gms | German Medical Science

Background: Methotrexate (MTX), a standard treatment for rheumatoid arthritis (RA), is known for its potential kidney and liver toxicity. Whether the concomitant use of analgesics (e.g. non-steroidal anti-inflammatory drugs (NSAIDs)), possibly affecting the same organs, has an impact on the rate or course of adverse drug reactions (ADR) remains unclear. Therefore, the aim of this study was to analyze spontaneous reports of MTX related ADR on kidneys and liver in patients with RA, with respect to case and treatment characteristics as well as outcomes.

Materials and Methods: We used all reports (until 2022) of suspected ADRs originating from Europe and associated with MTX as interacting or suspected drug in RA patients, from the EudraVigilance database. We used descriptive statistics to display case (e.g. age, comorbidity) and treatment (e.g. comedication, duration of MTX use, route of MTX administration) characteristics, stratified by the organ affected (kidneys, liver). Further, the outcome (fatal, non-fatal) was analyzed.

Results: We identified 10,319 cases of RA patients treated with MTX where ADRs were reported (mean age: 62.3 years, 72.6% female). Suspected drug reactions on the kidneys and liver were reported in 365 and 1082 cases, respectively. Patients with kidney impairment were older than those with liver dysfunction (mean age 65.8 vs. 59.6 years). Further, comedication (82.7% vs. 64.1%), especially treatment with NSAIDs (23.6% vs. 15.8%), acetaminophen (13.7% vs. 8.9%), metamizole (6.8% vs. 2.1%) and corticosteroids (38.1% vs. 24.6%), were more common in patients with kidney failure. More patients died from renal than liver failure (21.1% vs. 5.8%). Compared to non-fatal kidney cases, the fatal cases had more kidney (25.9% vs. 17.2%) and liver related (12.1% vs. 4.9%) comorbidities and comedication in general (87.0% vs. 81.6%), as well as use of NSAIDs (24.7% vs. 23.3%), acetaminophen (18.2% vs. 12.5%), metamizole (11.7% vs. 5.6%) and corticosteroids (42.9% vs. 36.8%) was more common. In the fatal liver cases, kidney (18.6% vs. 3.7%) and liver related (14.0% vs. 12.2%) comorbidities, the use of any comedication (86.7% vs. 62.4%), NSAIDs (20.0% vs. 15.7%), acetaminophen (21.7% vs. 8.5%), metamizole (10.0% vs. 1.7%) and corticosteroids (38.3% vs. 23.1%), was also more common than in the non-fatal liver cases.

Conclusion: Among all reported ADRs, liver dysfunction was nearly three times more often than renal impairment. However, the kidneys are the organs, that need to be especially watched for. Although there seem to be differences in some characteristics (e.g. corticosteroid use), drug management in patients with RA using MTX is a complex matter and caution should be exercised.