Methotrexate for inflammatory bowel disease: time for reconsideration

KEYWORDS:

• Crohn’s disease
• biologics
• inflammatory bowel disease
• methotrexate
• therapy
• ulcerative colitis

1. Introduction

Based on randomized, placebo-controlled trials (RCTs) performed in Crohn’s disease, methotrexate has been used primarily for patients failing thiopurines but also for ulcerative colitis under the assumption that methotrexate would be equally effective. First recently, RCTs in ulcerative colitis have been published, and this Editorial aim to provide the latest evidence of the use of methotrexate in inflammatory bowel disease (IBD).

Methotrexate is an inexpensive, well-characterized folic acid antagonist that was originally introduced in the 1940s for the treatment of various malignant disorders. Years later this drug was discovered to have anti-inflammatory properties in lower dosages by reducing cell proliferation, inducing pro-apoptotic properties (especially on T cells), raising anti-inflammatory endogenous adenosine concentrations, and altering cytokine production, ultimately resulting in broad immunosuppression [1–3]. For decades, orally administered methotrexate has been the mainstay of the treatment of rheumatoid arthritis [3]. Since the late 1980s methotrexate was introduced for the management of IBD [4], and in the mid-1990s, it was demonstrated that parenteral, but not oral, methotrexate was efficacious for Crohn’s disease (Figure 1). In this context, pharmacokinetic studies have revealed a substantial influence over tissue delivery of the drug [5]. Thus, a highly variable and unpredictable bioavailability has been shown in oral administration [6], whereas parenteral dosing results in a more consistent and complete absorption with a bioavailability of 87% of that of intravenous dosing [5,7]. Moreover, because similar bioavailability has been demonstrated between subcutaneous and intramuscular administration [7], subcutaneous administration is traditionally used in IBD as this is easier and less painful.

Figure 1. Recommendations for use of parenteral methotrexate monotherapy in inflammatory bowel disease (i.e. Crohn’s disease and ulcerative colitis) based on latest evidence from randomized controlled trials.

2. Evidence for use of methotrexate in Crohn’s disease

In 1995, an RCT showed that intramuscular methotrexate at 25 mg once weekly for 16 weeks in patients with Crohn’s disease was superior to placebo in inducing remission with withdrawal of glucocorticoids [8], and a subsequent RCT showed that 40 weeks of intramuscular methotrexate at 15 mg/week was superior to placebo for maintenance of remission without any use of concomitant medical therapies [9].

3. Evidence for use of methotrexate in ulcerative colitis

Although no RCTs existed for ulcerative colitis, methotrexate was used in the management of this indication as well supposing that methotrexate, inhibiting dihydrofolate reductase, with consequent inhibition of DNA, RNA, and protein synthesis [1], would be equally effective as a second-line immunomodulator and steroid-sparing agent in patients who were intolerant of thiopurines or in whom thiopurine treatment had failed. However, because the mechanism of action of low-dose methotrexate is more complicated than the crude cytotoxic effect employed in oncology/hematology (where substantially higher doses are used) [3], and because the inflammatory mechanisms differ between ulcerative colitis and Crohn’s disease [10], this extrapolation may have been unsubstantiated.

