Division of Rheumatology, Department of Medicine, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Pediatrico Bambino Gesù, Rome, Italy.
N Engl J Med. 2012 Dec 20;367(25):2385-95. doi: 10.1056/NEJMoa1112802.
Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA.
We randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension.
At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range.
Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).
全身型幼年特发性关节炎（JIA）是 JIA 中最严重的亚型；治疗选择有限。白细胞介素-6 在全身型 JIA 中起致病作用。
我们随机分配了 112 名年龄在 2 至 17 岁之间的患有活动性全身型 JIA（持续时间≥6 个月且对非甾体抗炎药和糖皮质激素反应不足）的儿童，接受抗白细胞介素-6 受体抗体托珠单抗（如果体重≥30 公斤，则剂量为 8 毫克/公斤体重，如果体重<30 公斤，则剂量为 12 毫克/公斤体重）或安慰剂，每 2 周静脉注射一次，持续 12 周的双盲期。不符合预定标准的患者可接受开放标签托珠单抗治疗。所有患者均可进入开放标签扩展期。
在第 12 周时，主要终点（无发热，美国风湿病学会 [ACR] JIA 核心标准中至少有三个变量改善≥30%，且没有一个变量恶化超过 30%）在托珠单抗组中明显更多的患者中得到满足（75 例中的 64 例 [85%]与 37 例中的 9 例 [24%]，P<0.001）。在第 52 周时，接受托珠单抗治疗的患者中有 80%至少有 70%的改善且无发热，包括 59%的患者有 90%的改善；此外，48%的患者没有活动关节炎的关节，52%的患者停止了口服糖皮质激素治疗。在双盲期，托珠单抗组发生了 159 起不良事件，包括 60 起感染（2 起严重感染），而安慰剂组发生了 38 起不良事件，包括 15 起感染。在双盲期和扩展期联合治疗中，接受托珠单抗治疗的患者中发生了 39 起严重不良事件（0.25 例/患者年），包括 18 起严重感染（0.11 例/患者年）。19 名患者（17 名患者为 3 级，2 名患者为 4 级）出现中性粒细胞减少症，21 名患者的转氨酶水平超过正常上限的 2.5 倍以上。
托珠单抗对严重、持续性全身型 JIA 有效。不良事件常见，包括感染、中性粒细胞减少症和转氨酶水平升高。（由 Hoffmann-La Roche 资助；ClinicalTrials.gov 编号，NCT00642460）。
