Methotrexate in inflammatory bowel disease

Gastroenterol Clin N Am

33 (2004) 407–420

Methotrexate in inflammatorybowel disease

Brian G. Feagan, MD*, Ahmad Alfadhli, MDUniversity of Western Ontario, 100 Perth Drive, London, ON N6A 5K8, Canada

Despite the introduction of several treatment advances over the pastdecade, significant limitations still exist in the medical management ofpatients with inflammatory bowel disease. Although corticosteroids arehighly effective for induction of remission [1,2], a substantial proportion ofpatients who respond relapse when steroids are withdrawn and becomesteroid dependent. Furthermore, corticosteroids exhibit significant adverseeffects [3].

Treatment alternatives are required for patients who are refractory toglucocorticoid therapy. Methotrexate is an effective and safe treatmentfor corticosteroid-dependent or corticosteroid-resistant patients in otherchronic inflammatory diseases, such as psoriasis and rheumatoid arthritis(RA) [4–8]. It is logical to consider methotrexate as a treatment for inflam-matory bowel disease.

Methotrexate has been used in clinical medicine for over 40 years.Developed initially as a treatment for leukemia, the drug was synthesizedbased on knowledge of the three-dimensional structure of the enzymedihydrofolate reductase, as identified by x-ray crystallography. This enzyme,which is essential for the synthesis of nucleic acid precursors, requires folicacid as a cofactor. Methotrexate was synthesized as a competitive antagonistof folic acid. Methotrexate is one of the earliest examples of a ‘‘designerdrug.’’ Inhibition of dihydrofolate reductase by high-dose methotrexateinterferes with DNA synthesis, which ultimately results in the death ofleukemic cells [9]. In the course of the initial successful experience withmethotrexate in oncology, it was recognized that children with leukemia andconcomitant psoriasis or RA showed improvement of the latter conditions.This observation subsequently led to the evaluation of low-dose (5–25 mgweekly) methotrexate as a treatment for a number of immune diseases. Over

* Corresponding author.

E-mail address: [email protected] (B.G. Feagan).

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408 B.G. Feagan, A. Alfadhli / Gastroenterol Clin N Am 33 (2004) 407–420

the past decade clinical trials have shown that methotrexate has an emergingrole for the treatment of Crohn’s disease (CD).

Clinical pharmacology

Methotrexate can be administered by the oral, subcutaneous, intramus-cular, or intravenous routes [10]. The drug is highly bioavailable at doses of15 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 approxi-mately 1 L/kg. The parent molecule is transported into cells through anenergy-dependent process. The enzyme hepatic aldehyde converts metho-trexate to a primary metabolite, 7-hydroxymethotrexate. The drug issubsequently eliminated from the body by glomerular filtration; bothtubular secretion and reabsorption also occur. As a consequence, organicacids, such as aminosalicylic acid (ASA), and some nonsteroidal anti-inflammatory drugs may interfere with renal tubular secretion and increaseserum methotrexate levels. Because clinically significant drug interactionshave been reported in patients with RA methotrexate should be usedcautiously in patients with renal impairment. Therapeutic drug monitoringhas not been shown to be useful in patients with RA [12].

Although the mechanism of the anti-inflammatory effect of methotrexateis poorly understood, it is not likely through the inhibition of dihydrofolatereductase because folate supplementation does not reduce clinical efficacy inpatients with RA [13]. Several immunosuppressive properties have beendemonstrated in vitro including suppression of proinflammatory molecules,a decrease in cytotoxic T-cell function, and reduction in neutrophil activity[14]. Inhibition of adenosine metabolism does not seem to be an importantmechanism of action in patients with inflammatory bowel disease [15].

Adverse event profile

Low-dose methotrexate was first identified as an effective treatment forsevere psoriasis in the early 1960s [5]. The dose used as treatment forpsoriasis and other autoimmune diseases is approximately one fortieth ofthat used in oncology. Despite impressive efficacy an unacceptably highincidence of hepatic toxicity was noted in psoriatic patients who hadreceived chronic treatment with methotrexate. For example, in a series of104 patients who were treated for a mean duration of 3.4 years with doses of20 to 25 mg/wk, 23% showed significant pathologic changes (cirrhosis oractive hepatitis) on liver biopsy [16]. These findings might have led to theabandonment of methotrexate as treatment for autoimmune disease if notfor subsequent pharmacokinetic investigations, which demonstrated thatcontinuous (daily) drug administration results in high hepatic methotrexate

