Managing Methotrexate Intolerance in Rheumatoid Arthritis: The Role of Oral-to-Subcutaneous Switching

Methotrexate (MTX) remains the anchor drug in the management of rheumatoid arthritis (RA). However, its clinical use is frequently limited by intolerance, leading to dose reduction or discontinuation. In addition, oral MTX exhibits pharmacokinetic limitations, including dose-dependent absorption and reduced bioavailability at higher doses, which may compromise therapeutic efficacy. Subcutaneous (SC) MTX has emerged as a strategy to overcome these limitations by providing more consistent bioavailability and potentially improved tolerability. Evidence suggests that switching from oral-to-SC MTX may improve gastrointestinal (GI) intolerance and support treatment persistence, whereas evidence for improved disease control or reduction of serious MTX-related toxicity remains limited. Recent Japanese studies suggest the potential utility of this approach at MTX doses commonly used in Japan, although evidence for the superiority of SC MTX over oral MTX in low-dose settings remains limited. This narrative review summarizes current evidence on MTX intolerance and oral-to-SC route switching in RA, with a focus on practical strategies for treatment optimization. Overall, oral-to-SC MTX switching may represent an important option to improve GI intolerance and support treatment persistence in patients with RA.