Spontaneous reports of adverse reactions to methotrexate: retrospective analysis in the Russian Federation
https://doi.org/10.17749/2070-4909/farmakoekonomika.2026.316
Abstract
Background. Methotrexate (MTX) is a widely prescribed medication known for its pronounced anti-inflammatory and anti-tumor effects. However, its use is associated with risks of adverse drug reactions (ADRs) including gastrointestinal tract, infectious and haematological complications. This study analyzes spontaneous reports on ADRs to MTX in Russia, highlighting the importance of pharmacovigilance in ensuring the safety of pharmacotherapy.
Objective: To examine the frequency and structure of ADRs that occurred following MTX administration through a retrospective analysis of spontaneous reports from the automated information system of the Federal Service for Surveillance in Healthcare (Roszdravnadzor) in Russia.
Material and methods. A retrospective analysis of spontaneous reports registered from 2019 to 2024 in the Pharmacovigilance federal database (Roszdravnadzor) was conducted. To ensure accurate comparisons across regions, the incidence rates of the studied events were calculated per 100,000 population.
Results. Between 2019 and 2024, a total of 2508 spontaneous reports concerning ADRs and/or MTX inefficacy were registered in Russia. The most frequent ADRs included gastrointestinal disorders (24.4%), combined reactions (21.9%), and drug inefficacy (15.1%). Male patients and those over 60 years of age had a statistically significantly higher risk of fatal outcomes. Allergic reactions resulted in “recovery without sequelae” in 51.7% of cases, while “condition improvement” was observed in gastrointestinal and neurological reactions (48.1% and 60.4%, respectively). Conversely, hematologic toxicity and infectious complications were associated with a higher risk of fatal outcomes (18.2% and 23.6%, respectively).
Conclusion. Both national and international data confirm the need for meticulous monitoring and rational use of MTX to ensure therapeutic safety.
About the Authors
S. A. Stefanova
Immanuel Kant Baltic Federal University
Russian Federation
Russian Federation
Svetlana A. Stefanova
WoS ResearcherID: JCP-1160-2023. Scopus Author ID: 57918372500
14 Nevsky Str., Kaliningrad 236041
Ya. D. Belousova
Immanuel Kant Baltic Federal University
Russian Federation
Russian Federation
Yana D. Belousova
Scopus Author ID: 57918372400
14 Nevsky Str., Kaliningrad 236041
V. V. Rafalskiy
Immanuel Kant Baltic Federal University
Russian Federation
Russian Federation
Vladimir V. Rafalskiy, Dr. Sci. Med., Prof.
WoS ResearcherID: G-3172-2013. Scopus Author ID: 15023010400
14 Nevsky Str., Kaliningrad 236041
References
1. Nasonov E.L., Amirjanova V.N., Olyunin Y.A., et al. The use of methotrexate in rheumatoid arthritis. Recommendations of the AllRussian public organization “Association of Rheumatologists of Russia”. Rheumatology Science and Practice. 2023; 61 (4): 435–49 (in Russ.). https://doi.org/10.47360/1995-4484-2023-435-449.
2. Gallyamova Yu.A., Asoskova A.V. Methotrexate in dermatology: from theory to practice. Lechaschy vrach. 2021; 5 (24): 46–51 (in Russ.). https://doi.org/10.51793/OS.2021.11.97.010.
3. Valiev T.T., Semenova V.V., Ikonnikova A.Y., et al. Role of pharmacogenetic factors in the development of side effects of methotrexate in the treatment of malignant tumors: a review. Journal of Modern Oncology. 2021; 23 (4): 622–7. https://doi.org/10.26442/18151434.2021.4.201127.
4. Wang W., Zhou H., Liu L. Side effects of methotrexate therapy for rheumatoid arthritis: a systematic review. Eur J Medicinal Chem. 2018; 158: 502–16. https://doi.org/10.1016/j.ejmech.2018.09.027.