409B.G. Feagan, A. Alfadhli / Gastroenterol Clin N Am 33 (2004) 407–420

concentrations [17]. This finding is explained by the observation thatpolyglutamic folic acid is concentrated intrahepatically. Because methotrex-ate is a folate analogue, the drug likewise accumulates in the liver and causestoxicity. High intrahepatic concentrations of methotrexate do not occur,however, if sufficient time is allowed between doses for the drug to beredistributed from the liver and excreted by the kidney [18]. This un-derstanding of the pharmacokinetics of methotrexate led to the developmentof once weekly dosing schedules for the treatment of RA, which in turnreduced the incidence of hepatic toxicity. The frequency of methotrexatehepatic toxicity may also relate to the underlying disease, however, becausethe incidence of this complication is higher in psoriasis and low in RA. Thismay reflect differences among populations in the prevalence of risk factors(alcohol use, diabetes mellitus, and obesity) for methotrexate toxicity. Onlylimited data are available to assess the potential risk of methotrexate-associated hepatic fibrosis in inflammatory bowel disease [19].

Other important adverse effects of methotrexate include nausea [20], bonemarrow suppression [21], and hypersensitivity pneumonitis [22]. Methotrex-ate must not be given to women of childbearing potential because of the riskof teratogenicity [23].

Methotrexate therapy for Crohn’s disease

Induction of remission

Munkholm et al [24] have documented the natural history of active CD inCopenhagen County. Most patients who are treated with a course ofconventional glucocorticoid therapy become either steroid dependent (36%)or steroid resistant (20%). Only a minority (44%) of patients experiencea durable treatment response to glucocorticoid therapy. Patients whorequire chronic steroid therapy experience important morbidity and are atrisk for disease-related mortality. Although surgery is an importanttreatment option, CD frequently recurs following a bowel resection. Forthis reason, it is current practice to offer patients who require chronic steroidtreatment immunosuppressive drug therapy. The greatest experience hasbeen with the purine antimetabolites 6-mercaptopurine (6-MP) and azathi-oprine. Although early studies demonstrated conflicting results as to theefficacy of these drugs [1], data from two subsequent randomized placebo-controlled trials [25,26] and a meta-analysis [27] indicate that they areeffective for the induction of remission and for maintenance therapy in CD[27,28]. The onset of action of azathioprine is relatively slow (3–6 months),which may be a consequence of individual variability in the time requiredobtaining a steady-state concentration of immunosuppressive drug metab-olites. Moreover, less than half of patients who receive maintenance therapywith the purine antimetabolites remain free of a relapse over 1 year [25,26].Although the purine metabolites are relatively well tolerated, serious toxicity


can occur [29], most notably pancreatitis, leukopenia, and infection.Alternative treatments are desirable. It is noteworthy that methotrexatehas been preferred to azathioprine for the treatment of RA on account ofa more rapid clinical effect and superior long-term tolerability [30–33].

In 1989 Kozarek et al [34] first reported the use of methotrexate for thetreatment of inflammatory bowel disease in an uncontrolled study thatevaluated 21 patients (14 with CD, 7 with ulcerative colitis) with chronicallyactive disease. Methotrexate was administered intramuscularly at a dose of25 mg once weekly with conversion to a maintenance dose of 15 mg orally inpatients who responded to therapy. Approximately two thirds of patientshad improvement in symptoms and a steroid-sparing effect was alsodemonstrated. Notably one third of the patients with CD demonstratedendoscopic improvement, whereas no such beneficial effect was seen in thepatients with ulcerative colitis. On the basis of these promising results threerandomized placebo-controlled trials were subsequently conducted. Theresults of these studies have been evaluated in a systematic review publishedin the Cochrane library [35].

In the largest study, the North American Crohn’s Study Group StudyInvestigators, conducted a randomized, multicenter, double-blind, placebo-controlled trial of intramuscular methotrexate in chronic steroid-dependentCD (N = 141) at seven centers in Canada and the United States [20]. Eligiblepatients had chronically active CDwith at least 3months of symptoms despitea daily dose of at least 12.5 mg of prednisone with at least one attempt todiscontinue treatment. A total of 141 patients were randomly assigned in a 2:1ratio to receive either 25 mg/wk methotrexate (94 patients) or placebo (47patients). Remission was defined as complete discontinuation of prednisonetherapy and CD activity index (CDAI) score of less than 150 points at the endof 16 weeks. After 16 weeks, 37 patients (39.4%) were in clinical remission inthe methotrexate group compared with 9 patients (19.1%) in the placebogroup (P = .025). The patients in the methotrexate group received lessprednisone overall than those in the placebo group (P = .026). The effect oftreatment was greatest in those patients who had required greater than 20 mgof prednisone per day to control their symptoms (Fig. 1).

