FOLIC ACID AND METHOTREXATE USE AND THEIR ASSOCIATION WITH COVID-19 DIAGNOSIS AND MORTALITY: AN ANALYSIS FROM THE UK BIOBANK
Authors: Topless Ruth K , Green Ralph , Morgan Sarah L. , Robinson Philip C , Merriman Tony R , Gaffo Angelo L. 
Published: February 2022

AbstractImportanceFolate metabolism is implicated in SARS-CoV-2 infectivity. Medication affecting folate metabolism may influence the risk of COVID-19 diagnosis and outcomes.Objectiveto determine if methotrexate (an antifolate) or folic acid prescription were associated with differential risk, for COVID-19 diagnosis or mortality.Design, Setting, and ParticipantsCase-control analysis of COVID-19 from the population-based UK Biobank (UKBB) cohort. Updated medical information was retrieved on the 13th December 2021. Data from 380,380 UKBB participants with general practice prescription data for 2019 to 2021 were used. Criteria for COVID-19 diagnosis were 1) a positive SARS-CoV-2 test or 2) ICD-10 code for confirmed COVID-19 (U07.1) or probable COVID-19 (U07.2) in hospital records, or death records. By these criteria 26,003 individuals were identified with COVID-19 of whom 820 were known to have died from COVID-19. Logistic regression statistical models were adjusted for age sex, ethnicity, Townsend deprivation index, BMI, smoking status, presence of rheumatoid arthritis, sickle cell disease, use of anticonvulsants, statins and iron supplements.ExposuresPrescription of folic acid and/or methotrexate.Main outcomes and measuresThe outcomes of COVID-19 diagnosis and COVID-19 related mortality were analyzed by multivariable logistic regression. The odds ratios from different exposures were compared.ResultsCompared with people prescribed neither folic acid nor methotrexate, people prescribed folic acid supplementation had increased risk of diagnosis of COVID-19 (OR 1.51 [1.42 ; 1.61]). The prescription of methotrexate with or without folic acid was not associated with COVID-19 diagnosis (P≥0.18). People prescribed folic acid supplementation had positive association with death after a diagnosis of COVID-19 (OR 2.64 [2.15 ; 3.24]) in a fully adjusted model. The prescription of methotrexate in combination with folic acid was not associated with an increased risk for COVID-19 related death (1.07 [0.57 ; 1.98]).Conclusions and RelevanceWe report increased risk for COVID-19 diagnosis and COVID-19-related death for people prescribed folic acid supplementation. Prescription and use of supplemental folic acid may confer increased risk of infection with SARS-CoV-2 and increased risk of death resulting from COVID-19. Our results indicate that methotrexate attenuates an increased risk for COVID-19 diagnosis and death conferred by folic acid.Key PointsQuestionDoes folate supplementation and/or methotrexate use affect the risk COVID-19 diagnosis and COVID-19 associated mortality?FindingsIn this epidemiological analysis from the UK Biobank, folic acid supplementation was associated with a 1.5-fold increased risk of COVID-19 diagnosis and a 2.6-fold increased risk of COVID-19 associated mortality. Methotrexate use might attenuate an increased risk for COVID-19 diagnosis and death conferred by folic acid.MeaningFolic acid supplementation appears to be associated with increased risk for COVID-19 diagnosis and associated mortality while methotrexate use attenuated this risk