5. General characteristics of the medicinal product Methotrexate. https://portal.eaeunion.org/sites/commonprocesses/ru-ru/Pages/CardView.aspx?documentId=64dded40fb44f13b9518d7f0&codeId=P.MM.01 (in Russ.) (accessed 25.03.2025).
6. Solomon D.H., Glynn R.J., Karlson E.W., et al. Adverse effects of lowdose methotrexate: a randomized trial. Ann Intern Med. 2020; 172 (6): 369–80. https://doi.org/10.7326/M19-3369.
7. Levêque D., Santucci R., Gourieux B., et al. Pharmacokinetic drug–drug interactions with methotrexate in oncology. Expert Rev Clin Pharmacol. 2011; 4 (6): 743–50. https://doi.org/10.1586/ecp.11.57.
8. Pflugbeil S., Müller-Ladner U., Lange U. Drug interactions in the treatment of rheumatoid arthritis and psoriatic arthritis. Rheumatol Intern. 2020; 40: 511–21. https://doi.org/10.1007/s00296-020-04526-3.
9. Doktorova S.A., Grabovetskaya Yu.Yu., Stefanov M., Rafalskiy V.V. Enhancing the efficacy and safety of methotrexate treatment: a focus on drug interactions (review). Safety and Risk of Pharmacotherapy. 2024; 12 (3): 285–98 (in Russ.). https://doi.org/10.30895/2312-7821-2024-416.
10. Krasheninnikov A.E., Matveev А.V., Egorova E.A. Development of adverse reactions databases, their introduction into pharmacovigilance systems and significance for the drug safety improve. Journal of Volgograd State Medical University. 2018; 3: 8–12 (in Russ.). https://doi.org/10.19163/1994-9480-2018-3(67)-8-12.
11. Klabukova D.L., Davydovskaya M.V. Implementation of the MedDRA international terminology base into the pharmacovigilance practice Russia. Moskovskaya meditsina. 2020; 1: 64–9 (in Russ.).
12. Shubnikova E.V. Postmarketing surveillance: review of open sources of drug safety data. Safety and Risk of Pharmacotherapy. 2024; 12 (3): 309–30 (in Russ.). https://doi.org/10.30895/2312-7821-2024-12-3-309-330.
13. Fouretier A., Malriq A., Bertram, D. Open access pharmacovigilance databases: analysis of 11 databases. Pharmaceut Med. 2016; 30: 221–31. https://doi.org/10.1007/s40290-016-0146-6.
14. de Vries S.T., Denig P., Ekhart C., et al. Sex differences in adverse drug reactions reported to the National Pharmacovigilance Centre in the Netherlands: an explorative observational study. Br J Clin Pharmacol. 2019; 85 (7): 1507–15. https://doi.org/10.1111/bcp.13923.
15. Martin R.M., Biswas P.N., Freemantle S.N., et al. Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies. Br J Clin Pharmacol. 1998; 46 (5): 505–11. https://doi.org/10.1046/j.1365-2125.1998.00817.x.
16. Sychev D.A., Ostroumova O.D., Pereverzev A.P., et al. Female gender as a risk factor for the development of drug-induced diseases. Safety and Risk of Pharmacotherapy. 2021; 9 (2): 85–94 (in Russ.). https://doi.org/10.30895/2312-7821-2021-9-2-85-94.
17. Attar S.M. Adverse effects of low dose methotrexate in rheumatoid arthritis patients. Saudi Med J. 2010; 31 (8): 909–15.
18. Sparks J.A., Barbhaiya M., Karlson E.W., et al. Investigating methotrexate toxicity within a randomized double-blinded, placebocontrolled trial: rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) study. Semin Arthritis Rheum. 2017; 47 (1): 133–42. https://doi.org/10.1016/j.semarthrit.2017.02.003.
19. Albrecht K., Müller-Ladner U. Side effects and management of side effects of methotrexate in rheumatoid arthritis. Clin Exp Rheumatol. 2010; 28 (5 Suppl. 61): S95.
