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

Abstract

In the pre-biologic era, immunomodulators such as azathioprine, 6-mercaptopurine, and methotrexate (MTX) were widely used as first-line maintenance therapies in Crohn’s disease. However, in the current era shaped by biologics, their role has shifted toward adjunctive use, primarily in combination with anti-tumor necrosis factor agents to reduce immunogenicity. Amid growing concerns about thiopurine-associated risks, MTX is receiving renewed attention for its favorable safety profile; however, this agent remains inconsistently utilized in gastroenterology despite its frontline status in rheumatology. This discrepancy was highlighted in a recent nationwide survey by Bonnaud et al published in the World Journal of Gastroenterology, which offers timely insights into MTX prescribing behaviors among French gastroenterologists. Although 71% of respondents reported using MTX, primarily via subcutaneous injection, it is still perceived as a secondary choice after thiopurines. Importantly, this underuse appears to be driven more by clinical inertia and limited guidance rather than by lack of efficacy or safety concerns. Clinicians increasingly recognize the value of MTX, particularly in patients with joint involvement, Epstein-Barr virus negativity, or increased malignancy risk. Notably, even non-prescribers viewed the drug favorably, suggesting that usage barriers may be modifiable. In light of evolving treatment goals that prioritize safety, cost-effectiveness, and individualized care, this editorial argues that MTX should no longer be viewed as a fallback but as a strategic first-line option in well-defined high-risk populations. The survey underscores a persistent gap between guidelines and real-world practice, reinforcing the urgent need for clearer algorithms and education to support the repositioning of MTX in modern Crohn’s disease management.

Key Words: Methotrexate; Crohn’s disease; Biologics; Immunosuppressants; Clinical practice

Core Tip: Methotrexate remains underutilized in Crohn’s disease management despite its favorable safety and established efficacy. The nationwide French survey by Bonnaud et al has shown that barriers are less about evidence than about clinical inertia and limited familiarity. Reconsidering methotrexate as a frontline immunomodulator, particularly in the biologic era, may provide a cost-effective and individualized therapeutic strategy.

INTRODUCTION

Methotrexate (MTX) has long been established as a cornerstone in rheumatology; however, its role within gastroenterology remains comparatively limited despite its consistent endorsement in international guidelines for Crohn’s disease (CD)[1,2]. For decades, thiopurines such as azathioprine (AZA) and mercaptopurine have dominated the immunomodulatory landscape, frequently relegating MTX to a secondary position. This dominance has been reinforced by historical prescribing habits and greater clinical familiarity with thiopurines.

Meanwhile, the therapeutic environment for CD has undergone a profound transformation. The widespread adoption of biologics has reshaped treatment algorithms, while increasing recognition of thiopurine-related risks, including an elevated risk of malignancies, has prompted clinicians to reconsider long-term strategies[3,4]. The growing demand for cost-effective, durable therapies has simultaneously renewed interest in agents with proven efficacy and established safety profiles. Within this evolving context, MTX has consistently demonstrated efficacy for both induction and maintenance of remission, particularly among corticosteroid-dependent patients or those intolerant to thiopurines, as evidenced by pivotal clinical trials[5-7].

Nevertheless, despite this robust evidence base, MTX continues to be underutilized in gastroenterology. Its marginal role reflects not so much a lack of efficacy or safety concerns but rather clinical inertia, limited experience, and the absence of practical guidance. This persistent gap between guidelines and real-world practice highlights the need for clearer clinical algorithms and a renewed focus on education. A recent systematic review by Sequier et al[8] has further emphasized that suboptimal real-world use, not intrinsic inferiority, accounts for much of the perceived underperformance of MTX.

In this context, the nationwide practice survey by Bonnaud et al[9] assumes particular significance. By capturing prescribing patterns, physician attitudes, and perceived barriers to MTX use among French gastroenterologists, this study offers timely and pragmatic insights into the real-world positioning of MTX. Importantly, the survey underscores that even non-prescribers hold favorable views of MTX, suggesting that barriers are potentially modifiable through education and clearer guidance. These findings invite renewed discussion of the place of MTX in modern CD therapy, not as a fallback option but as a strategic, individualized, and cost-conscious component of long-term management.

