Abstract Background/Aims Methotrexate is one of the most commonly used disease-modifying anti-rheumatic drugs, with a multitude of indications, spanning immune-mediated inflammatory diseases (IMID) and oncology. The British National Formulary (BNF) cites methotrexate’s interaction with proton pump inhibitors (PPIs) as an interaction; however, this is variably recognised in clinical practice. We performed a systematic review assess the clinical implications and significance of the interaction between methotrexate and PPIs. Methods We performed a Pubmed/MEDLINE and Embase literature search, utilising the search terms ‘methotrexate’, ‘proton pump inhibitor’, ‘omeprazole’, ‘lansoprazole’, ‘esomeprazole’, ‘pantoprazole’, ‘rabeprazole’, ‘dexlansoprazole’, from database inception to 25 August 2025. Studies reporting on serum methotrexate levels and methotrexate clearance with concomitant proton pump inhibitor use were eligible for inclusion. Baseline data were collected for age, methotrexate dosage, indication, proton pump inhibitor type, and reported adverse events. Additionally, studies registered on clinicaltrials.gov involving patients with rheumatoid arthritis (RA) receiving methotrexate as monotherapy or as combination DMARD therapy were screened to assess whether concomitant proton pump inhibitor use was an exclusion criterion for these trials. Results The search yielded 2,493 articles, which resulted in 12 articles being eligible for inclusion in the analysis after screening. Of these, 10 studies (n = 1,769 participants) reported on high-dose methotrexate (1g/m2 or more), which are not used in IMID indications, and two studies (n = 32) reported on low-dose methotrexate (up to 25mg/week). The median age at exposure was 45 years (IQR 30-60). Omeprazole and lansoprazole were the most commonly used PPIs. The indication for high-dose methotrexate was non-Hodgkin lymphoma (60%), acute lymphocytic leukaemia (20%), and other cancers (20%). Plasma methotrexate concentrations were higher than expected in all 10 hdMTX studies reported high-dose methotrexate use with concomitant PPI exposure, with delayed methotrexate excretion in 9/10 (90%) studies. In the low-dose methotrexate studies, serum methotrexate levels and its elimination were not impaired. 692 studies of methotrexate use in RA were registered on clinicaltrials.gov, of which 261 were interventional, with 431 being observational studies. 54 studies were phase 1; 199 phase 2; 190 phase 3; with 249 being phase 4 or unknown. Of the 692 studies, concomitant proton pump inhibitor use was recorded as an exclusion criteria in only one study. Conclusion The data suggest that high-dose MTX with concomitant PPI is associated with higher MTX levels and reduced clearance. While there are fewer data for low-dose MTX, the available data do not suggest increased MTX exposure. This requires further investigation. These data should help rheumatologists confidently negate the interaction between proton pump inhibitors and methotrexate despite the warnings highlighted in the BNF. Disclosure M. Baghaffar: None. R. Hassan: None. F. Haque: None. S. Goh: None. A. Joseph: None. D. Nagra: None. M. Jayasinghe: None. S. Kaur: None. A. Khan: None. M. Gayed: None. S. Banerjee: None. E. Stathopoulou: None. A. Mahto: None. C. Rosa: None. C. Wincup: None. M. Russell: None.
Baghaffar et al. (2026) studied this question.