20. Garton M., Teoh Y.P., Watson D. Adverse events during short-and long-term exposure to low-dose weekly methotrexate for rheumatic diseases. Rheumatol Adv Pract. 2023; 7 (2): rkad038. https://doi.org/10.1093/rap/rkad038.
21. Bulatović Ćalasan M., van den Bosch O.F., Creemers M.C., et al. Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis. Arthritis Res Ther. 2013; 15: 1–5. https://doi.org/10.1186/ar4413.
22. Leon L., Rodriguez-Rodriguez L., Freites D., et al. Long-term continuation of methotrexate therapy in giant cell arteritis patients in clinical practice. Clin Exp Rheumatol. 2018; 36 (1): 173.
23. Nalwa H.S., Prasad P., Ganguly N.K., et al. Methotrexate intolerance in rheumatoid arthritis. Transl Med Commun. 2023; 8 (1): 10. https://doi.org/10.1186/s41231-023-00142-y.
24. Almalag H., Abouzaid H.H., Alnaim L., et al. Risk factors associated with methotrexate intolerance in rheumatoid arthritis patients. Open Access Rheumatol. 2020; 12: 193–202. https://doi.org/10.2147/OARRR.S263287.
25. Jiang X., Zeng J., Chen F., Li J. Systematic review and metaanalysis on the efficacy of methotrexate in rheumatoid arthritis. Ann Palliat Med. 2021; 10 (10): 10652–60. https://doi.org/10.21037/apm21-2471.
26. Nakafero G., Grainge M.J., Card T., et al. What is the incidence of methotrexate or leflunomide discontinuation related to cytopenia, liver enzyme elevation or kidney function decline? Rheumatology. 2021; 60 (12): 5785–94. https://doi.org/10.1093/rheumatology/keab254.
27. Anghel L.A., Leucuta D.C., Farcas A.M., Oprean R.N. Utilization patterns of disease-modifying antirheumatic drugs (DMARDS) in patients with autoimmune rheumatic diseases. Farmacia. 2021; 67 (1): 184–92. https://doi.org/10.31925/farmacia.2019.1.25.
28. Jin X.M., Lee J., Choi N.K., et al. Utilization patterns of diseasemodifying antirheumatic drugs in elderly rheumatoid arthritis patients. J Korean Med Sci. 2014; 29 (2): 210–6. http://doi.org/10.3346/jkms.2014.29.2.210.
29. Khraishi M., Ivanovic J., Zhang Y., et al. Real-world utilization of methotrexate or prednisone co-therapy with etanercept among Canadian patients with rheumatoid arthritis: a retrospective cohort study. Curr Med Res Opin. 2019; 35 (11): 2025–33. https://doi.org/10.1080/03007995.2019.1636543.
30. Tadrous M., Lončar M., Dyrda P. Utilization patterns of diseasemodifying antirheumatic drugs for the treatment of rheumatoid arthritis: rationale for improving the harmonization of coverage criteria. Can J Health Technol. 2021; 1 (8). https://doi.org/10.51731/cjht.2021.133.
What is already known about thе subject?
► Methotrexate (MTX) is a widely used anti-inflammatory and anti-tumor drug with an established safety profile
► The frequency and spectrum of adverse drug reactions (ADRs) to MTX are shown to vary depending on the nosological group and individual patient characteristics
What are the new findings?
► The study found statistically significant differences in ADR outcomes according to gender, age, and system-organ class, which adds to existing knowledge on MTX safety
How might it impact the clinical practice in the foreseeable future?
► The study results highlight the need for an individualized approach to prescribing MTX, taking the identified ADR risk factors into account
► The findings may be used to develop differentiated pharmacovigilance strategies, optimize dosing and monitoring regimens, and potentially improve the safety and efficacy of pharmacotherapy
Review
For citations:
Stefanova S.A., Belousova Ya.D., Rafalskiy V.V. Spontaneous reports of adverse reactions to methotrexate: retrospective analysis in the Russian Federation. FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2026;1(19):122-132. (In Russ.) https://doi.org/10.17749/2070-4909/farmakoekonomika.2026.316
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