经验证实利妥昔单抗治疗血管炎效果最佳

加州新港滩——克利夫兰医院临床免疫科主任Leonard Calabrese博士在在2012年风湿病展望会议上指出，对于小血管炎(如韦格纳肉芽肿、显微镜下多血管炎和Churg-Strauss综合征)患者，利妥昔单抗是一种很好的缓解诱导药物。

他认为，对于某些患者，利妥昔单抗是比传统药物环磷酰胺更好的选择，但环磷酰胺仍是抗中性粒细胞胞浆抗体(ANCA)相关血管炎的标准缓解诱导药物。2011年，基于一项研究的结果，美国食品药品管理局(FDA)批准将利妥昔单抗用于治疗小血管炎，该研究中将环磷酰胺诱导和硫唑嘌呤维持治疗方案与利妥昔单抗治疗6个月的方案进行了比较，两组患者均同时接受强的松治疗。研究对象均为严重但非暴发性韦格纳氏肉芽肿或显微镜下多血管炎患者；超过一半有肾脏受累。结果显示，在接受利妥昔单抗治疗的99例患者中，63例 (64%)在6个月时达到主要终点——无类固醇激素缓解，而接受环磷酰胺治疗的98例患者中仅有52例(53%)达到这一终点(N. Engl. J. Med. 2010;363:221-32)。在为期18个月的随访期间，利妥昔单抗组36%的患者在未经治疗的情况下保持缓解状态。

Calabrese医生指出：“试验中所有趋势均对利妥昔单抗有利，因新发疾病就诊的患者预后相同，如在环磷酰胺治疗后复发，利妥昔单抗明显效果更优。”基于试验的结果以及利妥昔单抗的长期不良反应可能更少的事实，对于也可以处方环磷酰胺的患者，使用利妥昔单抗作为初始治疗可能更有利。更加明确的是，对于环磷酰胺治疗后复发者，可以选用利妥昔单抗。同样基于上述结果，对于新发的中度疾病患者，如在利妥昔单抗治疗后症状逐渐消失，可以停止治疗和观察。但对于出现复发或仅对利妥昔单抗部分应答的患者，“我不主张观察。我认为应该按顺序重复利妥昔单抗或一种抗代谢药物治疗。多数情况下，我会重复利妥昔单抗治疗。”尚不清楚对于什么样的患者最适合进行利妥昔单抗治疗。“需要对研究结果进一步分析。我们正在寻找预测因素。”

另一方面，“对于呼吸器依赖性和有肺或肾脏表现的患者，环磷酰胺和单采仍是我首选的治疗，”Calabrese医生说。

当患者接受传统环磷酰胺缓解治疗时，在降阶梯治疗中可选择硫唑嘌呤、甲氨蝶呤、来氟米特和麦考酚酯，但一项近期研究的结果显示，“毫无疑问，在缓解维持治疗中，硫唑嘌呤较麦考酚酯更有效，对于可耐受硫唑嘌呤的患者，这种治疗是相当好的”。(JAMA 2010;304:2381-8)

当患者无危及生命的靶器官受累、尿中无红细胞管型、无低氧性肺受累，且肌酐和肝功能正常时，甲氨蝶呤单药治疗可能是最好的选择。此类患者“倾向于较为年轻和患有上呼吸道限制性疾病。这些是非常好的甲氨蝶呤治疗候选者，剂量可以是20~25 mg/d，同时给予大剂量糖皮质激素治疗”。对于轻度的限制性疾病，“甲氨蝶呤效果非常好”。

Calabrese医生担任安万特、百时美施贵宝、基因泰克、杨森和辉瑞公司的顾问，同时也是安进公司的讲师。这次会议是由全球医学教育学院组织进行的。GAME及其新闻组织隶属于前线医学通信公司。

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By: M. ALEXANDER OTTO, Cardiology News Digital Network

NEWPORT BEACH, CALIF. – Rituximab is a good remission induction agent in patients with small vessel vasculitis, such as Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, according to Dr. Leonard Calabrese, chair of clinical immunology and professor of medicine at the Cleveland Clinic.

It appears to be a better choice in some patients than cyclophosphamide, the traditional option, although cyclophosphamide remains the standard of care for remission induction in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, he said at Perspectives in Rheumatic Diseases 2012.

The Food and Drug Administration approved rituximab for small vessel vasculitis in 2011 based on a trial that pitted cyclophosphamide induction and azathioprine maintenance against a 6-month regimen of rituximab, with patients in both arms of the study receiving prednisone. They all had severe but not fulminant Wegener’s granulomatosis or microscopic polyangiitis; over half had renal involvement.

Of the 99 rituximab patients, 63 (64%) reached the primary end point of steroid-free remission at 6 months, compared with 52 (53%) of the 98 cyclophosphamide patients. (N. Engl. J. Med. 2010;363:221-32).

At 18 months follow-up, 36% of rituximab patients remained in remission without treatment.

"All the trends in the trial favored rituximab. Patients who came in with [new] disease had equal outcomes. If they had relapsed on [cyclophosphamide], rituximab was significantly better," Dr. Calabrese said.

Given the results, and the fact that rituximab might have fewer long-term side effects, it "is favored as the initial therapy for patients who would otherwise be offered cyclophosphamide. Clearly, rituximab is the drug of choice for [cyclophosphamide] relapsers," he said.

Also based on the results, Dr. Calabrese said he is comfortable stopping therapy and observing patients "with new-onset moderate disease that melts away" with rituximab.

But for patients with a relapsing course or who respond only partially to rituximab, "I don’t favor observation. I think repeated rituximab or an antimetabolite is in order. Most the time, I’ve been doing repeated rituximab," he said.

The optimal rituximab patient remains unclear. "There’s more work to be done on the [study] results. We are looking for predictors," he said.

Meanwhile, "cyclophosphamide and apheresis are still my go-to therapies for patients who are ventilator dependent or have a pulmonary or renal presentation," Dr. Calabrese said.

Azathioprine, methotrexate, leflunomide, and mycophenolate are among the options for step-down therapy when patients are treated traditionally with cyclophosphamide for remission, but findings from a recent study showed "there’s no doubt that azathioprine is more effective than mycophenolate for remission maintenance. Azathioprine, in those who can tolerate it, is quite good," he said (JAMA 2010;304:2381-8).

When patients don’t have life-threatening target organ involvement – no red blood–cell casts in the urine, no hypoxic lung involvement, and normal creatinines and liver functions – methotrexate alone might be the best option.

Such patients "tend to be young and have upper-airway-limited disease. These people are very good methotrexate candidates, 20-25 mg/day with high dose glucocorticoids," he said.

For mild, limited disease, "methotrexate works great," he said.

Dr. Calabrese is a consultant for Aventis, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer. He is a speaker for Amgen. The meeting was held by Global Academy for Medical Education. GAME and this news organization are owned by Frontline Medical Communications.