Miloslavsky E M, Specks U, Merkel P A, Seo P, Spiera R, Langford C A, Hoffman G S, Kallenberg C G M, St Clair E W, Tchao N K, Viviano L, Ding L, Sejismundo L P, Mieras K, Iklé D, Jepson B, Mueller M, Brunetta P, Allen N B, Fervenza F C, Geetha D, Keogh K, Kissin E Y, Monach P A, Peikert T, Stegeman C, Ytterberg S R, Stone J H
Massachusetts General Hospital, Boston.
Arthritis Rheum. 2013 Sep;65(9):2441-9. doi: 10.1002/art.38044.
To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA).
The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other).
Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare.
Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.
评估在接受利妥昔单抗（RTX）或环磷酰胺/硫唑嘌呤（CYC/AZA）治疗的抗中性粒细胞胞浆抗体（ANCA）相关血管炎（AAV）患者中，部分患者未通过初始治疗实现完全缓解或维持缓解的原因。
AAV试验中的利妥昔单抗试验是一项随机、双盲、安慰剂对照试验，比较接受RTX治疗的患者（n = 99）和接受CYC序贯AZA治疗的患者（n = 98）的缓解诱导率。糖皮质激素在5个月内逐渐减量。主要结局指标是6个月时在无糖皮质激素治疗情况下无疾病活动。为确定未达到主要结局的最重要原因，回顾性定义了7个层次类别的原因（疾病未控制、导致治疗中断的不良事件、严重复发、轻度复发、韦格纳肉芽肿病的伯明翰血管炎活动评分>0、任何剂量的泼尼松治疗以及其他）。
尽管197例患者中有170例（86%）在最初6个月内实现了缓解（无疾病活动），但42%的患者未达到主要结局指标。有3例死亡。24%的患者因疾病活动未达到主要终点：10例（5%）在第一个月疾病未得到控制，37例（19%）在初始改善后出现复发。在大多数此类患者中，采用盲法交叉治疗或根据最佳医学判断进行治疗可实现疾病控制。疾病未得到控制或经历严重复发的患者中，91%有蛋白酶3（PR3）-ANCA。当将疾病未得到控制的患者排除在分析之外时，发现PR3-ANCA阳性的患者在接受RTX治疗时比接受CYC/AZA治疗时复发更少（59例中的8例[14%]对62例中的20例[32%]；P = 0.02）。ANCA滴度和B细胞计数均不能预测疾病复发。
当前治疗方案在很大程度上成功控制了AAV，但约四分之一的患者在最初6个月内尽管接受了治疗，疾病活动仍持续或复发。PR3-ANCA阳性是严重疾病复发或持续的危险因素。ANCA滴度和B细胞可检测性在最初6个月内对疾病复发和疾病缓解的预测能力较差。
