|XU, CHANG - Brigham & Women'S Hospital|
|SELHUB, JACOB - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|PAYNTER, NINA - Brigham & Women'S Hospital|
|MACFADYEN, JEAN - Brigham & Women'S Hospital|
|GLYNN, ROBERT - Brigham & Women'S Hospital|
|RIDKER, PAUL - Brigham & Women'S Hospital|
|SOLOMON, DANIEL - Brigham & Women'S Hospital|
Submitted to: Rheumatology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/14/2020
Publication Date: 11/27/2020
Citation: Xu, C., Selhub, J., Jacques, P.F., Paynter, N.P., MacFadyen, J.G., Glynn, R.J., Ridker, P.M., Solomon, D.H. 2020. Adverse effects related to methotrexate polyglutamate levels: adjudicated results from the cardiovascular inflammation reduction trial. Rheumatology. 60(6):2963-2968. https://doi.org/10.1093/rheumatology/keaa650.
Interpretive Summary: Methotrexate (MTX) is a folate antagonist that helps the immune system to reduce inflammation. It is used to treat various inflammatory conditions, especially among older adults, most notably rheumatoid arthritis. However, MTX also has many side effects. We explored whether different metabolites of MTX were related to important side effects. Higher levels of specific MTX metabolites were modestly associated with higher risk of anemia and liver function abnormalities, but a lower risk of platelet deficiency in the blood, lessening the risk bleeding, bruising, and other blood clotting problems. A better understanding of the relationships of these metabolites to the side effects will help identify ways to limit side effects.
Technical Abstract: Objectives Methotrexate is widely used at low dosages (LD-MTX) for non-oncologic indications and is associated with a variety of adverse effects (AEs). We sought to determine whether concentrations of the active metabolite, MTX polyglutamates (MTX-PGs) 1-5, correlate with AEs. Method We examined data from the LD-MTX arm of the randomized double-blind Cardiovascular Inflammation Reduction Trial (CIRT). All AEs were blindly adjudicated and monitoring laboratories were tested centrally. The MTX-PGs 1-5 were assessed in one reference laboratory using liquid chromatography-tandem mass spectrometry. Based on prior literature, MTX-PGs 3-5 were chosen as the exposure of interest and quartiles of MTX-PGs 3-5 were assessed for their relationship with all AEs and each pre-specified category of AE using adjusted Cox proportional hazards regression. Results Of the 2391 subjects randomized to LD-MTX, MTX-PG levels were available for 1319 subjects (median dosage 16.1mg/week) from the 8 month visit. We followed these subjects for a median of 2.2 years [interquartile range (IQR) 1.5-2.9]. Higher MTX-PG3-5 levels were related to an increased risk of anaemia [compared with quartile 1 (Q1); hazard ratio (HR) for Q4 1.27 (95% CI 0.98, 1.65), P for trend=0.05] and a decreased risk of thrombocytopenia [HR for Q4 0.52 (95% CI 0.32, 0.84), P for trend=0.05]. MTX-PG3-5 levels >134nmol/l were associated with an increased risk of liver abnormalities [HR 1.36 (95% CI 1.08, 1.72)]. Conclusions Higher MTX- PG3-5 levels were modestly associated with LD-MTX AEs, including anaemia and liver function abnormalities, but a reduced risk of thrombocytopenia and haemorrhage.