In a recent study posted to the medRxiv* preprint server, researchers evaluated if folic acid or methotrexate use impacts the risk of coronavirus disease 2019 (COVID-19) diagnosis or associated mortality in the United Kingdom (UK).
A β-vitamin called folate has vital functions in one-carbon units transfer in intermediary metabolism in mitochondria. Further, it is involved in various reactions such as methionine production from homocysteine and the synthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
Previous studies have established that folate metabolism is involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectiousness. Hence, medicines affecting folate metabolism may influence the probability of SARS-CoV-2 diagnosis and outcomes, including mortality.
Study: FOLIC ACID AND METHOTREXATE USE AND THEIR ASSOCIATION WITH COVID-19 DIAGNOSIS AND MORTALITY: AN ANALYSIS FROM THE UK BIOBANK. Image Credit: sfam_photo/Shutterstock
About the study
In the present study, the researchers determined whether methotrexate or folic acid prescriptions alone or combined were linked to a higher or lower probability for SARS-CoV-2 diagnosis or associated mortality, respectively, in an extensive population-based cohort from the UK.
The researchers conducted the case-control investigation of COVID-19 using the population-based UK Biobank (UKBB) cohort. Information, including general practice prescription data for 2019 to 2021, was gathered for 380,380 UKBB participants. Further, updated medical data was retrieved on December 13, 2021.
COVID-19 diagnosis was made using the following criteria: 1) a SARS-CoV-2-positive polymerase chain reaction (PCR) test or 2) 10th revision of International Classification of Diseases (ICD-10) code, U07.1 indicating confirmed SARS-CoV-2, or U07.2 for possible COVID-19 in hospital or death records. Of the 26,003 subjects with COVID-19 identified using the above-mentioned criteria, 820 had COVID-19 as the known cause of death.
The data were analyzed by logistic regression statistical models adjusted for gender, age, ethnicity, smoking status, body mass index (BMI), Townsend deprivation index, presence of sickle cell disease, rheumatoid arthritis (RA), use of statins, iron supplements, and anticonvulsants.
The results indicate that individuals prescribed with folic acid had high chances of COVID-19 diagnosis relative to those without either methotrexate or folic acid. Methotrexate prescription with or without folic acid did not increase the chances of COVID-19 diagnosis since the proportion of methotrexate recipients diagnosed with SARS-CoV-2 was comparable to the individuals who were not taking either of the drugs evaluated in the study.
Individuals in a fully adjusted model taking folic acid supplementation demonstrated a positive association with mortality following the COVID-19 diagnosis. In detail, those consuming folic acid had a 1.5- and 2.6-times risk of COVID-19 diagnosis and SARS-CoV-2-related death, respectively, compared to those who are not on this drug.
Further, the prescription of methotrexate combined with folic acid did not elevate the risk for COVID-19-associated mortality. Moreover, combining methotrexate with folic acid might reduce the risk of SARS-CoV-2 diagnosis and COVID-19-associated death induced by folic acid since cohorts on folic acid and methotrexate combination had no increased risk of SARS-CoV-2 diagnosis or COVID-19-related death. This finding indicates that the folate supply enhanced the replication of SARS-CoV-2, and using an antifolate drug like methotrexate potentially reduced this adverse effect.
The researchers failed to estimate the risk of COVID-19-related mortality in those administering methotrexate alone due to the small size of that cohort.
The study findings reinforce the hypothesis that high folate levels resulting from folic acid supplementation led to increased chances of acquiring clinically detectable SARS-CoV-2 infection and mortality following COVID-19 diagnosis. However, the generalizability of the current findings is limited to individuals older than 45 years and those from White European ethnicities of the UK population.
However, the study provides crucial information for future studies evaluating the impact of folic acid supplementation on COVID-19-associated morbidity and mortality, especially during gestation and individuals on anticonvulsants requiring supplemental folic acid.
Although an excessive level of folic acid increases SARS-CoV-2 replication, as seen in the present study, inadequate folic acid levels result in impaired host resistance to SARS-CoV-2 infection as indicated by previous investigations. Combining both the observations, an optimal range of physiological folate status may be related to host resistance to SARS-CoV-2 and disease severity.
Overall, the study demonstrates a high risk of SARS-CoV-2 diagnosis and associated death in those taking folic acid than those without this drug and suggests that co-administration of methotrexate with folic acid might attenuate this risk. Further investigations exploring the impact of folate status and folic acid intake on susceptibility to SARS-CoV-2 infection and its fatal complications are warranted.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.