The mean score on the CDAI after 16 weeks of treatment wassignificantly lower in the methotrexate group (162 � 12) than in the placebogroup (204 � 17, P = .002). In the methotrexate group, 16 patients (17%)withdrew from treatment because of adverse events as compared with 1patient (2%) in the placebo group.

In the second trial, Oren et al [36] conducted a randomized, double-blind,placebo-controlled trial in 12 centers in Israel. The aim of the study was toevaluate the effectiveness of oral methotrexate in chronic steroid-dependentCD. The study included patients with active CD who had received steroids orimmunosuppressives for at least 4 months during the preceding 12 months,who had aHarvey-Bradshaw Score of more than 7. Patients were randomizedto placebo, oral methotrexate, 12.5 mg/wk, or oral 6-MP, 50 mg daily for 9


months. Corticosteroids and 5-ASA compounds were administered asclinically indicated. The authors evaluated four outcomes; however, a primaryoutcome was not defined. Eighty-four patients were included (methotrexate,26 patients; 6-MP, 32 patients; placebo, 26 patients). There was nostatistically significant difference between the groups in the proportion ofpatients entering first remission or the proportion of patients relapsing afterfirst remission. The Harvey-Bradshaw Score and the mean monthly steroiddoses were not different between the methotrexate and placebo groups.

In the third trial, Arora et al [37] randomized 33 patients withcorticosteroid-dependent CD for at least 6 months and either a CDAI scoregreater than 150 despite 10 mg/d of prednisone or a score of less than 150despite treatment with at least 15 mg of prednisone daily to either placebo ormethotrexate, 15 mg/wk orally, with dose escalation to a maximum of 22.5mg/wk according to clinical response. The investigators evaluated efficacy bythe average reduction in prednisone dosage, CDAI scores, and laboratoryparameters. Treatment failure was defined as no improvement in the CDAI at3 months with any reduction in steroid dose or the development of severeclinical illness. Four patients were dropped from the study for noncomplianceand one because of an intercurrent illness leaving 28 evaluable patients. Therewas no statistically significant difference (P = .142) in exacerbations of CDbetween methotrexate-treated patients (6 of 13) and placebo-treated patients(12 of 15). No statistically significant difference was observed (P = .175) inthe number of adverse effects that occurred in methotrexate-treated patients(3 of 13) as compared with the placebo-treated patients (0 of 15).

What conclusions can be drawn from results of these three studies? Thefirst point to consider is that the trials [20,36,37] differed considerably with

0

25

50

19.1

39.4

10.0

39.035.3

40.0

All Patients High-Stratum Prednisone

Low-Stratum Prednisone

P=0.025 P=0.003 P=0.92P

erce

ntag

e in

Rem

issi

on (

%)

Placebo Methotrexate

Fig. 1. Percentages of patients in remission at week 16 according to study group and stratum of

daily prednisone dose before entry into the study. (From Feagan BG, Rochon J, Fedorak RN,

et al. Methotrexate for the treatment of Crohn’s disease. N Engl J Med 1995;332:292–7; with

permission.)


respect to patient populations, the intervention, and the outcome measuresused. Two studies, which used low doses of oral methotrexate, showed nostatistically significant difference between methotrexate- and placebo-treatedpatients, and one, which used a higher dose given intramuscularly, showeda substantial benefit (number needed to treat= 5). This study alsodemonstrated an important improvement in quality of life (Mean In-flammatory Bowel Disease Questionnaire scores: methotrexate 169� 4,placebo 151� 6, P\ .002) and a clinically meaningful reduction in the useof prednisone. The two trials that used low-dose oral methotrexate includedrelatively small numbers of patients and may have lacked sufficientstatistical power to show a benefit of treatment. In these two studies itwas also difficult to determine from the published results the precisenumbers of patients who were in clinical remission and the status of thesepatients with respect to continued steroid treatment. In clinical practice,intramuscular administration is associated with higher costs and reducedpatient quality of life because of the need for increased clinic visits. In RAsubcutaneous administration of drug has produced similar pharmacokinet-ics to intramuscular injection, is easier to administer, and leads to greaterpatient comfort and a reduced rate of reactions at the injection site [38–40].Adverse events were observed with approximately equal frequency in themethotrexate-treated (45%) and control (42%) groups in the study reportedby Feagan et al [20]. Although no severe adverse effects were observed, 17%of methotrexate-treated patients were withdrawn from treatment because ofadverse events, compared with 2% in the placebo group (P= .012). Themost common reasons for withdrawal were nausea and vomiting (sixpatients) and asymptomatic elevation of liver enzymes (seven patients).Although the protocol for this trial mandated withdrawal of the study drug,in clinical practice in patients with rheumatoid disease, adverse effects, suchas nausea, are often dealt with or prevented by the concomitant adminis-tration of folic acid [41,42] and asymptomatic elevations of transaminaseson a single serum sample are not considered to reflect or predict existing orfuture hepatic disease [43]. In the two trials that used lower doses of oralmethotrexate no serious adverse effects were observed. In one trial [37],however, alanine transaminase levels were increased in 53% of patientsreceiving methotrexate, compared with 22% of patients receiving placebo.No clinically significant hepatotoxicity was observed.

