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非感染性中间,后部或全视网膜炎皮质类固醇相关不良事件随皮质类固醇剂量而系统性增加:VISUAL-1和VISUAL-2试验事后分析

Suhler, E.B., Thorne, J.E., Mittal, M., et al.

期刊名称:Ophthalmology

卷期:2017年第124卷第12期

摘要

摘要:目的:长期使用糖皮质激素治疗葡萄膜炎与药物相关毒性和不良事件(AEs)有关。本研究探讨了皮质类固醇剂量与皮质类固醇相关AE发生率之间的关系。设计:VISUAL-1VISUAL-2安慰剂对照临床试验事后分析。研究对象:临床试验包括活动性(VISUAL -1)和非活动性(VISUAL-2)非感染性中间,后部和全葡萄膜炎。患者随机分配接受阿达木单抗或安慰剂,并接受方案确定的强制性逐步停止口服皮质类固醇。方法:每次随访时收集不良事件数据,并由研究者对皮质类固醇关系进行评估。使用纵向泊松回归模型估计时间依赖性皮质类固醇剂量,年龄,性别,既往口服皮质类固醇剂量,既往局部皮质类固醇的使用以及免疫抑制药物的应用。仅考虑随机进行安慰剂治疗的患者。主要观察指标:主要观察指标为AEs发作频率。结果:VISUAL-1泼尼松治疗期间安慰剂患者皮质类固醇相关性AEs的发生率在统计学上高于停药后(每100 454.2/100例患者.[PY]36.1,事件发生率= 12.6P <0.001)。 VISUAL-2组患者的发病率相似(317.5 / 100PY41.1 / 100PY,事件发生率= 7.7P <0.001)。基于泊松多变量纵向广义估计方程(GEE)模型,泼尼松剂量每增加10mg,则VISUAL-1VISUAL-2皮质类固醇相关AEs率分别增加1.5倍和2.6倍(P <0.001P <0.001)。这意味着与每天服用10mg的患者相比,每天服用泼尼松60 mg / d的活动性葡萄膜炎患者平均每年会有额外10.1次(95%可信区间(CI),6.3-14.5; P <0.001)的皮质类固醇相关AEs,而每天服用泼尼松35mg /天的非活动性葡萄膜炎患者每年平均会有额外23.5次(95CI7.6-52.7; P = 0.05)的皮质类固醇相关AEs。结论:来自VISUAL-1VISUAL-2的证据表明,皮质类固醇相关AEs的发生率随着皮质类固醇剂量的增加而呈系统性增加。

PURPOSE:Chronic use of corticosteroids for the treatment of uveitis has been linked with drug-associated toxicity and adverse events (AEs). This study examines the association between corticosteroid dosage and incidence rates of corticosteroid-related AEs.DESIGN:A post hoc analysis of the VISUAL-1 and VISUAL-2 placebo-controlled clinical trials.PARTICIPANTS:The clinical trials consisted of adults with active (VISUAL-1) and inactive (VISUAL-2) noninfectious intermediate, posterior, and panuveitis. Patients were randomized to receive adalimumab or placebo and underwent a protocol-defined mandatory taper to discontinue their oral corticosteroids.METHODS:Adverse event data were collected at each visit and included an assessment of the corticosteroid relationship by the investigator. A longitudinal Poisson regression model was estimated controlling for time-dependent corticosteroid dose, age, sex, prior oral corticosteroid dose, prior topical corticosteroid use, and concomitant immunosuppressive drug use. Only patients randomized to placebo were considered.MAIN OUTCOME MEASURES:The primary outcome measure was the frequency of AEs.RESULTS:The incidence rates of corticosteroid-related AEs among placebo patients during the prednisone treatment period in VISUAL-1 was statistically higher than after discontinuation (454.2 per 100 patient-years [PY] vs. 36.1 per 100 PY, incident rate ratio= 12.6, P < 0.001). Incidence rate ratios among VISUAL-2 patients were similarly high (317.5 per 100 PY vs. 41.1 per 100 PY, incident rate ratio= 7.7, P < 0.001). Based on the Poisson multivariate longitudinal Generalized Estimating Equation (GEE) model, each 10 mg increase in prednisone dose is associated with a 1.5- and 2.6-fold increase (P < 0.001 and P < 0.001) in the rate of corticosteroid-related AEs in VISUAL-1 and VISUAL-2, respectively. This implies in turn that a patient with active uveitis taking 60 mg/day of prednisone will experience, on average, an additional 10.1 (95% confidence interval (CI), 6.3-14.5; P < 0.001) corticosteroid-related AEs per year compared with a patient taking 10 mg/day, whereas a patient with inactive uveitis taking 35 mg/day of prednisone will experience, on average, an additional 23.5 (95% CI, 7.6-52.7; P= 0.05) corticosteroid-related AEs per year compared with a patient taking 10 mg/day.CONCLUSIONS:Evidence from VISUAL-1 and VISUAL-2 suggests that the incidence rates of corticosteroid-related AEs increase systematically with corticosteroid dose.


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