Beyond rheumatology: Reconsidering methotrexate for Crohn’s disease in the biologic era

Table 1 Comparative mechanistic and clinical characteristics of azathioprine and methotrexate in Crohn’s disease

Ref.	Aspect	AZA	MTX
[10-23]	Mechanism	Direct DNA incorporation of metabolites, direct interference with lymphocyte DNA replication, leading to impaired expansion of T and B cells	Indirect folate pathway inhibition (purine/pyrimidine synthesis decrease, reduced lymphocyte proliferation) and AICAR transformylase inhibition (adenosine accumulation increase, suppression of pro-inflammatory cytokines)
[24-27]	Dosing (induction and maintenance)	2.0-2.5 mg/kg/day orally (ECCO); low-dose 1.5 mg/kg/day may be sufficient in Asians	Induction: 25 mg/week IM or SC; maintenance: 15 mg/week IM/SC; oral dosing of 10-20 mg/week also used
[5,6,13]	Onset of action	Slow onset, often requiring several months (clinical efficacy generally observed after 8-12 weeks)	Similarly slow onset: Not superior to AZA (response typically seen after 8-12 weeks)
[5,6,25,30-32]	Efficacy (induction and Maintenance)	Effective for induction and maintenance; long clinical history	Demonstrated efficacy for both induction and maintenance; comparable to AZA in some trials
[8,25,31]	Risk of maintenance failure	Relatively low risk of relapse; stable long-term efficacy in both clinical trials and real-world cohort	Higher risk of treatment failure, largely related to suboptimal dosing, oral administration, and adherence issues; parenteral MTX at guideline-recommended doses performs more reliably
[6,32-35]	Rate of mucosal healing	Higher mucosal healing rates reported (e.g., approximately 50% with AZA monotherapy; further improved with AZA + anti-TNF)	Limited data; generally lower rates of mucosal healing (approximately 11% in some comparative studies)
[8,32,36]	Inhibition of anti-drug antibody formation	Strongly reduces ADA formation against anti-TNF therapy (e.g., SONIC trial showed improved infliximab pharmacokinetics and outcomes with AZA)	Demonstrated benefit in reducing immunogenicity in RA and psoriasis; in IBD, evidence is emerging that MTX ≥ 12.5-15 mg/week improves drug persistence and lowers ADA rates
[3-5,8,24,25,31,39-41]	Adverse effects and long-term safety	Associated with increased risk of lymphoproliferative disorders and non-melanoma skin cancer; myelosuppression, pancreatitis; risk higher in young males, EBV-negative patients, and with concomitant anti-TNF therapy	More frequent non-serious adverse effects: Nausea, fatigue, hepatotoxicity; no consistent association with increased lymphoma risk in IBD
[24,25]	Pregnancy considerations	Considered safe to continue during pregnancy, with no increase in congenital anomalies	Contraindicated in both women and men planning pregnancy or during pregnancy due to teratogenicity and risk of miscarriage

AZA: Azathioprine; MTX: Methotrexate; ECCO: European Crohn’s and Colitis Organization; TNF: Tumor necrosis factor; ADA: Anti-drug antibody; EBV: Epstein-Barr virus; AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; SC: Subcutaneous; IM: Intramuscularly; RA: Rheumatoid arthritis; IBD: Inflammatory bowel disease.