Review articleMethotrexate in inflammatory bowel disease
Section snippets
Clinical pharmacology
Methotrexate can be administered by the oral, subcutaneous, intramuscular, or intravenous routes [10]. The drug is highly bioavailable at doses of 15 mg or less; however, absorption may be erratic with high oral doses [11]. Following absorption, methotrexate is concentrated in the liver, kidneys, and synovium and has a steady-state volume of distribution of approximately 1 L/kg. The parent molecule is transported into cells through an energy-dependent process. The enzyme hepatic aldehyde
Adverse event profile
Low-dose methotrexate was first identified as an effective treatment for severe psoriasis in the early 1960s [5]. The dose used as treatment for psoriasis and other autoimmune diseases is approximately one fortieth of that used in oncology. Despite impressive efficacy an unacceptably high incidence of hepatic toxicity was noted in psoriatic patients who had received chronic treatment with methotrexate. For example, in a series of 104 patients who were treated for a mean duration of 3.4 years
Induction of remission
Munkholm et al [24] have documented the natural history of active CD in Copenhagen County. Most patients who are treated with a course of conventional glucocorticoid therapy become either steroid dependent (36%) or steroid resistant (20%). Only a minority (44%) of patients experience a durable treatment response to glucocorticoid therapy. Patients who require chronic steroid therapy experience important morbidity and are at risk for disease-related mortality. Although surgery is an important
How do these results compare with those obtained with the purine antimetabolites?
The benefits and adverse effects observed with methotrexate should be compared with those reported for azathioprine and 6-MP [45]. A meta-analysis of the results of eight trials yielded a risk difference of 20% and number needed to treat of 5, an identical figure to that for methotrexate in the trial of Feagan et al [20]. Most of the studies included in this overview analysis trial did not use complete clinical remission and total withdrawal from steroids as the primary measure of treatment
Maintenance of remission in Crohn's disease
Data from a number of sources indicate that the purine antimetabolites are efficacious in the maintenance of remission in high-risk patients. Methotrexate's efficacy as a maintenance agent in CD was confirmed by a multicenter study in 76 patients with chronically active CD. In this trial, patients who had entered remission following 16 to 24 weeks of treatment with 25 mg of methotrexate given intramuscularly once weekly [44] were randomly assigned to receive either methotrexate at a dose of 15
Use of methotrexate with infliximab
The chimeric monoclonal antibody to tumor necrosis factor-α, infliximab, is a highly effective treatment for CD and RA (Targan et al). In patients with RA, combination therapy with infliximab and methotrexate yields superior clinical outcomes and results in a lower incidence of human antichimeric antibodies compared with infliximab monotherapy [47]. It is for this reason that infliximab and methotrexate are routinely coadministered.
In patients with CD, the development of human antichimeric time
Methotrexate for the treatment of ulcerative colitis
Most patients with ulcerative colitis are managed successfully with 5-ASA and brief courses of glucocorticoids. Patients with refractory disease, as defined by the need for chronic glucocorticoid therapy, often undergo colectomy because many clinicians are reluctant to consider the use of chronic immunosuppression in a disease that can be treated surgically and has a time-dependent, increased risk of colon cancer [44]. It is not surprising that far less data are available to assess the efficacy
Methotrexate in clinical practice
Clinicians who gain experience with methotrexate find it relatively easy to use in practice. The most common minor adverse effect is nausea, which tends to develop for a period of 24 to 48 hours after the weekly injection. This problem, which occurs in at most 15% of patients, can usually be managed by coadministration of oral folate (1 mg every day); use of antinauseants around the time of dosing (metoclopramide, ondansetron); or, uncommonly, dose reduction. At the authors' institution the
Summary
Over the past decade methotrexate has emerged as a new treatment for chronically active CD. Notwithstanding the data described previously, the purine antimetabolites remain the most frequently prescribed drug for these patients. This practice is based on the results of three relatively small, randomized controlled trials that used an adequate dose of either 6-MP or azathioprine [25], [26], [29]. In RA methotrexate has superseded azathioprine as a therapy because of superior efficacy and
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Cited by (28)
Sustained clinical benefit and tolerability of methotrexate monotherapy after thiopurine therapy in patients with crohn's disease
2013, Clinical Gastroenterology and HepatologyCitation Excerpt :We did not observe a statistically significant difference between oral or parenteral administration of MTX regarding clinical benefit of MTX (P = .61). Monotherapy MTX was relatively well tolerated in most CD patients because only 20% of patients discontinued MTX therapy because of an AR, which is in line with previously reported data.5,6,9–11,13–17,19,20,22,28,30 Remarkably, concerns about MTX toxicity appear to be the main reason for restricted use of MTX in CD patients in daily clinical practice.8
The use of methotrexate for treatment of inflammatory bowel disease in clinical practice
2012, Digestive and Liver DiseaseCitation Excerpt :Methotrexate (MTX), a folate analogue, exerts its immunomodulatory effect interfering with DNA synthesis, acting as a reversible competitive inhibitor of dihydrofolate reductase (DHFR); however, its clinical efficacy is likely explained by additional anti-inflammatory mechanisms of action, such as decreased pro-inflammatory cytokine production and induction of lymphocyte apoptosis [1,2]. The achievement of the full therapeutic activity of MTX may require up to 3 months, even though it appears to be faster with respect to thiopurines [3]; similarly to other immunosuppressants, MTX treatment is complicated by several side-effects [4]. During the treatment, it is suggested that folic acid supplementation may prevent vitamin deficiency, may reduce the occurrence of nausea and stomatitis and possibly also liver toxicity [5].
Gastrointestinal and liver adverse effects of drugs used for treating IBD
2010, Best Practice and Research: Clinical GastroenterologyCitation Excerpt :Thus an AZA/6-MP metabolite with much less side effects will probably never be approved for IBD treatment. Methotrexate is used with long lasting experience in rheumatology and has been introduced into IBD therapy by the studies of Feagan and coworkers [33,34]. MTX acts as a dihydrofolic acid analogue that binds to the dihydrofolic acid reductase enzyme by inhibiting the synthesis of tetrahydrofolate, which is required for DNA synthesis.
Inflammatory bowel disease biomarkers
2022, Medicinal Research ReviewsAmeliorating effects of agomelatine on testicular and epididymal damage induced by methotrexate in rats
2020, Journal of Biochemical and Molecular Toxicology