A landmark pharmacovigilance study analyzing two decades of real-world data has unveiled significant gender and age-related differences in methotrexate adverse events, providing crucial insights for clinical practice and patient safety monitoring.
Comprehensive Safety Analysis Spans 20 Years
Researchers conducted an extensive analysis of 130,818 adverse event reports associated with methotrexate from the FDA Adverse Event Reporting System (FAERS) database, covering the period from Q1 2004 to Q4 2024. The study employed multiple statistical methods including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) to detect safety signals.
The analysis revealed that methotrexate, a widely used antimetabolite approved by the FDA in 1953, continues to demonstrate a complex safety profile affecting multiple organ systems. The drug's primary mechanism involves inhibiting dihydrofolate reductase (DHFR), which reduces tetrahydrofolate synthesis and ultimately blocks cell proliferation.
Immune System Disorders Show Strongest Safety Signal
Among the 27 System Organ Classes analyzed, Immune System Disorders demonstrated the strongest signal with a ROR of 2.35 (95% CI: 2.31-2.39), affecting 13,313 patients. This finding aligns with methotrexate's known immunosuppressive mechanism of action. Other significant safety signals included Musculoskeletal and Connective Tissue Disorders [ROR 2.20 (95% CI: 2.18-2.22)] and Blood and Lymphatic System Disorders [ROR 2.08 (95% CI: 2.05-2.11)].
The most commonly reported category was General Disorders and Administration Site Conditions, accounting for 106,183 reports with an ROR of 1.21 (95% CI: 1.21-1.22). The top 10 most frequently reported adverse events included nausea, drug intolerance, drug hypersensitivity, arthralgia, pain, fatigue, condition aggravated, treatment failure, diarrhea, and joint swelling.
Gender Disparities Reveal Distinct Risk Profiles
The study uncovered striking gender differences in methotrexate adverse events. Female patients accounted for 64.2% of all reports (83,928 cases) compared to 29.3% for males (38,348 cases). Notably, females experienced significantly longer median onset times of 227 days compared to 78 days for males.
Female patients were more likely to report nausea [ROR 1.08 (95% CI: 1.05-1.11)] and drug intolerance [ROR 10.89 (95% CI: 10.6-11.19)]. These delayed reactions may be related to variations in female immune system responses and hormonal influences, particularly estrogen fluctuations that can affect drug metabolism and immune responses.
Male patients demonstrated higher risks for severe complications, including drug hypersensitivity [ROR 4.33 (95% CI: 4.09-4.58)] and pancytopenia [ROR 7.17 (95% CI: 6.76-7.61)]. Males also showed increased susceptibility to pneumonia, pyrexia, asthenia, weight decrease, and hypertension.
Age-Related Patterns Emerge Across Patient Populations
Age-stratified analysis revealed distinct patterns in adverse event onset and severity. Adults aged 18-64.9 years represented the largest group (42.5% of reports), followed by those aged 65-85 years (23.9%).
Patients under 18 years old experienced the shortest median onset time of 15 days, potentially due to more active immune systems and faster drug metabolism in younger individuals. Adults aged 18-65 years had a median onset time of 104 days, while patients over 65 years experienced the longest delay at 296 days.
Elderly patients showed significantly increased risks for drug allergies and immune system-related adverse events, likely associated with age-related immune system decline and reduced liver and kidney function. The prolonged half-life of methotrexate in elderly patients may lead to drug accumulation and increased toxicity.
Temporal Patterns Reveal System-Specific Onset Times
The analysis identified distinct temporal patterns for different organ system involvement. Renal and urinary disorders showed the earliest median onset at 12 days, followed by skin and subcutaneous tissue disorders at 27 days, and hepatobiliary disorders at 32 days. These early-onset reactions reflect methotrexate's direct toxic effects on rapidly dividing cells.
Long-term adverse effects included musculoskeletal and connective tissue disorders (median onset 591 days) and surgical complications (median onset 795 days). Most concerning were neoplasms with a median onset of 1,096 days, highlighting the importance of long-term monitoring for malignancies, particularly hepatocellular carcinoma and non-Hodgkin lymphoma.
Fatal Adverse Events Highlight Critical Safety Concerns
The study documented 2,442 fatal events, with the most frequent being death (1,097 cases), pancytopenia (982 cases), and sepsis (656 cases). Other serious outcomes included toxicity to various agents (614 cases), pneumonia (538 cases), respiratory failure (465 cases), and septic shock (461 cases).
These fatal reactions typically resulted from methotrexate's immunosuppressive effects making patients more susceptible to infections, combined with bone marrow suppression leading to pancytopenia. Patients with pre-existing hepatic or renal disease showed particular vulnerability due to impaired drug metabolism and excretion.
Drug Interactions Amplify Safety Risks
Analysis of concomitant medications revealed significant interaction patterns. The most frequently co-administered drugs were prednisone (19,763 cases), Enbrel (17,657 cases), and Humira (15,194 cases). These combinations, particularly with other immunosuppressive agents, may enhance methotrexate's immunosuppressive effects and increase infection risks.
The combination with anti-TNF-α drugs like Enbrel and Humira showed particular concern for increased bacterial, fungal, and viral infections, as well as elevated risks of liver dysfunction and hematological abnormalities.
Previously Unrecognized Adverse Events Identified
The study identified several adverse reactions not explicitly mentioned in current prescribing information, including drug allergy, fatigue, headache, and alopecia. This suggests that methotrexate's adverse effect spectrum may be broader than currently recognized, necessitating enhanced clinical vigilance and potential updates to prescribing guidelines.
Clinical Implications for Patient Monitoring
The findings emphasize the need for individualized monitoring strategies based on patient demographics. Female patients require awareness of delayed-onset reactions, while male patients need closer monitoring for severe acute complications. Elderly patients warrant enhanced surveillance for immune-related adverse events and drug accumulation effects.
The research team noted several limitations, including potential underreporting bias in the FAERS database and challenges in establishing causal relationships. However, the large sample size and comprehensive analytical approach provide valuable real-world evidence for clinical decision-making.
This comprehensive analysis represents the most extensive real-world safety evaluation of methotrexate to date, offering healthcare professionals crucial insights for optimizing patient care and safety monitoring protocols.