To further contextualize the value of this national survey, it is worth noting its key strengths and limitations. The study’s major strengths include its real-world, practice-oriented design, its relevance to current shifts in immunomodulator use, and its qualitative insights identifying high-risk subgroups suitable for MTX. However, authors also acknowledged several limitations including the lack of patient-level data, reliance on physician opinion, potential selection bias, and the absence of a detailed treatment algorithm. These aspects together underscore both the importance of the study and the need for further guidance to bridge the evidence-practice gap.

MAIN COMMENTARY

The nationwide survey by Bonnaud et al[9] offers a rare lens into how gastroenterologists position MTX in the management of CD. The findings reveal that despite decades of evidence supporting the efficacy of MTX, only a minority of clinicians incorporate this agent into routine practice. This is consistent with reports from other regions, including North America and the United Kingdom, where MTX use remains strikingly limited despite guideline endorsement[5,10]. Such consistency across health systems underscores that the challenge is not unique to France but rather reflects a broader, international evidence-practice gap.

Key insights from the survey

Among 87 respondents, 71% reported prescribing MTX predominantly via the subcutaneous (SC) route in line with guideline recommendations. Clinical scenarios where MTX use was prioritized included patients with joint involvement, in those with Epstein-Barr virus (EBV) negativity, and in older age groups. Importantly, even among non-prescribers, MTX was generally viewed favorably, particularly with regard to its long-term safety profile, which was perceived as superior to that of AZA. The barriers to prescribing were largely non-evidence-based: Entrenched prescribing habits, limited familiarity with MTX protocols, and the absence of clear, practical guidance. This suggests that the underutilization of MTX is not due to lack of efficacy or safety concerns but rather to inertia and educational gaps.

Immunomodulatory mechanisms

AZA: AZA exerts its effect through direct cytotoxic suppression of lymphocytes and distinct modulation of purine metabolism[11]. Following administration, AZA is rapidly converted to 6-mercaptopurine, which is subsequently metabolized to active thioguanine nucleotides (Figure 1)[12]. These metabolites act as purine analogs that competitively inhibit de novo purine base synthesis, thereby interfering with nucleic acid metabolism. In addition, the thioguanine nucleotides incorporate into DNA and RNA, disrupting cellular replication and function and directly inhibiting lymphocyte proliferation (Table 1). Beyond these effects on nucleotide metabolism, AZA also interferes with Rac1 signaling, inducing apoptosis of activated T cells. This direct interference with both the metabolic and genetic machinery of immune cells explains the potent immunosuppressive capacity of AZA and accounts for its association with therapy-related malignancies, such as lymphoproliferative disorders[13-15].

Figure 1 Methotrexate (left) inhibits dihydrofolate reductase, reducing purine and pyrimidine synthesis and promoting adenosine accumulation, which together suppress lymphocyte proliferation and proinflammatory cytokine production. Azathioprine (right) is converted to 6-mercaptopurine, which undergoes metabolism via three major pathways: Incorporation into 6-thioguanine nucleotide that induces T-cell apoptosis and Rac1 inhibition; conversion to 6-methylmercaptopurine through thiopurine methyltransferase, which in excessive amounts is associated with hepatotoxicity; and degradation to 6-thiouric acid via xanthine oxidase, an inactive metabolite. Concomitant allopurinol therapy inhibits the xanthine oxidase-mediated pathway, thereby shunting 6-mercaptopurine metabolism toward 6-thioguanine nucleotide and increasing the risk of toxicity. MTX: Methotrexate; THF: Tetrahydrofolate; DHFR: Dihydrofolate reductase; DHF: Dihydrofolate; TNF: Tumor necrosis factor; IFN: Interferon; IL: Interleukin; 6-MP: 6-mercaptopurine; 6-MMP: 6-methylmercaptopurine; TPMT: Thiopurine methyltransferase; 6-TGN: 6-thioguanine nucleotide; 6-TGTP: 6-thioguanosine triphosphate; CH₂FH₄: 5,10-methylene tetrahydrofolate.

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.

