Development and validation of a prognostic model for predicting the risk of allopurinol-induced severe cutaneous adverse reactions: a retrospective new-user cohort study using linked primary care, hospitalisation, and mortality data.

IF 16.4 1区 医学 Q1 RHEUMATOLOGY
Edoardo Cipolletta, Georgina Nakafero, Davide Rozza, Satveer K Mahil, Catherine H Smith, Richard D Riley, Abhishek Abhishek
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引用次数: 0

Abstract

Background: Allopurinol, the most prescribed urate-lowering drug, is a known cause of severe cutaneous adverse reactions. We aimed to develop and validate a model to assess the risk of allopurinol-induced severe cutaneous adverse reactions in adults newly prescribed allopurinol.

Methods: In this retrospective new-user cohort study, we developed and validated a prognostic model using primary care, hospitalisation, and mortality data extracted from the UK Clinical Practice Research Datalink (CPRD) primary care database, for the period Jan 1, 2001, to March 29, 2021. Data from CPRD Aurum was used for model development and data from and CPRD GOLD was used for model validation. Adults (aged ≥18 years) residing in England who were newly prescribed allopurinol were followed up for 100 days to assess whether a severe cutaneous adverse reaction was recorded in hospitalisation or mortality records. Risk predictors included in the model were age, sex, ethnicity, chronic kidney disease stage, initial allopurinol dose, ischaemic heart disease, and heart failure. The primary outcome was to predict the 100-day risk of allopurinol-induced severe cutaneous adverse reactions in people newly prescribed allopurinol. We developed the model using multivariable Cox regression and pseudo-values, followed by penalisation and external validation. We assessed calibration, discrimination, and clinical utility in the risk range of 0·0001 to 0·003. People with lived experience of allopurinol use or gout were not involved in developing this research question, but will be involved in the dissemination of results.

Findings: 225 761 patients newly prescribed allopurinol were registered in the CPRD Aurum database (development cohort) and 173 812 were included in the study. 44 630 (25·7%) of 173 812 patients were female, 129 182 (74·3%) were male, 154 323 (88·8%) were White, and the mean age was 63·9 years (SD 15·0). Of the patients newly prescribed allopurinol with data in the CPRD GOLD database (validation cohort), 55 395 patients were screened and 41 610 were included in the study. 10 829 (26·0%) of 41 610 patients were female, 30 781 (74·0%) were male, 37 242 (89·5%) were White and the mean age was 64·4 years (SD 14·9). 63 (0·04%) severe cutaneous adverse events occurred in 173 812 patients in the development cohort and 16 (0·04%) occurred in 41 610 patients in the validation cohort. Age (adjusted hazard ratio 1·03 [95% CI 1·01-1·06]), chronic kidney disease stages 3, 4, and 5 (2·24 [1·20-4·17] for stage 3; 6·65 [2·90-15·23] for stage 4; 18·85 [6·32-56·19] for stage 5), initial allopurinol dose of 300 mg or higher (5·99 [3·56-0·08]), South Asian ethnicity (5·35 [2·37-12·07]), and other Asian ethnicity (5·63 [1·34-23·61]) were associated with the 100-day risk of allopurinol-induced severe cutaneous adverse reactions. In the development dataset, after optimism-adjustment, the model's explained variation (Royston and Sauerbrei's R2D) was 0·50 and Harrell's C was 0·82. In the validation dataset, the calibration slope was 0·93 (95% CI 0·18-1·68), the R2D was 0·44 (95% CI 0·20-0·62), and Harrell's C was 0·79 (95% CI 0·71-0·88). The model had clinical utility across the prespecified risk range.

Interpretation: We developed and validated a prognostic model for the 100-day risk of an allopurinol-induced severe cutaneous adverse reaction with good predictive performance and clinical utility. This model could be used to inform the choice of urate-lowering drugs.

Funding: University of Nottingham.

