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

OBJECTIVE: To determine if methotrexate or folic acid prescription was associated with differential risk for COVID-19 diagnosis or mortality. DESIGN: Case-control analysis. SETTING: The population-based UK Biobank (UKBB) cohort. PARTICIPANTS: Data 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 MEASURES: The 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. RESULTS: Compared 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: We 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 importance of inhibition of a catabolic pathway of methotrexate metabolism in its efficacy for rheumatoid arthritis.

Methotrexate (MTX), an antifolate, is the anchor drug for the treatment of rheumatoid arthritis (RA). It is inexpensive, effective, and generally safe. When clinical response is inadequate, biological therapies are commonly used in combination with MTX. However, biological agents have safety concerns (i.e. infections, malignancy) and the addition of a biologic agent is expensive, making strategies to improve MTX efficacy important. Inhibition of pathways of folate metabolism involving purine metabolism by MTX, have been traditionally emphasized as important in MTX efficacy. However, inhibition MTX catabolism may also be important. MTX is irreversibly hydroxylated to form 7-hydroxy methotrexate (7-OH-MTX) by aldehyde oxidase (EC 1.2.3.1) (AOX). Catabolism of MTX to 7-OH-MTX is the first metabolic process imposed on an oral dose of MTX and will alter subsequent interactions of MTX with other enzymes. 7-OH-MTX is less potent than MTX in the treatment of rat adjuvant arthritis. RA patients with a low capacity to catabolize MTX to 7-OH-MTX do better clinically than individuals who are rapid formers of 7-OH-MTX. Therefore, altering the catabolism of MTX may be an innovative way to improve MTX efficacy. Raloxifene is a FDA-approved therapy for postmenopausal osteoporosis and for the reduction of invasive breast cancers but has no known activity in RA. Raloxifene is a potent inhibitor of human liver AOX. Postmenopausal women with RA frequently have low bone mineral density and would be candidates for raloxifene and MTX combination therapy. The effect of raloxifene on MTX metabolism has never been studied. Our hypothesis is that in postmenopausal women with RA and osteoporosis treated with MTX and raloxifene, the inhibition of AOX with resultant decreased formation of 7-OH MTX; will increase MTX levels and improve MTX efficacy. This hypothesis could be studied in an open-label, proof of concept clinical study in individuals before and after the addition of raloxifene. Red blood cell MTX and 7-OH-MTX levels and RA disease activity (DAS28) would be measured. In possible future studies, there are dietary substances, as supplements, (e.g. epigallocatechin gallate in green tea and resveratrol) which inhibit human liver AOX which could be evaluated.

Dietary supplements and medical foods for osteopenia and osteoporosis.

Dietary supplements, medical foods, and pharmaceutical agents are all used in the management of metabolic bone disease. The intended populations, governing regulations, safety standards scientific requirements, physician supervision, and distribution vary markedly between supplements, medical foods, and drugs. This article will review characteristics of dietary supplements and medical foods and their use in osteoporosis care. A study that compares the pharmacokinetics of a supplement and a medical food containing similar ingredients is used to contrast the categories of dietary supplements and medical foods.

Trends in dual-energy X-ray absorptiometry in the United States, 2000-2009.

After a decade of policies encouraging dual-energy X-ray absorptiometry (DXA) use, Medicare incrementally decreased reimbursement for non-facility-based DXAs, effective 2007. This study quantifies trends in central DXA use before and after the reimbursement change. Using 2000-2009 claims data, we selected subjects aged 50+yr with Medicare supplemental or commercial insurance. The central site DXA test (using CPT codes) rate was calculated within each calendar quarter as the number of patients with a DXA test divided by the total number of patients. Piecewise linear regression was used to quantify change in DXA rates coincident with the 2007 reimbursement reductions. During 2000-2009, slightly over 5 million DXA tests were conducted. Annual rates for females with Medicare steadily increased until 2007, when they leveled off; a similar pattern was observed for the commercially insured. Regression modeling showed that pre-2007 rates increased annually by 0.76% (0.72-0.80) and 0.76% (0.70-0.82) among those with Medicare supplemental and commercial insurance, respectively, and over 2007-2009, rates changed annually by +0.07% (-0.05% to 0.19%) and -0.12% (-0.29% to 0.04%), respectively. During 2007-2009, there were 3.1 (2.4-3.8) and 4.0 (3.1-4.9) fewer tests per 100 person years for females with Medicare supplemental and commercial insurance, respectively, than would have been expected based on the pre-2007 trend. The post-2007 DXA rate was lower than what would have been expected had the observed trend of increasing annual DXA rates from 2000 to 2007 continued unabated beyond the Medicare reimbursement change in 2007. Continuing to provide access to DXA testing for women at increased risk of osteoporosis is important to providing high-quality care for metabolic bone disease in the United States.

