Jayne David R W, Bruchfeld Annette N, Harper Lorraine, Schaier Matthias, Venning Michael C, Hamilton Patrick, Burst Volker, Grundmann Franziska, Jadoul Michel, Szombati István, Tesař Vladimír, Segelmark Mårten, Potarca Antonia, Schall Thomas J, Bekker Pirow
Department of Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom;
Department of Renal Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
J Am Soc Nephrol. 2017 Sep;28(9):2756-2767. doi: 10.1681/ASN.2016111179. Epub 2017 Apr 11.
Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; =0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; =0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.
替代补体C激活参与抗中性粒细胞胞浆抗体相关性血管炎的发病机制。然而，用于治疗的糖皮质激素会导致血管炎的发病率和死亡率升高。我们确定口服选择性C5a受体抑制剂阿伐可泮（CCX168）是否能在不影响疗效的情况下替代口服糖皮质激素。在这项随机、安慰剂对照试验中，新诊断或复发的血管炎成人患者接受安慰剂加每日60mg起始剂量的泼尼松（对照组）、阿伐可泮（30mg，每日两次）加减量泼尼松（每日20mg）或阿伐可泮（30mg，每日两次）不加泼尼松治疗。所有患者均接受环磷酰胺或利妥昔单抗治疗。主要疗效指标是在第12周时伯明翰血管炎活动评分降低≥50%且任何身体系统均无恶化的患者比例。我们纳入了67例患者，对照组23例，阿伐可泮各治疗组22例。对照组20例患者中有14例（70.0%）在第12周时达到临床缓解，阿伐可泮加减量泼尼松组22例患者中有19例（86.4%）达到临床缓解（与对照组差异为16.4%；双侧90%置信区间，-4.3%至37.1%；非劣效性检验P=0.002），阿伐可泮不加泼尼松组27例患者中有17例（81.0%）达到临床缓解（与对照组差异为11.0%；双侧90%置信区间，-11.0%至32.9%；非劣效性检验P=0.01）。对照组23例患者中有21例（91%）发生不良事件，阿伐可泮加减量泼尼松组22例患者中有19例（86%）发生不良事件，阿伐可泮不加泼尼松组22例患者中有21例（96%）发生不良事件。总之，阿伐可泮抑制C5a受体在治疗血管炎方面可有效替代大剂量糖皮质激素。
