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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

Background:

Methotrexate is steroid-sparing in short-term trials for refractory Crohn’s disease. This study assesses the impact of dosing and administration on the long-term utility of methotrexate in Crohn’s disease.

Methods:

The efficacy and tolerability of methotrexate were assessed in all refractory Crohn’s disease patients treated at the University of Chicago from 1 September 1989 to 6 June 1997.

Results:

Seventy-six patients were identified: 43% male, mean age 35 years, mean Crohn’s disease duration 9.5 years. Mean methotrexate duration was 55 weeks; mean dose was 20 mg/week. Drug administration was parenteral (78%), oral (13%), or combination (8%). Improvement occurred in 63% after a mean of 9 weeks, for a mean duration of 65 weeks. Remission occurred in 37% after a mean of 22 weeks, for a mean duration of 59 weeks. Improvement and remission were highest with parenteral therapy, but dose-independent. Parenteral therapy maintained remission in 46%. Improvement (P=0.05) and remission (P=0.01) were more likely for patients under 40. Improvement rates were higher with concurrent steroids (P=0.02) or antibiotics (P=0.01). Side-effects occurred in 46%, resulting in discontinuation in 18%. Prednisone was decreased in 78%, and stopped in 40%.

Conclusions:

Long-term therapy with methotrexate in Crohn’s disease is safe, effective, steroid-sparing, and most efficacious in younger patients and when given parenterally.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

Crohn’s disease is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. In the past, medical therapy relied on aminosalicylates, antibiotics and steroids. Corticosteroid therapy is effective at improving symptoms,1, 2 but after 1 year, 36% of patients are steroid dependent and an additional 20% are steroid resistant,3 placing these patients at risk of chronic toxicity and further disease complications.4[5][6]–7 The unacceptable side-effect profile of steroids, as well as their inability to maintain remission in Crohn’s disease, has led to the use of immunomodulatory agents in patients with steroid-refractory or steroid-dependent disease. These include azathioprine, 6-mercaptopurine, methotrexate (methotrexate), ciclosporin and recently infliximab.

The efficacy of methotrexate for refractory Crohn’s disease was first described in small, uncontrolled studies in which therapy both induced remission and decreased steroid requirement.8[9]–10 Subsequent controlled trials confirmed these benefits.11, 12 A randomized placebo-controlled trial enrolling 141 steroid-dependent patients reported remission and steroid withdrawal rates of 39% with parenteral methotrexate (25 mg/week) vs. 19% with placebo.12 The effects of oral methotrexate have been less conclusive. Results of a small randomized trial of oral methotrexate suggested a trend towards a decrease in Crohn’s disease flares,11 but these findings were not substantiated by a larger Israeli study.13

The long-term efficacy of methotrexate in maintenance of remission in Crohn’s disease has recently been reported in a randomized trial, with 40-week drug remission rates of 65% vs. 39% for placebo.14 Other existing studies have been compromised by their small sample sizes, and varying endpoints and dosing schemes,15[16][17][18]–19 with relapse rates after improvement or remission ranging from 48%15 to 70%.18

Optimal dosing and mode of methotrexate administration remain unresolved. While the largest randomized trial and open series utilized a weekly parenteral dose of 25 mg,12 many reports describe subsequent substitution with orally administrated and reduced-dose methotrexate after 12 weeks.8 The aim of our report is to review the long-term utility and safety of methotrexate in a large population of patients with refractory Crohn’s disease.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

All patients seen at the University of Chicago’s Inflammatory Bowel Disease Clinic with a diagnosis of Crohn’s disease who started methotrexate treatment between 1 January 1989 through to 6 June 1997 were identified by searching a computerized inflammatory bowel disease database. Patient medical records were retrospectively reviewed to confirm that methotrexate was prescribed for Crohn’s disease, and to establish patient demographics, date of Crohn’s disease diagnosis and disease location, details of their clinical course, and remission and relapse dates.

Detailed information on steroid use and dose was collected from the charts, including change in, or elimination of, steroids. Information on the use of other medications was also tabulated, including mesalamine or sulfasalazine, azathioprine, 6-mercaptopurine, and antibiotics. Medication doses and therapeutic levels were not included for these other agents. Cigarette smoking and alcohol use were coded as ‘yes’ or ‘no’, and not quantified, due to variation of reporting.

Details regarding methotrexate therapy, including dose (mg/week, mg/kg body weight, cumulative), mode of delivery (parenteral, oral, combination), duration of therapy, side-effects, and reason(s) for drug discontinuation, were also collected. If the patients had more than one course of methotrexate, this was noted, although only information from their initial course was utilized for summary calculations.

All patients were the primary patient of a single physician (SBH). ‘Improvement’ was defined as a decrease in symptoms noted by the patient’s physician. ‘Remission’ was defined as an absence or near absence of symptoms and/or the physician’s statement that the patient was in remission, with the added requirement that the patient was not receiving any steroid-containing therapy. The improvement group included those patients who achieved remission. Subanalysis for ‘young’ patients (arbitrarily defined as those younger than 40 years old) vs. ‘older’ patients was also performed.

