Prognostic model stratifies risk for methotrexate toxicity

A prognostic model estimated the varying risk of methotrexate toxicity during long-term treatment and performed well across age groups, inflammatory conditions, methotrexate doses, and routes of administration.

To develop and validate the model for stratified decisions on frequency of monitoring blood tests during long-term methotrexate treatment, researchers conducted a retrospective cohort study using electronic health records within the U.K.'s Clinical Practice Research Datalink (CPRD) Gold and CPRD Aurum from January 2007 to December 2019. The researchers searched the databases for adults who had a diagnosis of an immune-mediated inflammatory disease and were prescribed methotrexate by their general practitioner for six months or more from 2007 to 2019. Results were published May 30 by The BMJ.

Patients were followed from six months after their first prescription for methotrexate to the earliest outcome: drug discontinuation for any other reason, leaving the practice, last data collection from the practice, death, five years, or an end date of Dec. 31, 2019. Researchers defined methotrexate toxicity-associated drug discontinuation as a prescription gap of 90 days or more with either an abnormal blood test result or a diagnostic code for an abnormal blood test result within 60 days of the last prescription date. Data from 13,110 patients (854 events) were included in the development cohort, and data from 23,999 patients (1,486 events) were included in the validation cohorts. Eleven candidate predictors (17 parameters) were included.

The study found that the prognostic model performed well predicting outcomes in clinically relevant subgroups of age, type of immune-mediated inflammatory disease, and methotrexate dose. The risk score output from the prognostic model could apply to individual monitoring strategies after the first six months of prescribing methotrexate.

“[It] would seem reasonable to offer patients at relatively low risk (eg, <10% over five years, representing 68.4% of the validation cohort) six monthly or annual testing, whereas those with moderate risk (eg, 10-20% over five years, representing 20.9% of the validation cohort) might continue with the current testing every three months, and those with high risk (eg, >20% over five years, representing 10.7% of the validation cohort) undergo more frequent testing,” the authors wrote.

The study noted that less frequent blood tests would save patients' and health professionals' time, minimize discomfort from unnecessary venipunctures, and conserve health care resources. “Patients taking methotrexate are usually adherent to monitoring recommendations and our model, if implemented, should reduce the volume of monitoring blood tests,” the authors wrote.

An editorial urged caution about a rare idiosyncratic toxicity that does not correlate with the dose, duration, or method of methotrexate administration and noted that most rheumatologists can identify the few patients who develop sudden leukopenia or thrombocytopenia or transaminitis severe enough to warrant stopping the drug.

“As in most of areas of medicine, the one-size-fits-all approach does not work for methotrexate users,” the editorial stated. “Monitoring for methotrexate toxicity needs to be tailored to individual patient characteristics backed by the clinical acumen of the practitioner, and individual patient preference for monitoring, creating a shared decision making process.”