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. 2023 May 30:381:e074678.
doi: 10.1136/bmj-2022-074678.

Risk stratified monitoring for methotrexate toxicity in immune mediated inflammatory diseases: prognostic model development and validation using primary care data from the UK

Georgina Nakafero  1 , Matthew J Grainge  2 , Hywel C Williams  2 , Tim Card  2 , Maarten W Taal  3 , Guruprasad P Aithal  4 , Christopher P Fox  5 , Christian D Mallen  6 , Danielle A van der Windt  6 , Matthew D Stevenson  7 , Richard D Riley  8 , Abhishek Abhishek  9
Affiliations

Risk stratified monitoring for methotrexate toxicity in immune mediated inflammatory diseases: prognostic model development and validation using primary care data from the UK

Georgina Nakafero et al. BMJ. .

Abstract

Objective: To develop and validate a prognostic model to inform risk stratified decisions on frequency of monitoring blood tests during long term methotrexate treatment.

Design: Retrospective cohort study.

Setting: Electronic health records within the UK's Clinical Practice Research Datalink (CPRD) Gold and CPRD Aurum.

Participants: Adults (≥18 years) with a diagnosis of an immune mediated inflammatory disease who were prescribed methotrexate by their general practitioner for six months or more during 2007-19.

Main outcome measure: Discontinuation of methotrexate owing to abnormal monitoring blood test result. Patients were followed-up from six months after their first prescription for methotrexate in primary care to the earliest of outcome, drug discontinuation for any other reason, leaving the practice, last data collection from the practice, death, five years, or 31 December 2019. Cox regression was performed to develop the risk equation, with bootstrapping used to shrink predictor effects for optimism. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination.

Results: Data from 13 110 (854 events) and 23 999 (1486 events) participants were included in the development and validation cohorts, respectively. 11 candidate predictors (17 parameters) were included. In the development dataset, the optimism adjusted R2 was 0.13 and the optimism adjusted Royston D statistic was 0.79. The calibration slope and Royston D statistic in the validation dataset for the entire follow-up period was 0.94 (95% confidence interval 0.85 to 1.02) and 0.75 (95% confidence interval 0.67 to 0.83), respectively. The prognostic model performed well in predicting outcomes in clinically relevant subgroups defined by age group, type of immune mediated inflammatory disease, and methotrexate dose.

Conclusion: A prognostic model was developed and validated that uses information collected during routine clinical care and may be used to risk stratify the frequency of monitoring blood test during long term methotrexate treatment.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Institute for Health and Care Research. AA has received institutional research grants from AstraZeneca and Oxford Immunotech and personal fees from UpToDate (royalty), Springer (royalty), Cadilla Pharmaceuticals (lecture fees), NGM Bio (consulting), and Limbic (consulting), and personal fees from Inflazome (consulting) unrelated to the work. GP Aithal has received consulting fees from Clinipace, Amryth, GSK, DNDi, Pfizer, BenevolentAI Bio, Albireo Pharma, Abbott Products Operations, AstraZeneca, Merck, and PureTech paid to the University of Nottingham unrelated to the work. CPF has received consultancy or advisory board fees from Abbvie, GenMab, Incyte, Lily, Morphosys, Roche, Takeda, Ono, Kite/Gilead, BMS/Celgene, and BTG/Veriton and departmental research funding from BeiGene unrelated to the work.

Figures

Fig 1
Fig 1
Equation to predict risk of methotrexate discontinuation owing to abnormal monitoring blood test results after six months of primary care prescription and within next five years. Connective tissue diseases include lupus, systemic sclerosis, myositis, and small vessel vasculitis. Other immunosuppressant glucocorticoid sparing agents include leflunomide, azathioprine, ciclosporin, and tacrolimus. Antiepileptics include carbamazepine, levetiracetam, and sodium valproate. Blood test abnormality defined as either cytopenia (neutrophil count <2×109/L, total leucocyte count <4×109/L, or platelet count <150×109/L) or raised transaminase levels (alanine transaminase and/or aspartate transaminase >35 IU/L) during the first six months of a prescription for methotrexate in primary care
Fig 2
Fig 2
Calibration of a prognostic model for methotrexate discontinuation with abnormal monitoring blood test results at five years in development cohort. Data from a single imputed dataset were used for illustration. Baseline survival function (S0) was 0.895 at five years of follow-up. Black line reflects perfect prediction
Fig 3
Fig 3
Calibration of a prognostic model for methotrexate discontinuation with abnormal monitoring blood test results at five years in validation cohort. Data from a single imputed dataset were used for illustration. Baseline survival function (S0) was 0.895 at five years of follow-up. Black line reflects perfect prediction
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