MTX: In contrast, MTX primarily acts as an indirect immunomodulator. By inhibiting dihydrofolate reductase, it reduces folate-dependent purine and pyrimidine synthesis, thereby slowing lymphocyte proliferation[16,17]. In addition, inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide transformylase results in accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide and increased extracellular adenosine, which downregulates pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, interferon-γ, interleukin (IL)-17] and attenuates T-cell activity[18,19]. Importantly, MTX does not directly damage DNA; instead, it modulates lymphocyte function through metabolic pathways, contributing to its relatively favorable long-term safety profile[20-22]. Moreover, MTX induces apoptosis of activated T cells through a CD95-independent pathway, achieving clonal deletion of activated peripheral blood T cells[23]. It also specifically modulates cytokine production, reducing spontaneous and IL-15 induced TNF-α secretion by both T cells and macrophages[24].

Dosage (induction and maintenance)

According to the current European Crohn’s and Colitis Organization (ECCO) and American College of Gastroenterology (ACG) guidelines, the recommended dose of AZA in CD is 2.0-2.5 mg/kg/day orally (Table 1), with evidence that a reduced dose of 1.5 mg/kg/day may be sufficient in Asian populations with a lower risk of toxicity[25,26]. To enhance tolerability, a step-up strategy is often adopted, starting at 1.0 mg/kg/day and increasing by 0.5 mg/kg every 2-4 weeks until the target dose is reached. TPMT and NUDT15 genotyping is strongly advised prior to initiation to optimize dosing and minimize the risk of severe myelotoxicity.

Recent guidelines support MTX as a therapeutic option in moderate-to-severe CD, particularly in patients who are intolerant of or have contraindications for thiopurines[25-28]. For MTX, induction therapy consists of 25 mg once weekly administered intramuscularly (IM) or subcutaneously, followed by 15 mg once weekly IM or SC for maintenance of remission. Although oral MTX at 10-20 mg/week has been evaluated, its variable bioavailability makes parenteral administration (IM or SC) the preferred route. Given the variable bioavailability of oral formulations, both the ECCO and ACG guidelines emphasize that parenteral administration remains the standard route for MTX in CD. While the ECCO guidelines do not recommend oral MTX, the 2025 ACG guidelines suggest that low-dose oral MTX (12.5-15 mg weekly) may be considered as an adjunct to biologic therapy to reduce immunogenicity but that it should not be used as monotherapy for induction or maintenance.

Cost perspective

In many public and national formularies, the annual acquisition cost of parenteral MTX is comparable to that of AZA when only drug cost is considered. For example, in one inflammatory bowel disease (IBD) cost-utilization analysis, the annual cost for oral MTX was 526.82 dollars and for parenteral MTX was 87.41 dollars, whereas for AZA, the annual cost was 254.64 dollars[29]. In earlier pharmacoeconomic modeling, AZA was estimated to confer greater net cost savings than MTX in IBD populations, but both were considered cost-saving relative to no therapy[30].

Efficacy

Onset of action: Both AZA and MTX show a delayed onset of efficacy, which limits their use as induction agents but supports their role in long-term maintenance therapy. For AZA, clinical responses usually appear after 8-12 weeks (Table 1), reflecting the time required for active 6-thioguanine nucleotide metabolites to reach therapeutic steady-state levels[14]. MTX shows a comparable pattern, with improvement often noted by 9-12 weeks and remission confirmed around week 16 in randomized trials of parenteral therapy[5,6]. Given this slow onset, concomitant use of corticosteroids or biologics is frequently required during the initial treatment period to achieve and stabilize remission in CD.

Induction and maintenance: Induction and maintenance efficacy represent critical points of comparison between AZA and MTX. AZA has long been established as the reference immunomodulator in CD, with decades of clinical experience confirming its effectiveness for both induction and long-term maintenance of remission (Table 1). Randomized studies and longitudinal follow-up consistently show durable remission with AZA[31,32], and large trials underscore its meaningful role even when monotherapy is used, despite the superiority of combination therapy with anti-TNF agents[33]. The North American Crohn’s Study Group reported that parenteral MTX at 25 mg weekly effectively induced remission in active CD, and subsequent maintenance studies confirmed its superiority over placebo in sustaining remission over 40 weeks[5,6]. Comparative trials further suggested that MTX may achieve efficacy comparable to AZA in certain contexts, particularly among steroid-dependent patients[31].