别嘌呤醇诱导的严重皮肤不良反应风险预测模型的开发和验证:一项回顾性新用户队列研究,使用相关的初级保健、住院和死亡率数据。
背景:别嘌呤醇是处方最多的降尿酸药物,是已知的严重皮肤不良反应的原因。我们的目的是建立和验证一个模型,以评估成人新开别嘌呤醇诱导的严重皮肤不良反应的风险。方法:在这项回顾性新用户队列研究中,我们开发并验证了一个预后模型,该模型使用了从英国临床实践研究数据链(CPRD)初级保健数据库中提取的2001年1月1日至2021年3月29日期间的初级保健、住院和死亡率数据。CPRD Aurum的数据用于模型开发,CPRD GOLD和CPRD GOLD的数据用于模型验证。对新开别嘌呤醇处方的居住在英国的成年人(年龄≥18岁)进行100天的随访,以评估在住院或死亡记录中是否记录了严重的皮肤不良反应。模型中的风险预测因素包括年龄、性别、种族、慢性肾脏疾病分期、初始别嘌呤醇剂量、缺血性心脏病和心力衰竭。主要结局是预测新开别嘌呤醇处方的患者发生别嘌呤醇诱导的严重皮肤不良反应的100天风险。我们使用多变量Cox回归和伪值开发模型,然后进行惩罚和外部验证。我们在0.001 ~ 0.003的风险范围内评估了校准、鉴别和临床效用。有别嘌呤醇使用或痛风生活经验的人没有参与开发这个研究问题,但将参与结果的传播。结果:在CPRD Aurum数据库(开发队列)中登记了225761例新开别嘌呤醇的患者,其中17812例纳入了研究。173 812例患者中,女性44 630例(25.7%),男性129 182例(74.3%),白人154 323例(88.8%),平均年龄63.9岁(SD 15.0)。在CPRD GOLD数据库(验证队列)中有数据的新开别嘌呤醇的患者中,筛选了55395例患者,其中41010例纳入研究。41 610例患者中,女性10 829例(26.0%),男性30 781例(71.4%),白人37 242例(89.5%),平均年龄64.4岁(SD 14.9)。发展组中有173 812例患者发生63例(0.04%)严重皮肤不良事件,验证组中有41 610例患者发生16例(0.04%)严重皮肤不良事件。年龄(校正危险比1.03 [95% CI 1.01 - 1.06])、慢性肾脏疾病3、4、5期(3期2.24[1.20 - 4.17]、4期6.65[2.90 - 15.23]、5期18.85[6.32 - 56.19])、初始别嘌呤醇剂量≥300 mg(5.99[3.56 - 0.08])、南亚民族(5.35[2.37 - 12.07])和其他亚洲民族(5.63[1.34 - 23.61])与别嘌呤醇诱导的100天严重皮肤不良反应风险相关。在发展数据集中,经过乐观调整后,模型的解释变异(Royston和Sauerbrei的R2D)为0.50,Harrell的C为0.82。在验证数据集中,校正斜率为0.93 (95% CI为0.18 - 1.68),R2D为0.44 (95% CI为0.20 - 0.62),Harrell’s C为0.79 (95% CI为0.71 - 0.88)。该模型在预先规定的风险范围内具有临床效用。解释:我们开发并验证了别嘌呤醇诱导的严重皮肤不良反应100天风险的预后模型,具有良好的预测性能和临床实用性。该模型可用于指导降尿酸药物的选择。资助:诺丁汉大学。
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来源期刊
Lancet Rheumatology
Lancet Rheumatology RHEUMATOLOGY-
CiteScore
34.70
自引率
3.10%
发文量
279
期刊介绍: The Lancet Rheumatology, an independent journal, is dedicated to publishing content relevant to rheumatology specialists worldwide. It focuses on studies that advance clinical practice, challenge existing norms, and advocate for changes in health policy. The journal covers clinical research, particularly clinical trials, expert reviews, and thought-provoking commentary on the diagnosis, classification, management, and prevention of rheumatic diseases, including arthritis, musculoskeletal disorders, connective tissue diseases, and immune system disorders. Additionally, it publishes high-quality translational studies supported by robust clinical data, prioritizing those that identify potential new therapeutic targets, advance precision medicine efforts, or directly contribute to future clinical trials. With its strong clinical orientation, The Lancet Rheumatology serves as an independent voice for the rheumatology community, advocating strongly for the enhancement of patients' lives affected by rheumatic diseases worldwide.
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