Statistical comparisons utilized standard software from Stata (Stata Corporation, College Station, Texas) Nominal comparisons were made using the χ2-test (with Yates’ correction) or the Fisher exact test. Interval comparisons utilized Student’s t-test. Survival analysis employed the methods of Kaplan and Meier. Multivariate analysis was performed where appropriate. A two-sided P-value of 0.05 was the criterion for statistical significance.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

Demographics

Seventy-six Crohn’s disease patients who received methotrexate for Crohn’s disease were identified through searching the computerized database. Population demographics are shown in Table 1. Twelve patients were included in the multicentre controlled clinical trial of methotrexate in active Crohn’s disease,12 and four were in the maintenance trial.14

Table 1.  Demographics of patients with Crohn’s disease receiving methotrexateThumbnail image of

Improvement and remission

Adequate data were available on 68 of the 76 patients to determine ‘improvement’ and 67 patients for ‘remission’. Improvement and remission calculations were based on these patients alone. The medical chart data was incomplete for the other patients; most had received methotrexate from a source outside the University of Chicago system during the specified study time period.

Sixty-three per cent of the patients achieved criteria for ‘improvement’, and 37% for ‘remission’ (Figure 1). Exclusion of the four patients who were not on steroids at the time of initiation of methotrexate therapy augments the improvement and remission rates to 67% and 40%, respectively. An analysis of the impact of the clinical variables following improvement or remission is shown in Table 2, and detailed below.

image

Figure 1. Improvement and remission on methotrexate. Bar height indicates the percentage of patients who improved (shaded bar) or achieved remission (unshaded bar) while on methotrexate therapy. Improvement: Time to improvement: 9 ± 1 week (range 1–27), cumulative dose 191 ± 29 mg (29–652), duration 65 ± 12 weeks (8–289). Remission: time to remission: 22 ± 5 weeks (range 1–81), cumulative dose 382 ± 82 mg (13–1478), duration 59 ± 12 weeks (2–217). Values are mean ± standard error of the mean (range).

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Table 2.  Association between variables and patient improvement or remission while treated with methotrexateThumbnail image of

Gender

Forty-six per cent (n=31) of the patients who received methotrexate were male and 54% (n=37) were female. There was no significant association between patient sex and either improvement or remission.

Age at initiation of methotrexate therapy

There was a trend towards a greater likelihood of improvement and remission in younger patients. Sub-group analysis revealed that patients who were younger than 40 years of age at the time of methotrexate initiation were more likely to improve (71% vs. 42%; P=0.05) and to achieve remission (47% vs. 11%; P=0.01) than those over 40. Only 2 of the 18 (11%) patients over the age of 40 achieved remission (Figure 2). There was no significant association between age over 40 and patient sex, race, duration or location of Crohn’s disease, duration and cumulative dose of methotrexate, mode of drug delivery or other medications. These results were substantiated by multivariate analysis controlling for Crohn’s disease duration and concomitant medication usage.

image

Figure 2. Rates of patient improvement and remission vs. age in patients treated with methotrexate. Patients younger than 40 years old at the time of methotrexate initiation were more likely to improve (P=0.05) or achieve remission (P=0.01) than those older than 40 years. ‘n’ indicates the number of patients at each data point.

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Route of administration

Drug delivery information was available for 60 patients. Seventy-eight per cent initiated parenteral methotrexate at a mean weekly dose of 24.6 mg (12.5–25 mg). Thirteen per cent began oral methotrexate at a mean weekly dose of 7.8 mg (5–12.5 mg). Five patients (8%) received ‘combination therapy’: four started on parenteral methotrexate, and eventually switched to oral methotrexate after an average of 15.7 weeks (10.7–22.3). The others began 7.5 mg of oral methotrexate and eventually switched to 7.5 mg of parenteral methotrexate after 34.7 weeks. Improvement and remission rates for patients on parenteral vs. oral methotrexate were 68% vs. 38% (P=0.12), and 35% vs. 25% (P=0.71), respectively. The small number of patients receiving oral therapy (n=8) limited the ability to show a statistical difference between therapies.

Methotrexate dose

Initial methotrexate dose was available for 62 patients. Seventy-nine per cent started on an initial weekly dose of 25 mg, 2% on 20 mg, 3% on 12.5 mg, 2% on 10 mg, 10% on 7.5 mg, and 5% on 5 mg. Mean average weekly methotrexate dose was 20.1 mg (s.d. 6.47 mg, range 5–25). There was no association between mean average weekly methotrexate dose and improvement vs. no improvement (20.1 mg vs. 20.2 mg, P=0.97) or remission vs. no remission (19.0 mg vs. 21.3 mg, P=0.19). Subanalysis of patients who received on average greater than 15 mg or greater than 20 mg weekly also failed to reveal any benefit in remission (P=0.13 and P=0.19, respectively) or in improvement (P=1.00 and P=0.25, respectively).