Risk of maintenance failure: A key distinction between AZA and MTX lies in the risk of maintenance failure. AZA exerts its effect through direct cytotoxic inhibition of T and B lymphocytes, providing potent and durable immunosuppression. This mechanism translates into relatively stable long-term maintenance efficacy, with consistently lower rates of relapse reported in clinical trials and real-world cohorts (Table 1)[26,32]. In contrast, MTX functions as an indirect immunomodulator, primarily “tuning” lymphocyte proliferation through folate metabolism and adenosine-mediated pathways rather than abolishing it completely. As a result, the efficacy of MTX during long-term maintenance is more variable and susceptible to differences in dose, route of administration, and adherence[26,32].

Several factors underline this discrepancy. Unlike AZA, which achieves durable suppression once therapeutic metabolite levels are reached, MTX displays a narrower therapeutic window, and its clinical benefit diminishes when suboptimal oral dosing is used or when patients demonstrate poor compliance. While SC administration of MTX improves bioavailability and is guideline-preferred, oral MTX at equivalent doses has shown inconsistent efficacy, likely contributing to higher rates of loss of response[26]. Furthermore, real-world practice often employs lower maintenance doses than those used in pivotal clinical trials, which may further compromise efficacy.

Furthermore, recent reports underscore that the risk of MTX maintenance failure is not necessarily due to intrinsic inferiority of the drug but rather to suboptimal use in clinical practice. Bonnaud et al[9] emphasized that although guidelines recommend parenteral administration (25 mg/week SC or IM for induction and 15 mg/week SC/IM for maintenance), many clinicians still prefer oral MTX or prescribe lower doses, often citing lack of familiarity or experience with optimized MTX protocols. Similarly, a 2024 systematic review underscored that MTX efficacy is strongly dose- and route-dependent; however, real-world practice frequently employs rheumatology-style regimens (7.5-15 mg/week orally), which fall short of gastroenterology standards and likely contribute to reduced mucosal healing and higher relapse rates[8]. In this context, it is inaccurate to conclude that MTX is intrinsically inferior to AZA for long-term maintenance. Rather, the observed differences likely reflect pharmacologic and practical considerations including dosing, route, and adherence rather than fundamental efficacy gaps.

Mucosal healing: AZA has been consistently associated with higher rates of mucosal healing in CD, particularly when combined with anti-TNF therapy. In clinical studies, AZA monotherapy has achieved healing rates of approximately 40%-50% (Table 1), while combination regimens with infliximab further increased these outcomes[33,34]. In steroid-dependent CD, MTX is effective for maintenance of remission vs placebo over 40 weeks[6]. However, in contrast, a prospective study showed that mucosal healing with MTX monotherapy was infrequent (11%) compared with AZA (50%) or infliximab (60%)[35], and a previous randomized clinical trial showed that although the combination of infliximab and MTX demonstrates a favorable safety profile, its clinical efficacy appears comparable to that of infliximab monotherapy[36]. Thus, while MTX remains a safer long-term option in patients at high risk of thiopurine-related complications, AZA is better supported for achieving endoscopic healing, especially when used in conjunction with biologics.

These differences can be partly explained by the distinct pharmacological profiles of these two agents. AZA directly suppresses lymphocyte proliferation and more effectively facilitates mucosal clearance of inflammatory cells, thereby achieving higher rates of endoscopic healing. In contrast, MTX acts in a more regulatory manner, slowing but not abolishing inflammatory responses, which may limit its capacity to induce complete mucosal healing within a short timeframe. Moreover, real-world data suggest that underuse of MTX, particularly reliance on oral formulations with poor bioavailability and frequent prescription of rheumatology-style low-dose regimens (≤ 15 mg/week), further contributes to its lower observed healing rates[8]. The ECCO guidelines and recent reviews consistently emphasize that parenteral administration (25 mg/week for induction, 15 mg/week for maintenance) is essential for achieving optimal outcomes[26]. However, this standard is not consistently applied in clinical practice. Thus, the apparent inferiority of MTX in mucosal healing likely reflects both mechanistic limitations and suboptimal real-world use rather than an intrinsic lack of therapeutic potential.

