Folic acid and methotrexate use and their association with COVID-19 diagnosis and mortality: a case–control analysis from the UK Biobank

Abstract

ObjectiveTo determine if methotrexate or folic acid prescription was associated with differential risk for COVID-19 diagnosis or mortality.DesignCase–control analysis.SettingThe population-based UK Biobank (UKBB) cohort.ParticipantsData from 380 380 UKBB participants with general practice prescription data for 2019–2021. Updated medical information was retrieved on 13 December 2021.Primary and secondary outcome measuresThe outcomes of COVID-19 diagnosis and COVID-19-related mortality were analysed by multivariable logistic regression. Exposures evaluated were prescription of folic acid and/or methotrexate. 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, body mass index, smoking status, presence of rheumatoid arthritis, sickle cell disease, use of anticonvulsants, statins and iron supplements.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)).ConclusionsWe report an association of increased risk for COVID-19 diagnosis and COVID-19-related death in people prescribed folic acid supplementation. Our results also suggest that methotrexate might attenuate these associations.

The Role of Folic Acid in SARS-CoV-2 Infection: An Intriguing Linkage under Investigation

“…Conversely, as stated by Topeless et al, folate supplementation may aid the production of large amounts of the virus through a simple biosynthetic role, thus calling into question all the in silico findings mentioned above [ 36 ]. Topless et al investigated FA and methotrexate usage and their association with COVID-19 diagnosis and mortality using the UK Biobank [ 36 ].…”

“…Conversely, as stated by Topeless et al, folate supplementation may aid the production of large amounts of the virus through a simple biosynthetic role, thus calling into question all the in silico findings mentioned above [ 36 ]. Topless et al investigated FA and methotrexate usage and their association with COVID-19 diagnosis and mortality using the UK Biobank [ 36 ]. There were specific criteria for COVID-19 diagnosis, such as 1. a positive SARS-CoV-2 test or 2. an ICD-10 code for confirmed COVID-19 (U07.1) or probable COVID-19 (U07.2) in the hospital or death records.…”

“…There were specific criteria for COVID-19 diagnosis, such as 1. a positive SARS-CoV-2 test or 2. an ICD-10 code for confirmed COVID-19 (U07.1) or probable COVID-19 (U07.2) in the hospital or death records. According to these criteria, 26,003 individuals were identified with COVID-19, of whom 820 were known to have died from SARS-CoV-2 infection [ 36 ].…”

“…Further statistical analysis was carried out using logistic regression statistical models, which were adjusted for age, ethnicity, sex, Townsend deprivation index, body mass index (BMI), presence of rheumatoid arthritis, smoking status, sickle cell disease, and use of other medications, such as anticonvulsants, statins, and iron supplements [ 36 ]. Compared with subjects prescribed neither FA nor methotrexate, subjects prescribed FA supplementation had an increased risk of a diagnosis of COVID-19 (OR: 1.51, 1.42–1.61) [ 36 ].…”

Associations of habitual glucosamine use with SARS-CoV-2 infection and hospital admission and death with COVID-19: Evidence from a large population based cohort study

“…Although habitual glucosamine use has been identified to reduce the risk of lung cancer, type 2 diabetes, cardiovascular diseases, and all-cause mortality by several observational studies [12][13][14][15][16][17] , its association with COVID-19 remains unknown. In addition, several studies on other dietary supplements, including vitamin C 18 , vitamin D 19 , and folic acid 20 , did not identify any significantly reduced risks for the COVID-19-related outcomes under their use.…”