Recently, two high-quality RCTs investigated methotrexate for the management of ulcerative colitis. First, the METEOR trial, including steroid-dependent patients with inactive to moderate disease activity, investigated the efficacy of parenteral methotrexate 25 mg/week versus placebo for 24 weeks for induction of remission of active ulcerative colitis [11]. Notably, the primary endpoint as well as nine of ten secondary endpoints failed (Figure 1). The only secondary endpoint that reached statistical significance was clinical (i.e. symptomatic) remission at week 16 in favor of methotrexate (42% versus 24%, p= 0.04), which, however, was lost at week 24 (40% versus 35%, p= 0.61) [11]. Second, the MERIT-UC trial, including moderately to severely active disease, investigated parenterally applied methotrexate for maintenance of remission at a dose of 25 mg/week for 32 weeks in patients with response to 16-week open-label methotrexate induction therapy [12]. The primary outcome was proportion of patients who remained relapse-free and were in combined clinical and endoscopic remission at week 48 without the need for other drugs than mesalamine to control disease activity. No differences between methotrexate (27%) and placebo (30%) were, however, observed (p= 0.78). Further, there were no differences in key secondary outcomes, e.g. mucosal healing at week 48 (30% versus 38%, p= 0.36), relapses between weeks 16 and 48 (50% versus 55%, p= 0.67), and steroid-free clinical remission or response and fecal calprotectin (FCP) levels < 250 mg/kg at week 48 in the subgroup of patients with FCP ≥ 250 mg/kg at screening (23% versus 20%, p= 0.63). Thus, the MERIT-UC study failed to demonstrate that methotrexate is effective for maintaining remission in ulcerative colitis [12] (Figure 1).

Although it has been criticized that that none of these two trials studied the population of patients with ulcerative colitis where monotherapy with methotrexate would be considered in a real-world clinical setting; based on these RCTs, including symptomatic and endoscopic endpoints as now recommended by regulatory agencies on both sides of the Atlantic, it is time to reconsider the use of methotrexate monotherapy in the management of IBD as a whole. The sum of available evidence supports the effectiveness of methotrexate monotherapy (parenterally at 15–25 mg/week) in maintaining clinical remission in Crohn’s disease (Figure 1). However, when collectively considering efficacy, including lack of data on mucosal healing, safety, and compliance, we recommended methotrexate monotherapy to be reserved primarily as a second-line maintenance agent following thiopurines. Even though methotrexate monotherapy has demonstrated symptomatic effects in the management of flaring Crohn’s disease (parenterally at a dose of 25 mg/week), and although it cannot be completely ruled out that methotrexate is superior to placebo in the symptomatic treatment of active ulcerative colitis, the availability of far more potent and well-documented agents to induce clinical remission and mucosal healing, including biologics [13] and novel small-molecule drugs (e.g. the jakinibs) [14], renders methotrexate monotherapy unsubstantiated in the treatment of acute flares of IBD (Figure 1). Finally, based on existing data, methotrexate monotherapy is not effective in maintaining remission in ulcerative colitis. Nevertheless, as extraintestinal joint manifestations (i.e. peripheral arthritis and axial arthropathies) occur frequently in patients with IBD, and as rheumatologists may advocate for use of methotrexate in the management of peripheral arthritis [15], methotrexate monotherapy may be considered for this indication in order to target joints. In Crohn’s disease this may also be beneficial for the gut symptoms whereas as mentioned, the effect on the gut is doubtful in ulcerative colitis.

4. Concomitant therapy with methotrexate and biologics

Clinical effectiveness of combination therapy with methotrexate and a biologic agent has thus far only been investigated for infliximab and in Crohn’s disease. In spite of promising exploratory reports, later studies including the state-of-the-art COMMIT RCT failed to demonstrate overall superior clinical outcomes of methotrexate-infliximab combination therapy as compared with infliximab monotherapy [16]. Nevertheless, methotrexate can suppress antibodies against infliximab and adalimumab [17,18] (and potentially other biologics as well), and there are reports that initiation of methotrexate in addition to continued treatment with an existing TNF inhibitor can reverse anti-drug antibodies and regain efficacy [19,20]. Whereas this indicates favor of combination therapy, the risks of adverse effects over a wide range of severity associated with methotrexate therapy (as opposed to changing to another biologic) have to be considered.

5. Conclusion

Based on the latest evidence the use of methotrexate monotherapy in the management of patients with IBD should be carefully considered and restricted to situations where there is reliable evidence of benefit.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

A reviewer of this manuscript has declared that they have had a working relationship with Ferring, MSD, Abbvie, Takeda, Janssen, Mylan, Pfizer, Sandoz.

Additional information

Funding

This paper was not funded.