Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system
Methotrexate (MTX) is an essential anti-rheumatic drug used to treat rheumatoid arthritis (RA). Prevention or management of adverse reactions, including interstitial lung disease (ILD), hepatotoxicity, myelosuppression, and infection, remains fundamental for safe MTX therapy. Using the Food and Drug...
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1030832/full |
| _version_ | 1828009816297046016 |
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| author | Kenji Onda Takeshi Honma Koichi Masuyama |
| author_facet | Kenji Onda Takeshi Honma Koichi Masuyama |
| author_sort | Kenji Onda |
| collection | DOAJ |
| description | Methotrexate (MTX) is an essential anti-rheumatic drug used to treat rheumatoid arthritis (RA). Prevention or management of adverse reactions, including interstitial lung disease (ILD), hepatotoxicity, myelosuppression, and infection, remains fundamental for safe MTX therapy. Using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) (JAPIC AERS), we performed disproportionality analyses of adverse events related to MTX use and the impact of concomitant medications. Upon analyzing all reported cases in FAERS between 1997 and 2019, the crude reporting odds ratios (cRORs; 95% confidence intervals) for ILD, hepatotoxicity, myelosuppression, and tuberculosis (TB) in relation to MTX use were 4.00 (3.83–4.17), 1.99 (1.96–2.02), 3.66 (3.58–3.74), and 7.97 (7.65–8.3), respectively. Combining MTX with folic acid (FA) or tumor necrosis factor-alpha inhibitors (TNFis) tended to reduce cRORs for these adverse events (except for TB). Multiple logistic regression analysis in patients with RA was conducted to calculate adjusted reporting odds ratios (aRORs) for age, sex, and MTX treatment patterns (MTX alone and combined with FA and TNFi). Higher age (except for hepatotoxicity) and male sex were significantly associated with adverse events. Combining FA or TNFi with MTX reduced aRORs for MTX-related hepatotoxicity and myelosuppression; in contrast, the effect of FA was not obvious in ILD or TB. Although studies assessing spontaneous reporting systems have limitations such as reporting bias, data from our logistic regression analysis demonstrated that adding FA to MTX-based therapy could help reduce the dose-dependent adverse events of MTX, thereby providing clinical evidence that supports the beneficial effect of FA. This study also demonstrated the usefulness of FAERS in comparing adverse events based on treatment patterns. |
| first_indexed | 2024-04-10T08:45:28Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T08:45:28Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-1550b575571149a480933cbdfa0dc7622023-02-22T08:29:53ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-02-011410.3389/fphar.2023.10308321030832Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting systemKenji Onda0Takeshi Honma1Koichi Masuyama2Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, JapanBohsei Pharmacy, Kanagawa, JapanRegulatory Science laboratory, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, JapanMethotrexate (MTX) is an essential anti-rheumatic drug used to treat rheumatoid arthritis (RA). Prevention or management of adverse reactions, including interstitial lung disease (ILD), hepatotoxicity, myelosuppression, and infection, remains fundamental for safe MTX therapy. Using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) (JAPIC AERS), we performed disproportionality analyses of adverse events related to MTX use and the impact of concomitant medications. Upon analyzing all reported cases in FAERS between 1997 and 2019, the crude reporting odds ratios (cRORs; 95% confidence intervals) for ILD, hepatotoxicity, myelosuppression, and tuberculosis (TB) in relation to MTX use were 4.00 (3.83–4.17), 1.99 (1.96–2.02), 3.66 (3.58–3.74), and 7.97 (7.65–8.3), respectively. Combining MTX with folic acid (FA) or tumor necrosis factor-alpha inhibitors (TNFis) tended to reduce cRORs for these adverse events (except for TB). Multiple logistic regression analysis in patients with RA was conducted to calculate adjusted reporting odds ratios (aRORs) for age, sex, and MTX treatment patterns (MTX alone and combined with FA and TNFi). Higher age (except for hepatotoxicity) and male sex were significantly associated with adverse events. Combining FA or TNFi with MTX reduced aRORs for MTX-related hepatotoxicity and myelosuppression; in contrast, the effect of FA was not obvious in ILD or TB. Although studies assessing spontaneous reporting systems have limitations such as reporting bias, data from our logistic regression analysis demonstrated that adding FA to MTX-based therapy could help reduce the dose-dependent adverse events of MTX, thereby providing clinical evidence that supports the beneficial effect of FA. This study also demonstrated the usefulness of FAERS in comparing adverse events based on treatment patterns.https://www.frontiersin.org/articles/10.3389/fphar.2023.1030832/fullmethotrexateFAERS databasefolic acidTNFalpha inhibitorinterstitial lung diseasehepatotoxicity |
| spellingShingle | Kenji Onda Takeshi Honma Koichi Masuyama Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system Frontiers in Pharmacology methotrexate FAERS database folic acid TNFalpha inhibitor interstitial lung disease hepatotoxicity |
| title | Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system |
| title_full | Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system |
| title_fullStr | Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system |
| title_full_unstemmed | Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system |
| title_short | Methotrexate-related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor-alpha inhibitors: An assessment using the FDA adverse event reporting system |
| title_sort | methotrexate related adverse events and impact of concomitant treatment with folic acid and tumor necrosis factor alpha inhibitors an assessment using the fda adverse event reporting system |
| topic | methotrexate FAERS database folic acid TNFalpha inhibitor interstitial lung disease hepatotoxicity |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1030832/full |
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