In addition to the data from controlled trials, several large centers havepublished observational data regarding the efficacy and safety of metho-trexate. Although these data are retrospective and not placebo controlled,they confirm methotrexate induces remission in a high proportion ofpatients, many of whom had previously failed treatment with a purineantimetabolite. In a review of 70 cases (48 CD, 322 ulcerative colitis) theremission rate was 62% for those patients who completed more than 3months treatment and 45% for all patients who were treated for 1 year. Ina similar study 76 steroid-refractory patients with CD were treated for


a mean duration of 55 weeks with a mean dose of 20 mg [44]. Sixty-fourpercent improved and 37% were able to discontinue steroids.

How do these results compare with those obtained

with the purine antimetabolites?

The benefits and adverse effects observed with methotrexate should becompared with those reported for azathioprine and 6-MP [45]. A meta-analysis of the results of eight trials yielded a risk difference of 20% andnumber needed to treat of 5, an identical figure to that for methotrexate inthe trial of Feagan et al [20]. Most of the studies included in this overviewanalysis trial did not use complete clinical remission and total withdrawalfrom steroids as the primary measure of treatment success, however, makingcomparisons of the relative efficacy difficult. Moreover, these trials were forthe most part not conducted in steroid-dependent patients. The only studythat has directly compared the two drugs was performed by Ardizonne et al[46] who randomized 54 patients with steroid-dependent disease to either 25mg of methotrexate administered intravenously once weekly or oralazathioprine, 2 mg/kg/d. The primary outcome of the trial was completewithdrawal from corticosteroid therapy and a CDAI score of less than 150in 3 months. At the end of 3 months 44% of methotrexate-treated patientshad entered remission as compared with 33% of those who receivedazathioprine (P = .28). The respective figures at 6 months were 56% and63% (P = .39). Drug-related adverse events requiring withdrawal oftreatment occurred in three patients in each treatment group. Althoughthe authors concluded that their results did not support a more rapidtreatment effect of methotrexate it should be noted that the number ofpatients studied in the trial was inadequate to address this question. In fact,the 11% absolute difference in favor of methotrexate is consistent witha clinically meaningful difference in the 3-month remission rates (95%confidence interval for the 11% difference; �36.9%, 15%).

With respect to the issue of the relative toxicity of the purineantimetabolites, in the meta-analysis [27], adverse events requiring with-drawal from study medication were observed in 9.3% of patients receivingazathioprine or 6-MP. A large retrospective observational study [29] listsserious adverse events occurring with 6 MP with the following frequencies:infection, 7.4%; pancreatitis, 3.3%; neoplasm, 3.1%; marrow suppression,2%; allergy, 2%; and hepatitis 0.3%.

On the basis of a single large randomized trial and several retrospectivestudies, methotrexate seems to be safe and effective medication forinduction of remission in patients with refractory, steroid-dependent CDwhen administered parenterally in a dose of 25 mg weekly. There is noevidence that lower doses administered orally are effective. The relativeefficacy of methotrexate and the purine antimetabolites for this indicationis unclear.


Maintenance of remission in Crohn’s disease

Data from a number of sources indicate that the purine antimetabolitesare efficacious in the maintenance of remission in high-risk patients.Methotrexate’s efficacy as a maintenance agent in CD was confirmed bya multicenter study in 76 patients with chronically active CD. In this trial,patients who had entered remission following 16 to 24 weeks of treatmentwith 25 mg of methotrexate given intramuscularly once weekly [44] wererandomly assigned to receive either methotrexate at a dose of 15 mgintramuscularly once weekly or placebo for 40 weeks. No other treatmentsfor CD were permitted. Remission was defined as a score of 150 or less on theCDAI. Forty patients received methotrexate, and 36 received placebo. Atweek 40, 26 patients (65%) were in remission in the methotrexate group, ascompared with 14 (39%) in the placebo group (P = .04; absolute reductionin the risk of relapse, 26.1%; 95% confidence interval, 4.4%–47.8%) (Fig. 2).Fewer patients in the methotrexate group than in the placebo group requiredprednisone for relapse (28% versus 58%, P = .01). None of the patients whoreceived methotrexate had a severe adverse event; one patient in this groupwithdrew because of nausea.

