Methotrexate is administered once a week. The route of administration can be parenteral (subcutaneous or intramuscular) or oral. Since there are no head-to-head prospective trials comparing the efficacy of oral and parenteral methotrexate for IBD, it remains controversial whether there is a preferred route of administration. Retrospective reports leave the answer to this question vague. For example, two uncontrolled, observational studies published within a year of each other differed in their conclusions with one showing no difference between oral and parenteral methotrexate [24] and the other showing clear advantage to the parenteral route [25].

Pharmacokinetic studies have been performed to see if there is a significant difference in absorption between the two routes. Studies of adult patients [26] as well as pediatric IBD patients [27] have demonstrated a wide individual range of methotrexate bioavailability. Interestingly, the adult study showed the oral route to provide about 73% of the bioavailability that was seen with the parenteral route while no such difference was seen in the pediatric study. Both of these pharmacokinetic studies were performed on subjects who were clinically stable on methotrexate maintenance therapy. Therefore, neither provides bioavailability data on patients being induced with methotrexate and there is retrospective data to suggest that parenteral route may induce a more rapid remission [12]. Additionally, in pediatric arthritis patients, there is evidence for improved efficacy of subcutaneous methotrexate compared to oral methotrexate [28].Therefore, until further data is available it seems prudent to recommend the parenteral route be utilized for induction with a possible conversion to the oral route once a durable remission is achieved.

In addition to the ongoing questions with regard to the optimal route of administration, the actual ideal dose of methotrexate for pediatric IBD patients has not been studied. The dosing schedule that is utilized at our center is listed in Table 32.2. All patients are supplemented daily with folic acid 1 mg orally while the methotrexate is administered once a week and ondansetron is given orally as pre-medication before the first eight doses to prevent drug-associated nausea [29]. Once clinical remission is achieved and maintained for three or more months, an attempt to reduce the weekly dose and convert to oral administration is made. The dosing and monitoring strategies are listed in Table 32.2 and further discussed in the Toxicity section below.

In 1995, Feagan et al. published their 16-week induction study demonstrating that weekly intra-muscular injections of 25 mg of methotrexate is an effective, steroid-sparing, induction strategy in adult patients with active Crohn disease [9]. This study of 141 patients showed that 39% were in a steroid-free remission at 16 weeks compared to 19% of placebo patients. Those who achieved remission with methotrexate were then offered enrolment in a 40-week double-blind placebo-controlled maintenance trial of 15 mg of methotrexate administered intra-muscularly on a weekly basis. 76 patients participated and demonstrated a methotrexate remission rate of 65% compared to 39% with placebo. No serious adverse events were noted [10]. These results have been confirmed in at least one other controlled, prospective trial [30]. In addition, there have been head-to-head trials suggesting that the effect of methotrexate is similar to that seen with thiopurines [31, 32]. Two retrospective chart reviews have suggested efficacy out to 18 months [24, 25] while others have suggested about a 30% long-term (greater than one year) remission rate [33].

Published experience with methotrexate in pediatric IBD is growing. Mack et al. [34] first reported on 14 patients with a mean age of 10.6 years who had active Crohn disease and were intolerant or unresponsive to 6MP. Subcutaneous administration of methotrexate was used and 64% of the patients showed clinical improvement by as early as 4 weeks. Steroid sparing was also demonstrated. Adverse events attributed to methotrexate were nausea and headache leading to withdrawal of therapy in two patients. No patients demonstrated bone marrow suppression, abnormal liver chemistries, or pulmonary complications. There was one death in a child who was also on steroids and had an acute intercurrent illness. Post-mortem examination was unrevealing and adrenal suppression from chronic corticosteroid use rather than the methotrexate was felt to have contributed to the patient’s demise.

Another single center experience [35] demonstrated a 12-month steroid-free remission rate of about 33% which is similar to that seen in reports of adult patients with Crohn disease. Good tolerance of the methotrexate therapy was reported. Two larger, multicenter retrospective reports [12, 36] demonstrated a 40–45% 1-year steroid-free remission rate with methotrexate as a second-line immunomodulator in pediatric Crohn disease patients. No difference in effect was seen whether the indication for the methotrexate was lack of thiopurine efficacy or intolerance. Again, overall good drug tolerance was demonstrated as were a steroid sparing effect and a positive effect on linear growth [12].

In patients with IBD, low-dose methotrexate has been shown to be a well-tolerated agent with more than 90% of clinical trial patients able to complete study drug [22]. Reported side effects are usually transient or respond to dose reduction and, less commonly, drug withdrawal. There is a suggestion from the rheumatology literature that pediatric patients may be even more tolerant to methotrexate than adult patients [37]. A full discussion of potential side effects follows and is summarized in Table 32.3.

Nausea is the most common side effect and has been correlated with inhibition of folate-dependent enzymes. As a result, folic acid supplementation may help limit this side effect, which has been reported in more than 20% of the adult patients who participated in clinical IBD trials [22]. Recently, it has been reported that using ondansetron as a pre-medication for the first 4–8 weeks can effectively ­mitigate against the development of nausea [29]. Other gastrointestinal side effects include abdominal pain, diarrhea, and stomatitis that may even evolve into mucositis involving the esophagus [38].

In light of the potential for hepatic toxicity with high-dose methotrexate, liver-related complications have been well studied with low-dose methotrexate. There may be a disease-related rate of liver complications following therapy with low-dose methotrexate. Patients with psoriasis were shown to have a 7% rate of hepatic fibrosis [39] as compared to the 1% rate in rheumatoid arthritis [40]. The low rate of hepatic fibrosis and cirrhosis in RA has led to the official recommendation of the American College of Rheumatology that routine, surveillance liver biopsies not be performed [40]. Studies in JRA patients have shown at least as good hepatic tolerance [41]. Similarly negligible rates of drug-related hepatotoxicity have been seen in IBD patients treated with prolonged low-dose methotrexate [42]. Rather than biopsy, routine liver chemistry monitoring should be performed as shown in Table 32.2.