Nakafero, G, Grainge, MJ, Card, T, Taal, MW, Aithal, GP, Zhang, W, Doherty, M, Fox, CP, Mallen, CD and Abhishek, A (2021) Development and validation of a prognostic model for leflunomide discontinuation with abnormal blood-tests during long-term treatment: cohort study using data from Clinical Practice Research Datalink Gold and Aurum. Rheumatology. ISSN 1462-0332

[thumbnail of keab790.pdf]
keab790.pdf - Accepted Version

Download (468kB) | Preview


OBJECTIVE: To develop and validate a prognostic model for leflunomide discontinuation with abnormal blood-test results. METHODS: Data from CPRD Gold and Aurum were used for model development and external validation respectively. Participants prescribed leflunomide between 01/01/2007 and 31/12/2019 were followed-up from six-months after first GP-prescription to the earliest of date of outcome, death, 5-year follow-up or 31/12/2019. Candidate prognostic factors were ascertained using theory and data driven approaches. Penalised Cox regression was performed to develop the risk equation, followed by internal validation using 500-bootstraps to correct for optimism. Multiple imputation was applied to handle missing data. Model performance was assessed in terms of calibration and discrimination. RESULTS: Data for 1,487 and 2,329 participants contributing 3,140 and 5,246 person-years follow-up were included in the development and validation cohorts, respectively. Thirteen candidate predictors were included in the model. Epilepsy, and either cytopenia or elevated liver enzymes during first six months of shared-care leflunomide prescription were strong predictors of drug discontinuation with hazard ratio (95%CI) 4.39 (1.74 -11.06) and 3.06 (2.15 - 4.35), respectively. The unadjusted and optimism adjusted calibration slope in development data was 1.00 (95% CI 0.75-1.25) and 0.72 (95% CI 0.47-0.97), respectively. The calibration slope in validation data was 0.91 (95% CI 0.74-1.07). The model showed prognostic separation with optimism adjusted Royston D statistic of 0.73 (95% CI 0.44-1.02). CONCLUSION: We have developed and externally validated an easy-to-use prognostic model that may be used to risk-stratify monitoring for leflunomide toxicity and to make informed choices about risks when choosing treatments.

Item Type: Article
Additional Information: © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
Uncontrolled Keywords: leflunomide; rheumatoid arthritis; psoriatic arthritis; drug toxicity; monitoring
Subjects: R Medicine > R Medicine (General)
R Medicine > RA Public aspects of medicine
R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine
Related URLs:
Depositing User: Symplectic
Date Deposited: 08 Dec 2021 09:59
Last Modified: 10 Jun 2022 09:32

Actions (login required)

View Item
View Item