The long-term tolerability and efficacy of methotrexate is also suggestedby the study of Kozarek et al [34], who reported that 51% of methotrexate-treated patients continued to receive the drug after 69 weeks.

Use of methotrexate with infliximab

The chimeric monoclonal antibody to tumor necrosis factor-a, inflix-imab, is a highly effective treatment for CD and RA (Targan et al). Inpatients with RA, combination therapy with infliximab and methotrexateyields superior clinical outcomes and results in a lower incidence ofhuman antichimeric antibodies compared with infliximab monotherapy [47].It is for this reason that infliximab and methotrexate are routinelycoadministered.

In patients with CD, the development of human antichimeric timeantibodies may lead to loss of clinical response. Baert et al studied 125consecutive patients with refractory luminal or fistulizing CD who weretreated with infliximab [48]. Concomitant medications including immuno-suppressive agents and corticosteroids were used as indicated to controlsymptoms. Treatment with immunosuppressive agents consisted of azathi-oprine (2 to 2.5 mg/kg/d), MP (1 to 1.25 mg/kg/d), or methotrexate (15 mgintramuscularly once weekly) for a median of 9.5 months (range, 2 to 84)before infliximab therapy was initiated. At the baseline visit no patients hadantibodies to infliximab. After the fifth infusion, 76 patients (61%) haddetectable antibodies. Patients receiving immunosuppressive drug agentshad a lower incidence of antibody formation: 43% (24 of 56) as comparedwith 75% (52 of 69) (P\ .01). Concomitant immunosuppressive therapy


was predictive of low titers of antibodies against infliximab (P\ .001) andhigher serum concentrations of infliximab 4 weeks after an infusion(P\ .001). These data provide strong evidence that concomitant treatmentwith immunosuppressives reduces the risk of forming antibodies toinfliximab. Independent of any synergistic treatment effect this interactionshould be beneficial in reducing the risk of infusion reactions andprolonging the duration of response. It is currently unknown whetherazathioprine and methotrexate are equally effective in preventing theformation of antibodies. Likewise, the minimum dose of these agents thatis required to obtain the protective effect is unknown and should be thesubject of future clinical trials.

Methotrexate for the treatment of ulcerative colitis

Most patients with ulcerative colitis are managed successfully with5-ASA and brief courses of glucocorticoids. Patients with refractory disease,as defined by the need for chronic glucocorticoid therapy, often undergocolectomy because many clinicians are reluctant to consider the use of

Fig. 2. Kaplan-Meier estimates of the time to relapse in the methotrexate group and the

placebo group. (From Feagan BG, et al. A comparison of methotrexate with placebo for

the maintenance of remission in Crohn’s disease. N Engl J Med 2000;342:1627–32; with

permission.)


chronic immunosuppression in a disease that can be treated surgically andhas a time-dependent, increased risk of colon cancer [44]. It is not surprisingthat far less data are available to assess the efficacy of immunosuppressivedrugs in this condition as compared with CD.

Although no large randomized controlled trials have demonstrated efficacyfor the purine antimetabolites in patients with chronically active ulcerativecolitis, Hawthorne et al [49] have performed a withdrawal study thatevaluated the efficacy of azathioprine in 79 patients who entered remissionafter receiving azathioprine therapy. Patients who were assigned to withdrawfrom azathioprine had a greater rate of relapse at 1 year compared with thosewho remained on drug therapy (59% versus 35%, P = .04).

The initial uncontrolled study by Kozarek et al [34] in 1989 reported thatmethotrexate induced remission in five of seven patients with ulcerativecolitis. Two randomized, double-blind, placebo-controlled trials of metho-trexate in chronic active ulcerative colitis have been performed. Oren et al[50] compared oral methotrexate (12.5 mg weekly) with placebo for 9months in 67 patients who had received steroids or immunosuppressivedrugs for at least 4 of the 12 preceding months. No statistically significantdifferences were demonstrated between the treatment groups in the pro-portion of patients achieving remission, the time required to achieveremission, or the proportion of patients experiencing a relapse aftera remission had been obtained. Mate-Jimenez et al [51] randomized 34patients with chronically active steroid-dependent ulcerative colitis toreceive either 1.5 mg/kg/d of 6-MP, 15 mg/wk of methotrexate, or 3 g/d of5-ASA. At the end of 76 weeks of treatment 63.6% of those who received6-MP were in remission compared with 14.3% of those assigned tomethotrexate and 0% of those who received 5-ASA.

Although these studies are at a high-risk of a false-negative conclusiontheir collective results do not support the use of methotrexate as a therapyfor ulcerative colitis. A research priority should be to evaluate the efficacy ofa higher dose of methotrexate than 15 mg per week.