Inhibition of anti-drug antibody formation: In CD, concomitant immunomodulation is used to blunt biologic immunogenicity. AZA co-therapy with infliximab consistently reduces anti-drug antibody (ADA) formation, raises trough concentrations, and improves clinical outcomes (Table 1): In the SONIC trial, combination therapy achieved higher rates of steroid-free remission than either monotherapy, largely explained by reduced immunogenicity and improved pharmacokinetics[33]. Post-hoc pharmacokinetic analyses further corroborated that AZA co-therapy increases infliximab trough levels by limiting immunogenicity[37]. Mechanistically, AZA directly interferes with B-cell proliferation and antibody production, thereby exerting potent and reliable inhibition of ADA formation.

MTX provides a more modest effect on ADA suppression, acting primarily through indirect modulation of immune responses rather than direct cytotoxicity. Evidence from rheumatology and psoriasis shows that MTX at doses ≥ 12.5-15 mg weekly reduces immunogenicity and improves drug persistence[8]. In IBD, the COMMIT trial did not demonstrate clinical superiority of infliximab plus MTX over infliximab monotherapy; however, pharmacokinetic and ADA trends favored the combination, suggesting that MTX can attenuate anti-TNF immunogenicity even if its impact is less pronounced than that of AZA. Thus, MTX represents a practical alternative when AZA is contraindicated or poorly tolerated, offering a safer though less potent approach to ADA inhibition.

Combination with other biologics

While the synergistic role of MTX with anti-TNF agents is well established, its impact when combined with newer biologic classes, such as ustekinumab (anti-IL-12/23), vedolizumab (anti-α4β7 integrin), and risankizumab (anti-IL-23), remains less clear. Recent studies have shown that combination therapy with MTX does not significantly improve clinical remission or endoscopic healing rates compared with biologic monotherapy with these newer agents[38,39]. Nevertheless, MTX co-therapy may still be considered in specific contexts, such as in patients with concomitant arthropathy or mild ADA formation, where it can modestly improve drug persistence and pharmacokinetics. Furthermore, in elderly patients or those with comorbid CD, the favorable safety and non-DNA-damaging mechanism of MTX make it a reasonable adjunct or monotherapy alternative when thiopurines are contraindicated.

Adverse events

AZA: The direct interference of AZA with DNA replication underlies both its efficacy and its toxicity profile. Serious but less frequent adverse events include myelosuppression and idiosyncratic pancreatitis[40,41]. More concerning are therapy-related malignancies, such as lymphoproliferative disorders (Table 1) and non-melanoma skin cancers, with the highest risk observed in young, EBV-negative males and in those receiving concomitant anti-TNF therapy[3,4,42]. These long-term risks have been a major driver of declining thiopurine use in routine practice and have prompted guideline recommendations for careful risk-benefit assessment, regular monitoring, and EBV serology before initiation. Furthermore, AZA appears to carry a higher overall carcinogenic risk than MTX, with stronger associations with hematologic malignancies and more consistent evidence across studies[3,43,44]. A large population-based study in IBD reported an increased risk of overall cancer in AZA users[3], while a separate multi-disease cohort found a 7-fold increased risk of myeloid neoplasms with AZA, with no such association for MTX[45].

MTX: In contrast, MTX is associated with a higher frequency of generally non-severe adverse effects. Nausea, fatigue, and hepatotoxicity are the most common, with hepatotoxicity requiring regular monitoring of liver enzymes[8]. Importantly, unlike AZA, MTX has not been consistently linked to an increased risk of lymphoma in IBD cohorts, contributing to its perception as a safer long-term alternative in patients at heightened malignancy risk[32]. Nonetheless, MTX carries its own limitations: Teratogenicity precludes its use in women and men planning conception, and cumulative hepatotoxicity remains a concern with prolonged therapy[25,26].

Pregnancy consideration

Pregnancy considerations further differentiate the safety profiles of AZA and MTX. AZA is generally considered safe to continue during pregnancy (Table 1), with large cohort studies and meta-analyses showing no increased risk of congenital malformations or adverse neonatal outcomes when appropriately monitored[25,26]. In contrast, MTX is strictly contraindicated in both women and men planning conception as well as during pregnancy due to its well-established teratogenicity and association with miscarriage[25,26].