Nutrition and bone: it is more than calcium and vitamin D.

Unlike pharmacological agents that are taken for proscribed periods of time, food and nutrient intakes have the possibility of affecting bone health over the entire lifespan. While deficiencies or excesses of individual nutrients have been shown to affect bone, it is likely that individual foods or dietary patterns have important effects related to skeletal health. While biochemical mechanisms exist to relate a deficiency of vitamin K to altered bone metabolism, clinical trials related to supplementation of this nutrient have been confusing. It is likely that these disparate results are related to the fact that interactions of nutrients have not been considered or the possibility that suboptimal nutrient status is a marker of poor nutritional status. Vitamin A excess has been postulated to be related to high fracture risk; however, it is likely that retinol is not the best marker for the proposed interaction. Altering whole food patterns, such as the Dietary Approaches to Stop Hypertension diet, have demonstrated beneficial effects on bone metabolism. Individuals who select some vegetarian patterns may need to consider supplementation with nutrients such as calcium and protein. Future studies should center on whole food and dietary patterns and their relationship to bone metabolism and fracture risk.

The safety of flavocoxid, a medical food, in the dietary management of knee osteoarthritis.

This study was designed to determine the safety of a medical food, flavocoxid, a proprietary blend of free-B ring flavonoids and flavans from the root of Scutellaria baicalensis (Chinese skullcap) and the bark of Acacia catechu in the dietary management of knee osteoarthritis. The 12-week, randomized, double-blind, placebo-controlled trial in an academic medical center enrolled 59 patients with moderate osteoarthritis of at least one knee who were recruited who were classified as having "below average" to "a moderately above average cardiovascular risk" with a Framingham-based scoring tool. Subjects were randomized to flavocoxid 250 mg twice a day versus identical placebo. Safety measures, including recording of adverse events, incidence of serious adverse events, and results of routine laboratory values, were compared between the two groups. There were no major differences in the baseline demographic characteristics of the placebo and flavocoxid groups. With one exception no significant differences were found between the two groups with respect to adverse events by body system, blood pressure, or laboratory values. There was a significantly higher incidence of upper respiratory adverse events in the placebo group (35.4% vs. 5.8%, P = .0003). There were no intra- or inter-group differences in any of the laboratory parameters from study baseline to completion. Thus, flavocoxid is safe when used in a population with "below average" to "moderately above average cardiovascular risk" compared to placebo.

Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation.

OBJECTIVE: To assess the catabolism of methotrexate (MTX) to 7-hydroxy-MTX (7-OH-MTX) in patients with rheumatoid arthritis as well as the effect of folic acid and folinic acid on this catabolism. METHODS: Urinary excretion of MTX and its catabolite, 7-OH-MTX, was measured in 2 24-hour urine specimens collected after MTX therapy. Urine samples were collected from patients after the sixth and seventh weekly doses of MTX. MTX and 7-OH-MTX concentrations were determined by high-performance liquid chromatography mass spectrometry. Swelling and pain/tenderness indices were used to measure symptoms before and at 6 and 7 weeks of therapy. Patients received either folic acid or folinic acid supplements (1 mg/day) from week 6 to week 7. RESULTS: Folic acid inhibited aldehyde oxidase (AO), the enzyme that produces 7-OH-MTX, but folinic acid did not. Excretion of 7-OH-MTX (determined as a percentage of the dose of MTX or as mg 7-OH-MTX/gm creatinine) was not normally distributed (n=39). Patients with marked improvement in swelling and pain/tenderness indices had a lower mean 7-OH-MTX excretion level (P<0.05). Patients who received folic acid supplements had decreased 7-OH-MTX excretion (P=0.03). Relatively high 7-OH-MTX excretion was correlated with relatively high MTX excretion and with relatively low MTX retention in vivo (P<0.05) (n=35). CONCLUSION: Our findings of a non-normal distribution of 7-OH-MTX excretion suggest that there are at least 2 phenotypes for this catabolism. Decreased 7-OH-MTX formation suggests folic acid inhibition of AO and a better clinical response, while increased 7-OH-MTX formation may interfere with MTX polyglutamylation and binding to enzymes and, therefore, may increase MTX excretion and decrease MTX retention and efficacy in vivo.

Not just calcium and vitamin D: other nutritional considerations in osteoporosis.

Calcium and vitamin D are the mainstays of nutritional intervention for the prevention and treatment of osteoporosis. However, conditions that alter nutritional status as well as other nutrients should be considered when diagnosing and treating osteoporosis and osteopenia. Current research supports the early diagnosis and treatment of anorexia nervosa to prevent associated bone loss and increased risk of fracture. Weight restoration in patients with anorexia nervosa is central to bone mass stabilization. Other nutritional considerations include nutrients such as vitamin B-12 and vitamin K that may reduce fracture risk by increasing bone mineral density as well as the improvement of bone microarchitecture. Diets high in fruits and vegetables contribute nutrients such as magnesium associated with bone health and may also produce an alkaline environment, reducing calcium excretion and thus improving bone density.