Methotrexate in clinical practice

Clinicians who gain experience with methotrexate find it relatively easy touse in practice. The most common minor adverse effect is nausea, whichtends 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 bemanaged by coadministration of oral folate (1 mg every day); use ofantinauseants around the time of dosing (metoclopramide, ondansetron);or, uncommonly, dose reduction. At the authors’ institution the sub-cutaneous route of administration is now used, because data from studiesof RA show it is pharmacokinetically equivalent to intramuscular injection[39]. As with the purine antimetabolites, leukopenia and associatedopportunistic infections occur uncommonly. In the authors’ experience,


the overall frequency of leukopenia is lower than that observed withazathioprine treatment and lower than that reported in the rheumatologicliterature; however, a complete blood count should be obtained monthly.Hypersensitivity pneumonitis occurs in no more than 1% of patients. A highclinical index of suspicion, prompt discontinuation of treatment, and ini-tiation of corticosteroid therapy are essentials of management.

Hepatotoxicity was first documented in psoriatic patients. Subsequentunderstanding of pharmacokinetics and the conversion to weekly, fromdaily, dosing has virtually eliminated this problem. Patients should bemonitored according to the American Rheumatological Association guide-lines [43], paraphrased as follows: avoid treating patients with risk factorsfor hepatotoxicity (obesity, diabetes, excessive alcohol use); and measuretransaminases every 4 to 6 weeks. If, over the course of 1 year, more thanhalf of the transaminases are abnormal, perform a liver biopsy beforecontinuing treatment. At the authors’ institution, they have not encounteredclinically important hepatotoxicity using this strategy and very few liverbiopsies are necessary. Finally, no good data indicate that methotrexate isassociated with malignancy. In summary, methotrexate is a safe and ef-fective maintenance therapy in patients with Crohn’s disease.

Summary

Over the past decade methotrexate has emerged as a new treatment forchronically active CD. Notwithstanding the data described previously, thepurine antimetabolites remain the most frequently prescribed drug for thesepatients. This practice is based on the results of three relatively small,randomized controlled trials that used an adequate dose of either 6-MP orazathioprine [25,26,29]. In RA methotrexate has superseded azathioprine asa therapy because of superior efficacy and long-term tolerability. In theabsence of good comparative data, clinicians must decide which ofmethotrexate or the purine antimetabolites is the preferred treatment forCD [52,53]. Extensive long-term experience exists with the purine antimeta-bolites, whereas the risk of liver disease from methotrexate remains an issue.The risk of significant hepatic toxicity in RA is low, however, and surveillanceliver biopsy is no longer recommended. In the absence of biopsy data frompatients with CD, the American Rheumatology Association guidelinesregarding surveillance for hepatic toxicity should be followed [43]. Theemergence of infliximab as a new therapy for patients with refractory Crohn’s[54,55] should also focus additional attention on the use of methotrexate as analternative to the purine antimetabolites. In patients with RA concomitanttreatment with methotrexate has been shown to enhance the response toinfliximab therapy. Furthermore, patients who are receivingmethotrexate areless likely to develop human antichimeric antibodies [47]. These antibodies,which may block the beneficial action of infliximab or cause adverse effects,are a significant limitation to the long-term use of this form of treatment. A


strong rationale exists to consider methotrexate-infliximab combinationtherapy in CD.

Although controlled trials to compare the relative efficacy and safety ofazathioprine and methotrexate in therapy-resistant patients are desirable, inthe authors’ opinion these studies are difficult, if not impossible to conductbecause of the relatively small differences in potency and tolerabilitybetween these agents. A more productive area for future investigations isto explore the use of these drugs in combination with infliximab and otherbiologic treatments.

References

[1] Summers RW, Switz DM, Sessions JT Jr, et al. National Cooperative Crohn’s Disease

Study: results of drug treatment. Gastroenterology 1979;77:847–69.

[2] Rutgeerts P, Lofberg R, Malchow H, et al. A comparison of budesonide with prednisolone

for active Crohn’s disease. N Engl J Med 1994;331:842–5.

[3] Yang Y-X, Lichtenstein GR. Corticosteroids in Crohn’s disease. Am J Gastroenterol 2002;

97:803–23.

[4] Klippel JH, Decker JL. Methotrexate in rheumatoid arthritis. N Engl J Med 1985;312:

853–4.

[5] Black RL, O’Brien WM, Van Scott EJ, et al. Methotrexate therapy in psoriatic arthritis:

double-blind study on 21 patients. JAMA 1964;189:743–7.

