Review article
Methotrexate in inflammatory bowel disease

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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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