Enhancing adherence and tolerability of MTX

In practice, weekly parenteral dosing is a major determinant of MTX success. Adherence improves with self-injection/auto-injectors, brief nurse education, and scheduled check-ins. Routine folic acid supplementation (≥ 5 mg/week) reduces gastrointestinal and hepatic adverse events without diminishing efficacy; for patients with anticipatory nausea, a short course of ondansetron around injection day is effective[46]. Finally, given its variable oral bioavailability in CD (approximately 73% of SC on average), parenteral delivery should be the default for induction and early maintenance to stabilize exposure and persistence.

Clinical relevance: Who benefits most?

AZA remains advantageous when mucosal healing or strong suppression of ADA formation with anti-TNF therapy is the primary therapeutic goal[33,35,37]. In contrast, MTX is best suited for steroid-dependent patients, those intolerant of thiopurines, and individuals at increased risk of thiopurine-related malignancies, particularly EBV-negative young males or patients with a cancer history. MTX is also valuable in patients with joint involvement, offering dual benefit in both CD and arthritis[8,42].

Practical roadmap for enhancing MTX utilization

Actionable strategies to close the evidence-practice gap. First, establish micro-curriculum modules for gastroenterologists and IBD nurses focusing on parenteral MTX dosing and escalation, self-injection technique training, and standardized monitoring protocols (complete blood count, liver function tests, pregnancy counseling). In rheumatology and dermatology settings, autoinjector training has been shown to improve adherence and patient confidence[46]. Second, integrate a single-page decision algorithm into electronic health record order sets or prescribing templates that stratify patients by EBV serostatus, malignancy risk, and extraintestinal involvement, automatically prechecking SC/IM MTX and weekly folic acid supplementation to reduce human error. Third, deploy follow-up pathways at weeks 2, 4, and 8 to monitor tolerability (nausea, fatigue), support adherence, and provide interventions (e.g., short-course ondansetron). In similar settings for biologics, nurse support and structured follow-up programs have demonstrably improved persistence and reduced discontinuation[47].

Reframing MTX in the biologic era: From backup to first-line in high-risk CD

In the pre-biologic era, immunomodulators such as AZA, 6-mercaptopurine, and MTX were the mainstays of maintenance therapy in CD. Today, with the advent of biologics, their role has shifted toward adjunctive use, particularly in combination with anti-TNF agents to reduce immunogenicity and prevent ADA formation. This shift mirrors a broader therapeutic transition: From maximizing immunosuppression to prioritizing long-term safety, risk reduction, and individualized treatment. As such, the choice of immunomodulator must now account for patient-specific factors including EBV status, age, cancer risk, and drug tolerability.

Against this backdrop, MTX has reemerged as a compelling alternative to AZA in high-risk populations. While AZA remains effective, its use is limited by well-established concerns, especially in EBV-seronegative individuals, patients with a prior malignancy, or those at risk for lymphoma. In contrast, MTX lacks DNA-damaging effects, offers a favorable safety profile, and contributes to immunogenicity control when used alongside anti-TNF agents. As highlighted in a recent French nationwide survey, MTX should not be viewed merely as a fallback option but rather as a first-line immunomodulator in select subgroups. For patients with joint involvement, EBV seronegativity, or increased malignancy risk, MTX may represent a safer and more strategic choice. Embracing this shift could better align clinical practice with modern, risk-adapted models of care while addressing persistent concerns associated with thiopurines.

CONCLUSION

MTX should no longer be regarded merely as a fallback when thiopurines are contraindicated or poorly tolerated. Rather, it deserves to be reframed as a strategic immunomodulator with clearly defined roles in modern CD management. Accumulating data support its efficacy for both induction and maintenance of remission, while its long-term safety profile compares favorably to that of thiopurines, particularly in high-risk populations. The nationwide survey by Bonnaud et al[9] highlights that MTX remains underutilized not because of a lack of efficacy but due to entrenched prescribing habits and insufficient clinical guidance, barriers that are both identifiable and reversible. In this context, current treatment guidelines may warrant revision to reflect emerging real-world data and to prioritize MTX in specific subgroups, such as EBV-seronegative patients, those with a history of malignancy, or others at increased risk for thiopurine-related toxicity.