Methotrexate and erythro-9-(2-hydroxynon-3-yl) adenine therapy for rat adjuvant arthritis and the effect of methotrexate on in vivo purine metabolism.

The objectives were: (1) to test the association of methotrexate (MTX) efficacy in rat adjuvant arthritis (rat AA) with interference of purine biosynthesis and adenosine metabolism and (2) to test the efficacy of erythro-9-(2-hydroxynon-3-yl) adenine (EHNA), an inhibitor of adenosine deaminase, and the efficacy of aminoimidazolecarboxamide (AICA) riboside plus MTX in rat AA. Radiographic and histologic examinations of the hind limbs were measures of efficacy. Urinary excretions of AICA and adenosine were markers of AICA ribotide transformylase inhibition (i.e., blockage of purine biosynthesis) and interference with adenosine metabolism, respectively. AICA and adenosine excretions increased during the day of MTX dosing (treatment day) compared to the previous baseline day in animals responding well to MTX (i.e., low radiographic and histologic scores). Based on radiographic and histologic scores, adjuvant injected rats were separated into two disease categories (i.e., no/mild and moderate/severe). Only AICA excretion was significantly elevated on the treatment day in rat AA with no/mild disease (i.e., those responding well to MTX therapy). AICA (not adenosine) excretion was significantly correlated with the above scores. EHNA was not efficacious, even at toxic levels, while AICA riboside potentiated the efficacy of MTX. The data suggests that efficacious MTX therapy in rat AA (1) blocks purine biosynthesis; (2) increases in in vivo AICA levels. Also adenosine accumulation and blockage of adenosine deaminase (i.e., by EHNA) appear to be less critical to MTX efficacy. Increased levels of AICA metabolites may suppress the immune response in rat AA.

Medical foods: products for the management of chronic diseases.

Medical foods are a specific category of therapeutic agents created under the Orphan Drug Act of 1988, which separated medical foods from drugs for regulatory purposes. Products in this category share the requirements that they are intended for the nutritional management of a specific disease, are used under the guidance of a physician, and contain ingredients that are generally recognized as safe (GRAS). An example of medical foods are formulations intended to manage patients with inborn errors in amino acid metabolism. Newer medical foods are designed to manage hyperhomocysteinemia, pancreatic exocrine insufficiency, inflammatory conditions, cancer cachexia, and other diseases.

Zinc status of women with low bone mineral density who receive calcium supplements.

We evaluated whether a daily high-dose calcium supplement perturbs the zinc status in 23 postmenopausal women (mean age: 63 yr) with low bone mineral density. Plasma and erythrocyte zinc concentrations, plasma bone-specific alkaline phosphatase (BSAP) and 5'-nucleotidase activities, and urinary zinc and calcium excretion were determined first at the end of 4 wk of daily oral calcium (1200 mg) and were measured again at the end of the subsequent 4 wk of daily cosupplementation with calcium (1200 mg) and zinc (30 mg). Mean plasma and erythrocyte zinc concentrations after 4 wk of calcium alone were not significantly different from concentrations after cosupplementation of calcium and zinc. Mean plasma BSAP activities before cosupplementation with zinc was significantly higher than that after zinc (p < 0.02), whereas plasma 5'-nucleotidase activities were not affected by zinc supplementation. Urinary zinc excretion slightly, but significantly, increased after the supplementation of zinc (p < 0.05), whereas calcium excretion remained similar. Our data indicate that a 4-wk zinc supplementation did not significantly improve zinc status. Although limited by the small sample size and short study duration, our data suggest that a daily calcium dose of 1200 mg had no effect on the zinc status of our subjects.

The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis.

OBJECTIVE: To determine if folinic acid supplementation during methotrexate (MTX) therapy for rheumatoid arthritis (RA) reduces both urinary 5-aminoimidazole-4-carboxamide (AICA) and urinary adenosine excretion more than does folic acid supplementation. AICA and adenosine are markers for MTX interference with purine metabolism. METHODS: Forty patients with RA who received MTX for 6 weeks were randomized to receive either daily folic acid or folinic acid supplements during an additional week of MTX therapy. Colorimetric and radioimmunocompetition assays were used to measure 24-hour urinary AICA and adenosine excretion levels, respectively. RESULTS: At the end of 6 weeks, 24-hour urinary levels of AICA, but not adenosine, were elevated as compared with baseline levels (i.e., prior to MTX therapy). Folinic acid, but not folic acid, supplementation normalized urinary AICA levels during MTX therapy. Relatively high urinary levels of AICA were correlated with reduced disease activity. No similar correlations were seen with urinary adenosine levels. CONCLUSION: The blockade of purine nucleotide biosynthesis by MTX at the AICA ribonucleotide transformylase-catalyzed step may be related to the efficacy of MTX, and this blockade is effectively relieved by folinic acid, but not by folic acid, supplementation.

