

Jones博士的研究得到剑桥大学附属医院NHS信托基金会、霍夫曼-罗氏公司、加拿大卫生研究院、加拿大肾病基金会、加拿大神经科学学会以及阿尔伯塔医学研究传统基金会的资助。Jones博士及其合作者报告与霍夫曼-罗氏公司、先灵葆雅公司、惠氏公司、雅培实验室、Biogen Idec 公司、葛兰素史克公司、Biovitrum公司以及 Talecris Biotherapeutics公司有联系。Stone博士的研究得到美国国家过敏与传染病研究所、基因泰克公司、Biogen公司、美国国家研究资源中心、美国国立卫生研究院、关节炎基金会以及欧蒙公司的资助。Falk 博士和Jennette博士在北卡罗来纳大学查珀尔希尔分校任职，两者均无与本研究或其编者按相关的经济利益冲突的报告。

 

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