[6] Willkens RF, Sharp JT, Stablein D, et al. Comparison of azathioprine, methotrexate, and

the combination of the two in the treatment of rheumatoid arthritis: a forty-eight-week

controlled clinical trial with radiologic outcome assessment. Arthritis Rheum 1995;38:

1799–806.

[7] Weinstein GD, Jeffes E, McCullough JL. Cytotoxic and immunologic effects of

methotrexate in psoriasis. J Invest Dermatol 1990;95:49S–52S.

[8] Weinblatt ME, Coblyn JS, Fox DA. Efficacy of low-dose methotrexate in rheumatoid

arthritis. N Engl J Med 1985;312:818–22.

[9] Goodman LS, Gilman A. The pharmacological basis of therapeutics. New York: McGraw

Hill; 1996.

[10] Jundt JW, Browne BA, Fiocco GP, et al. A comparison of low dose methotrexate

bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing.

J Rheumatol 1993;20:1845–9.

[11] Hillson JL, Furst DE. Pharmacology and pharmacokinetics of methotrexate in rheumatic

disease: practical issues in treatment and design. RheumDis ClinNorthAm1997;23:757–78.

[12] Bannwarth B, Pehourcq F, Schaeverbeke T, et al. Clinical pharmacokinetics of low-dose

pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet 1996;30:194–210.

[13] Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during

methotrexate therapy for rheumatoid arthritis. Ann Intern Med 1994;121:833–41.

[14] Cronstein BN, Naime D, Ostad E. The anti-inflammatory mechanism of methotrexate.

J Clin Invest 1993;92:2675–82.

[15] Egan LJ, Sandborn WJ, Mays DC, et al. Plasma and rectal adenosine in inflammatory

bowel disease: effect of methotrexate. Inflamm Bowel Dis 1999;5:167–73.

[16] Malatjalian DA, Ross JB, Williams CN, et al. Methotrexate hepatotoxicity in psoriatics:

report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and

alcohol consumption during long term follow-up. Can J Gastroenterol 1996;10:369–75.

[17] Hall PD, Jenner MA, Ahern MJ. Hepatotoxicity in a rat model caused by orally

administered methotrexate. Hepatology 1991;14:906.


[18] Lewis JH, Schiff E. Methotrexate-induced chronic liver injury: guidelines for detection and

prevention. Am J Gastroenterol 1988;88:1337–45.

[19] Te HS, Schiano TD, Kuan SF, et al. Hepatic effects of long-term methotrexate use in the

treatment of inflammatory bowel disease. Am J Gastroenterol 2000;95:3150–6.

[20] Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s

disease. N Engl J Med 1995;332:292–7.

[21] Al-Awadhi A, Dale P, McKendry RJR. Pancytopenia associated with low dose

methotrexate therapy: a regional survey. J Rheumatol 1993;20:1121–5.

[22] Searles G, McKendry RJ. Methotrexate pneumonitis in rheumatoid arthritis: potential risk

factors: four case reports and a review of the literature. J Rheumatol 1987;14:1164–71.

[23] Kozlowski RD, Steinbrunner JV, MacKenzie AH, et al. Outcome of first-trimester

exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med

1990;88:589–92.

[24] Munkholm P, Langholz E, Davidsen M, et al. Frequency of glucocorticoid resistance and

dependency in Crohn’s disease. Gut 1994;35:360–2.

[25] O’Donoghue DP, Dawson AM, Powell-Tuck J, et al. Double-blind withdrawal trial of

azathioprine as maintenance treatment for Crohn’s disease. Lancet 1978;2:955–7.

[26] Candy S, Wright J, Gerber M, et al. A Controlled double blind study of azathioprine in the

management of Crohn’s disease. Gut 1995;37:674–8.

[27] Pearson DC, May GR, Fick GH, et al. Azathioprine and 6-mercaptopurine in Crohn’s

disease: a meta-analysis. Ann Intern Med 1995;122:132–42.

[28] Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn’s disease with

6-mercaptopurine: a long-term, randomized, double-blind study. N Engl J Med 1980;

302:981–7.

[29] Present DH, Meltzer SJ, Krumholz MP, et al. 6-Mercaptopurine in the management of

inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989;111:

641–9.

[30] Ward MM. Trends in the use of disease modifying antirheumatic medications in

rheumatoid arthritis, 1980–1995: results from the National Ambulatory Medical Care

Surveys. J Rheumatol 1999;26:546–50.

[31] Maetzel A, Bombardier C, Strand V, et al. How Canadian and US rheumatologists treat

moderate or aggressive rheumatoid arthritis: a survey. J Rheumatol 1998;25:2331–8.

[32] Cron RQ, Sharma S, Sherry DD. Current treatment by United States and Canadian

pediatric rheumatologists. J Rheumatol 1999;26:2036–8.

