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This is a plain English summary of an original research article. The views expressed are those of the author(s) and reviewer(s) at the time of publication.

People taking methotrexate (for inflammatory conditions such as rheumatoid arthritis) have regular blood tests to check for certain side effects. Researchers developed a tool to predict the likelihood of them discontinuing methotrexate due to these side effects. The tool could in future lead to less frequent testing for most people (68%) on methotrexate, they say. A few (11%) might need more frequent testing.

The tool uses information routinely collected by GPs. The study found that it could predict people’s risk of discontinuing methotrexate because of side effects. The tool was accurate for most people and across different ages, inflammatory conditions, methotrexate doses, and routes of administration.

The researchers say the tool could in future be used by GPs to identify people who need more (or less) frequent blood tests. This could save the NHS time and resources.

For more information on methotrexate, visit the NHS website.

The issue: who will discontinue methotrexate?

Methotrexate reduces inflammation. It is used to treat many conditions including inflammation of the skin in psoriasis, and of joints in rheumatoid arthritis or psoriatic arthritis. Approximately 1.3 million people in the UK take methotrexate.

Methotrexate can cause liver problems. It can also affect blood cells and cause low white cell count, which increases the risk of infection; and low platelet count, which can lead to bleeding. Methotrexate itself does not cause kidney problems, but in people with reduced kidney function, high levels of methotrexate can build up and cause side-effects.

When people first start taking the drug, they have a blood test every 2 to 4 weeks to detect these issues early. This means that treatment may be stopped before someone gets unwell. Later, blood tests are checked every 3 months. This is standard practice but there is no evidence to support the need for 3 monthly tests in all patients during long-term treatment. Previous research has shown that these side effects of methotrexate are uncommon after the first year of treatment.

In this study, researchers explored whether they could predict people’s risk of having to discontinue methotrexate due to blood, liver, or kidney problems. This could allow GPs to identify people in need of more (or less) frequent testing.  

What’s new?

The researchers analysed patient primary care records from 2 large databases. People were included in the study if they had a new diagnosis of an inflammatory condition and were prescribed methotrexate for 6 months or more during 2007 – 2019. Most (62%) had rheumatoid arthritis; most (63%) were female. People were followed up from 6 months after their first prescription in primary care for up to 5 years (or to drug discontinuation, death, leaving the practice, last data collection, or to end of study).

The researchers analysed the records to identify which disease and demographic factors were associated with the discontinuation of methotrexate following an abnormal blood test (within 60 days of the last prescription). Diabetes, chronic kidney disease (stage 3), and either blood thinning (low blood cell count) or liver problems (identified via raised liver enzymes) during the first 6 months of treatment (or both) were strong predictors of discontinuation.  

The researchers built a tool to predict people’s risk of methotrexate discontinuation based on factors such as age, sex, alcohol intake, smoking status, diabetes, other medications (such as statins and aspirin). They used one database (including 13,000 people and 854 events) to develop the tool, and a second database (including 24,000 people and 1,486 events) to test it.

The study found that the tool:

  • accurately predicted who would discontinue methotrexate
  • was accurate across age groups, conditions, methotrexate doses, and routes of administration.

The tool could divide people into risk groups according to their likelihood of discontinuing methotrexate over 5 years. The study found that, over the 5 years of follow-up:

  • most people (68%) had a low risk of discontinuation (fewer than 10% discontinued methotrexate)
  • some (21%) had a moderate risk (10 – 20% discontinued)
  • few (11%) had a high risk (more than 20% discontinued).

Why is this important?

The tool could in future be used by GPs to decide how often individuals need blood tests, the researchers say. Those at higher risk of side effects may need more frequent monitoring. But most were at low risk and could be monitored less often, which would save time and healthcare resources. Fewer tests could reduce anxiety and be more convenient for patients.  

The large, real-world datasets used in the study make the results generalisable. The tool uses routinely collected data and could be incorporated into electronic health records for use in consultations.

The tool is designed to assess people’s risk of discontinuation 6 months after a first prescription of methotrexate in primary care; it cannot assess risks for people who started treatment more recently. In addition, the model may not be accurate for people who are monitored in secondary care (such as those with multiple long-term conditions).

The researchers caution that some discontinuations may not have been due to methotrexate side effects. The drug may have been stopped because it was not effective, or because patients no longer needed it.

What’s next?

The researchers have shared their findings with the British Society of Rheumatology and the British Association of Dermatology. Changes to guidance on monitoring of methotrexate will be needed before clinicians change practice.

More research could confirm how frequently people should be monitored; but the tool is not intended to override patient preference or clinical judgement. Further research could also assess the cost-effectiveness and acceptability of targeted monitoring among clinicians and the public.

This study was part of a larger project assessing people’s risk of drug side effects. The researchers have developed a similar tool to predict risk of side effects with thiopurine,  leflunomide, and anti-TNF alpha drugs (drugs that also dampen the immune response).  

You may be interested to read

This is a summary of: Nakafero G, and others. Risk stratified monitoring for methotrexate toxicity in immune mediated inflammatory diseases: prognostic model development and validation using primary care data from the UK. British Medical Journal. 2023; 381: 1 – 10.

A BMJ commentary article about the study.

Another summary of the study produced by the NIHR.

A related study about predicting discontinuations of thiopurines: Nakafero G and others. Risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation. eClinical Medicine. 2023; 64: 1 – 13. 

A related study about predicting discontinuations of leflunomide: Nakafero G and others. Development and validation of a prognostic model for leflunomide discontinuation with abnormal blood tests during long-term treatment: cohort study using data from the Clinical Practice Research Datalink Gold and Aurum. Rheumatology. 2022; 61: 2783 – 2791.

A related study on patient and health professional views: Fuller A, and others. Patient and health professional views on risk-stratified monitoring of immune-suppressing treatment in adults with inflammatory diseases. Rheumatology. 2024; keae175.

Funding: this study was funded by the NIHR Research for Patient Benefit programme and the Health Technology and Assessment programme.

Conflicts of Interest: some study authors received fees and funding from pharmaceutical companies. See paper for full disclosures.

Disclaimer: Summaries on NIHR Evidence are not a substitute for professional medical advice. They provide information about research which is funded or supported by the NIHR. Please note that the views expressed are those of the author(s) and reviewer(s) at the time of publication. They do not necessarily reflect the views of the NHS, the NIHR or the Department of Health and Social Care.

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