Effect of methotrexate therapy on bone mineral density and body composition in rat adjuvant arthritis.

OBJECTIVE: To test whether methotrexate (MTX) therapy of rat adjuvant arthritis (AA) prevents loss of bone mineral density (BMD) and loss of adipose and lean body mass compared to pair-fed controls with untreated rat AA (positive controls) and rats without AA (negative controls). METHODS: AA was induced by a Mycobacterium butyricum injection at the base of the tail of 5-week-old female Lewis rats. The MTX-treated group was injected with adjuvant and then treated twice weekly with MTX (1.0 mg/kg/wk intraperitoneally). To control for the effects of AA on appetite and weight, food given to control animals and MTX-treated rats with AA was limited to that consumed by rats with untreated AA. At 42 days post-adjuvant injection, the animals were sacrificed and tibial BMD was measured. Body composition was analyzed for percentage fat, protein, ash, and water. RESULTS: There was no difference in ankle edema score or ankle width between the negative controls and MTX-treated group at necropsy. BMD was significantly higher in the negative controls versus positive controls and MTX-treated and in MTX-treated versus positive controls. There was significantly less body fat and protein and greater body water in the positive controls and MTX group compared to the negative controls. CONCLUSION: MTX prevents loss of BMD in the tibia in the rat AA model compared to positive controls. While MTX is effective in lowering inflammation in rat AA, there are still significant losses in BMD and body composition, which may have implications for rheumatoid arthritis.

The energy cost of adjuvant-induced arthritis in rats.

OBJECTIVE: To test the hypothesis that rats with adjuvant-induced arthritis (AIA) need more metabolic energy to maintain body weight than healthy control rats or rats with AIA treated with methotrexate (MTX). METHODS: Rat AIA was induced by Mycobacterium butyricum injection at the base of the tail. The MTX-treated group was injected with MTX (1.0 mg/kg/week) in phosphate buffered saline. Negative controls (i.e., disease-free) and the MTX-treated group were pair-fed with positive controls (i.e., untreated AIA rats) to ensure equal mean body weights. RESULTS: An additional 0.85 gm of food per day per rat was needed by the positive control group and 0.54 gm per day by the MTX-treated group to maintain a body weight comparable with that of the negative control group during days 5-15 post-adjuvant injection. During days 15-34 post-adjuvant injection an additional 1.4 gm of food per day per rat was needed by the positive controls and 0.62 gm by the MTX-treated group. CONCLUSION: The results of this study indicate that adjuvant arthritis has a metabolic cost, which increases substantially as the disease becomes clinically apparent (days 15-34). MTX treatment does not completely eliminate the caloric cost of the disease. During days 5-15 post-adjuvant injection, an average of 6% of the total calories eaten by the positive controls was metabolized to support subclinical inflammation and other physiologic processes of this disease. During the active phase of the disease (i.e., clinical inflammation), this value increased to 18% of total calories.

Practice patterns in the use of supplemental folic acid in rheumatoid arthritis patients treated with methotrexate

Objetivo: Determinar na prática nao só os padroes de uso de suplementaçao com ácido fólico (FA) em pacientes com artrite reumatóide (RA) tratados com metotrexato (MTX) em nosso centro médico, como também o tempo de permanência em uso e toxicidade da droga entre diferentes grupos de pacientes. Métodos: Foi constituído um grupo de 40 pacientes com RA que iniciaram MTX logo após estarem disponíveis os resultados do primeiro estudo de suplementaçao com ácido fólico. Foram obtidos de todos os pacientes, durante três anos, os dados clínico/demográficos e, anualmente, a administraçao e toxicidade acumulada de MTX/FA. Foram examinadas estatísticas descritivas e curvas de sobrevida. Resultados: Três padroes surgiram na prática: pacientes que receberam MTX desde o início (FAO n = 18), aqueles que receberam-no às vezes durante o estudo por causa da toxicidade (FAD n=8) e aqueles que nunca o receberam (FAN n = 14). O tempo global de permanência em uso da droga durante três anos foi de 69 por cento, sendo comparável nos três grupos. Os valores basais MCV (volume corpuscular médio) e os índices de toxicidade acumulada foram maiores entre os pacientes do grupo FAD. Conclusao: Nao foi universal a implementaçao de alteraçoes nas práticas terapêuticas entre nossos clínicos. A permanência em uso da droga foi comparável entre os três grupos terapêuticos. Pacientes que na linha basal tinham MCV anormal ou normal alto deveriam ter suplementaçao com ácido fólico desde o início