[33] Willkens RF, Stablein D. Combination treatment of rheumatoid arthritis using

azathioprine and methotrexate: a 48 week controlled clinical trial. J Rheumatol 1996;44:

64–8.

[34] Kozarek RA, Patterson DJ, Geland MD, et al. Methotrexate induces clinical and

histologic remission in patients with refractory inflammatory bowel disease. Ann Intern

Med 1989;110:353–6.

[35] Alfadhli AA, McDonald JW, Feagan BG. Methotrexate for induction of remission in

refractory Crohn’s disease. Cochrane Database Syst Rev 2003;1:CD003459.

[36] Oren R, Arber N, Odes S, et al. Methotrexate in chronic active Crohn’s disease: a double

blind, randomized, Israeli multicentre trial. Am J Gastroenterol 1997;92:2203–9.

[37] Arora S, Katkoc W, Cooley J, et al. Methotrexate in Crohn’s disease: results of

a randomized double-blind, placebo-controlled trial. Hepatogastroenterology 1999;46:

1724–9.

[38] Balis FM, Mirro J Jr, Reaman GH, et al. Pharmacokinetics of subcutaneous methotrexate.

J Clin Oncol 1988;6:1882–6.

[39] Brooks PJ, Spruill WJ, Parish RC, et al. Pharmacokinetics of methotrexate administered

by intramuscular and subcutaneous injections in patients with rheumatoid arthritis.

Arthritis Rheum 1990;33:91–4.


[40] Egan LJ, Sandborn WJ, Mays DS, et al. Systemic and intestinal pharmacokinetics of

methotrexate in patients with inflammatory bowel disease. Clin Pharmacol Ther 1999;65:

29–39.

[41] Griffith SM, Fisher J, Clarke S, et al. Do patients with rheumatoid arthritis established on

methotrexate and folic acid 5mg daily need to continue folic acid supplements long term?

Rheumatology 2000;39:1102.

[42] Lorenzi AR, Johnson AH, Gough A. Daily folate supplements is adequate prophylaxis

against methotrexate-induced nausea and vomiting and avoids the need for expensive

anti-emetic prescription. Rheumatol 2000;39:812–3.

[43] Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis:

suggested guidelines for monitoring liver toxicity. American College of Rheumatology.

Arthritis Rheum 1994;37:1829–30.

[44] Chong RY, Hanauer SB, Cohen RD. Efficacy of parenteral methotrexate in refractory

Crohn’s disease. Aliment Pharm 2001;15:35–44.

[45] Sandborn WJ, Sutherland L, Pearson D, May G, Modigliani R, Prantera C. Azathioprine

or 6-mercaptopurine for induction of remission in Crohn’s disease (Cochrane Review). The

Cochrane Library (database on disk and CD-ROM) (3). Oxford: Update software; 2002.

[46] Ardizzone S, Bollani S, Manzionna G, Imbesi V, Colombo E, Bianchi Porro G.

Comparison between methotrexate and azathioprine in the treatment of chronic active

chron’s disease: a randomised, investigator blind study. Dig Liver Dis 2003;35:619–27.

[47] Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous

infusion of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose

weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552–63.

[48] Baert F, Norman MR, Vermeire S, et al. Influence of immunogenicity on the long-term

efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601–8.

[49] Hawthorne AB, Logan RFA, Hawkey CJ, et al. Randomized controlled trial of

azathioprine withdrawal in ulcerative colitis. BMJ 1992;305:20–2.

[50] Oren R, Arber N, Odes S, et al. Methotrexate in chronic active ulcerative colitis: a

double-blind, randomized, Israeli multicenter trial. Gastroenterology 1996;110:1416–21.

[51] Mate-Jimenez J, Hermida C, Cantero-Perona J, et al. 6-Mercaptopurine or methotrexate

added to prednisone induces and maintains remission in steroid-dependent inflammatory

bowel disease. Eur J Gastroenterol Hepatol 2000;12:1227–33.

[52] Korelitz BI, Present DH. Methotrexate for Crohn’s disease. N Engl J Med 1995;333:600–1.

[53] Feagan BG, McDonald JWD. Methotrexate for Crohn’s disease. N Engl J Med 1995;332:

292–7.

[54] Targan SR, Rutgeerts P, Hanauer SB, et al. A multicenter trial of anti-tumor necrosis

factor (tnf) antibody (ca2) for treatment of patients with active Crohn’s disease.

Gastroenterology 1995;110:A1026.

[55] Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients

with Crohn’s disease. N Engl J Med 1999;340:1398–405.

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Methotrexate in inflammatory bowel disease