Oral Versus Subcutaneous Methotrexate in Immune-Mediated Inflammatory Disorders: an Update of the Current Literature

Abstract

Purpose: This review aims to critically evaluate the potential benefit of either oral or subcutaneous administration of methotrexate (MTX) in various immune-mediated inflammatory disorders (IMIDs) through analysis of efficacy, toxicity, pharmacokinetics and pharmacodynamics of both administration routes.

Recent findings: Recent studies comparing the efficacy of oral versus subcutaneous MTX administration in IMIDs have revealed contradicting results. Some reported higher efficacy with subcutaneous administration, while others found no significant difference. Regarding toxicity, some studies have challenged the notion that subcutaneous administration is better tolerated than oral administration, while others have supported this. Pharmacokinetic studies suggest higher plasma bioavailability and increased accumulation of MTX-polyglutamates (MTX-PGs) in red blood cells (RBCs) with subcutaneous administration during the initial treatment phase. However, after several months, similar intracellular drug levels are observed with both administration routes. There is no conclusive evidence supporting the superiority of either oral or subcutaneous MTX administration in terms of efficacy and adverse events in IMIDs. Subcutaneous administration leads to higher plasma bioavailability and initial accumulation of MTX-PGs in RBCs, but the difference seems to disappear over time. Given the variable findings, the choice of administration route may be based on shared decision-making, offering patients the option of either oral or subcutaneous administration of MTX based on individual preferences and tolerability. Further research is needed to better understand the impact of MTX-PGs in various blood cells and TDM on treatment response and adherence to MTX therapy.

Keywords: Crohn’s disease; Inflammatory bowel disease; Juvenile idiopathic arthritis; Methotrexate; Methotrexate polyglutamates; Rheumatoid arthritis.

Fig. 1

MTX cellular pharmacology and mechanism of action. Methotrexate (MTX), as well as the main circulating plasma folate 5-methyltetrahydrofolate, is taken up by (immune) target cells via 3 possible transport routes: the reduced folate carrier (RFC), proton-coupled folate transporter (PCFT) and folate receptor β (FRβ). Next, MTX is converted into MTX-polyglutamates (MTX-PGs) by the action of the enzyme folylpolyglutamate synthetase (FPGS), which are no longer substrates for ATP-binding cassette (ABCC1-5 and ABCG2) drug efflux transporters, thereby promoting their intracellular retention. MTX-PGs inhibit enzymes dihydrofolate reductase (DHFR) and thymidylate synthase (TS), but particularly, inhibition of the purine de novo enzymes GART (glycinamide ribonucleotide formyltransferase) and ATIC (5-aminiimidazole-4-carboamide ribonucleotide formyltransferase) induces upregulation of intracellular adenosine and its non-lytic extracellular release and binding to adenosine receptor 2a/b provoking an anti-inflammatory response