Saag K G, Koehnke R, Caldwell J R, Brasington R, Burmeister L F, Zimmerman B, Kohler J A, Furst D E
Department of Internal Medicine, University of Iowa, Iowa City.
Am J Med. 1994 Feb;96(2):115-23. doi: 10.1016/0002-9343(94)90131-7.
The purpose of this study was to better define the toxicity of low dose (less than or equal to 15 mg/d prednisone or equivalent) long-term (greater than 1 year) corticosteroids in the treatment of rheumatoid arthritis (RA).
We examined an historical cohort of 112 RA patients on low dose (6.1 +/- 3.1 mg/d, mean +/- SD) long-term (6.2 +/- 4.6 years) prednisone (CS) and compared them to 112 matched RA patients not using prednisone (CO). CS were matched one-to-one with CO for sex (75% women), age (+/- 5 yrs), race (98% white), and duration of disease (+/- 5 yrs). Subjects were determined by review of unselected medical records from three distinct rheumatology practice settings. For CS, charts were abstracted from the date of prednisone start for predefined adverse events (AEs).
Ninety-two (92) AEs were noted in CS versus 31 in CO and included: fracture (CS:21 versus CO:8), serious infections (CS:14 versus CO:4), gastrointestinal (GI) bleed or ulcer (CS:11 versus CO:4), and cataracts (CS:17 versus CO:5). At time of first AE, CS prednisone average dose was 7.0 +/- 2.6 mg with a duration of 4.9 +/- 3.9 years. Stepwise multiple logistic regression analysis was used to create a model which included all clinically relevant variables and all parameters significantly different at the cohort inception. Prednisone average dose of greater than 10 to less than or equal to 15 mg/d correlated most strongly with the development of an AE (Odds Ratio (OR) = 32.3, 95% Confidence Interval (CI) 4.6, 220). Average prednisone 5 to 10 mg (OR = 4.5, 95% CI 2.1, 9.6), RA nodules (OR = 3.9, 95% CI 1.9, 8.0), and bony erosions (OR = 2.4, 95% CI 1.2, 4.7) also entered the final model. Kaplan Meier survival curves for the development of the first AE showed a dose-response relationship between prednisone and AE occurrence, independent of rheumatoid nodules. Subset analyses utilized a nested case control design for the development of three serious AEs: fractures, serious infections, and GI events. These analyses revealed possible relationships between prednisone use and the development of each specific AE (prednisone use OR: fracture 3.9, 95% CI 0.8, 18.1; infection 8.0, 95% CI 1.0, 64.0; and GI event 3.3, 95% CI 0.9, 12.1).
Although disease severity is an important confounding factor, low dose long-term prednisone use equal to or greater than 5 mg/d is correlated with the development of specific adverse events in a dose-dependent fashion.
本研究旨在更明确低剂量（小于或等于15毫克/天泼尼松或等效药物）长期（超过1年）使用皮质类固醇治疗类风湿关节炎（RA）的毒性。
我们研究了112例接受低剂量（6.1±3.1毫克/天，均值±标准差）长期（6.2±4.6年）泼尼松（CS）治疗的RA患者的历史队列，并将他们与112例未使用泼尼松的匹配RA患者（CO）进行比较。CS组与CO组在性别（75%为女性）、年龄（±5岁）、种族（98%为白人）和病程（±5年）方面进行一对一匹配。通过查阅来自三个不同风湿病诊疗机构的未经筛选的医疗记录来确定研究对象。对于CS组，从泼尼松开始使用日期起提取病历，记录预先定义的不良事件（AE）。
CS组记录到92例AE，而CO组为31例，包括：骨折（CS组：21例 vs CO组：8例）、严重感染（CS组：14例 vs CO组：4例）、胃肠道（GI）出血或溃疡（CS组：11例 vs CO组：4例）以及白内障（CS组：17例 vs CO组：5例）。首次出现AE时，CS组泼尼松平均剂量为7.0±2.6毫克，用药时长为4.9±3.9年。采用逐步多元逻辑回归分析建立一个模型，该模型纳入了所有临床相关变量以及在队列起始时所有显著不同的参数。泼尼松平均剂量大于10至小于或等于15毫克/天与AE发生的相关性最强（比值比（OR）=32.3，95%置信区间（CI）4.6，220）。泼尼松平均剂量5至10毫克（OR = 4.5，95% CI 2.1，9.6）、类风湿结节（OR = 3.9，95% CI 1.9，8.0）以及骨侵蚀（OR = 2.4，95% CI 1.2，4.7）也纳入了最终模型。首次出现AE的Kaplan Meier生存曲线显示泼尼松与AE发生之间存在剂量反应关系，与类风湿结节无关。亚组分析采用巢式病例对照设计，针对三种严重AE（骨折、严重感染和胃肠道事件）的发生情况进行研究。这些分析揭示了使用泼尼松与每种特定AE发生之间可能存在的关系（使用泼尼松的OR：骨折3.9，95% CI 0.8，18.1；感染8.0，95% CI 1.0，64.0；胃肠道事件3.3，95% CI 0.9，12.1）。
尽管疾病严重程度是一个重要的混杂因素，但长期使用低剂量泼尼松（等于或大于5毫克/天）与特定不良事件的发生呈剂量依赖性相关。