There was no association between mean methotrexate dose (expressed as mg methotrexate/kg body weight/week) and improvement (0.31 mg/kg vs. 0.28 mg/kg, P=0.34) or remission (0.28 mg/kg vs. 0.32 mg/kg, P=0.18). Average cumulative methotrexate dose was higher in patients who improved (1400 mg vs. 306 mg, P=0.0001) and who achieved remission (1327 mg vs. 838 mg, P=0.07), as expected since only those who showed improvement or remission were likely to be continued long-term on the medication.

Medications

Steroids.

Eighty-nine per cent of patients had used steroids prior to methotrexate therapy. There was no significant relationship in either improvement or remission according to prior steroid use. All except four (94%) of the patients were on prednisone at the time of initiation of methotrexate therapy [mean daily dose 22.8 mg (s.d. 15.8; range 0–80)]. Sixty-six per cent were receiving greater than 20 mg daily at the initiation of methotrexate therapy. Seventy-eight per cent of patients decreased their prednisone dose while receiving methotrexate; 71% to < 7.5 mg, and 40% completely tapered off steroids. Patients receiving methotrexate with steroids were more likely to improve (67% vs. 0%; P=0.02) than those treated with methotrexate alone. This was confirmed by multivariate analysis controlling for Crohn’s disease duration, age and other concomitant therapies. Univariate analysis revealed no association between steroid use and patient sex, age, race, duration or location of Crohn’s disease, mode of drug delivery or other medications.

There was a trend towards remission in patients treated with methotrexate and steroids vs. methotrexate alone (40% vs. 0%; P=0.29). Power calculation suggested that 11 more patients would have needed to be included to achieve an α of 0.05 and β of 0.80.

Antibiotics.

Seventy-five per cent of patients were receiving antibiotics prior to initiation of methotrexate therapy. There was no significant association with improvement or remission. Patients were more likely to improve (84% vs. 51%, P=0.01) if they were treated concurrently with antibiotics. This was confirmed by a multivariate analysis controlling for Crohn’s disease duration, other concomitant therapies, and age. Univariate analysis revealed no association between concurrent antibiotic use and patient sex, age, race, duration or location of Crohn’s disease, mode of drug delivery or other medications.

There was a trend towards remission in patients treated with methotrexate and antibiotics vs. methotrexate alone (48% vs. 32%; P=0.20). a power calculation suggested that 60 more patients would have needed to be included to achieve an α of 0.05 and β of 0.80.

Other drugs.

Sixty-two per cent of patients had used mesalamine or sulfasalazine prior to, and 23% during methotrexate therapy. Eighty-five per cent of patients had used azathioprine or 6-mercaptopurine prior to methotrexate therapy, and 13% during therapy. There was no significant association of either improvement or remission with the use of any of these agents prior to or concurrent with methotrexate therapy.

Smoking and alcohol use

Data on smoking and subsequent remission or improvement were available on 69 patients, 46% of whom smoked. Data on alcohol use was available on 68 patients, 32% of whom reported alcohol usage. The quantity of alcohol ingested was not reported. There was no significant association of either smoking or alcohol use with improvement or remission in these patients. There was no association between alcohol use and liver function abnormalities.

Maintenance of improvement and remission

Survival analysis predicting the likelihood of maintaining improvement and remission for all patients treated with methotrexate is shown in Figure 3. There was a steep decline in remission sustained between the first and second year, with a more gradual ‘tailing off’ to a rate of 21% by the fourth year. Improvement rates declined less dramatically. Both curves levelled off after 3 years.

image

Figure 3. Survival curve indicating the maintenance of improvement (dashed line) and remission (solid line) in all patients maintained on methotrexate therapy. The x-axis indicates months since improvement or remission where attained.

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The survival analysis for those who received parenteral therapy alone (i.e. excluding those who received oral methotrexate or sequential parenteral then oral methotrexate) is shown in Figure 4. The curve for improvement remains similar, but the remission curve is dramatically better, with 47% maintained in remission at 48 months.

image

Figure 4. Survival curve indicating the maintenance of improvement (dashed line) and remission (solid line) in patients maintained on parenteral methotrexate therapy. The x-axis indicates months since improvement or remission where attained.

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Adverse effects

Adverse effects of any type occurring during methotrexate therapy were reported in 46% of patients and are detailed in Table 3. The most common adverse symptoms were nausea, headache and fatigue. All of the adverse events were transient, and resolved with either continuation of therapy, dose reduction, or cessation of therapy. There were no long-term complications reported in any of the patients treated with methotrexate. Eighteen per cent discontinued methotrexate due, at least in part, to side-effects. Overall, 73% of patients discontinued therapy. The most common reasons were disease relapse or lack of response (Table 4).

Table 3.  Adverse events experienced by patients during treatment with methotrexateThumbnail image of
Table 4.  Reasons for discontinuation of methotrexate therapyThumbnail image of

Four patients experienced pulmonary (n=2) or hepatic (n=2) complications. Both pulmonary patients had pneumonia-like symptoms. One had a nonproductive cough, night sweats and dyspnea 1 month after stopping low dose methotrexate (5 mg/week). Chest X-ray suggested a diffuse infiltrate consistent with pneumonia. CAT scan and pulmonary function tests were normal. The patient improved completely with ciprofloxacin. The other patient developed sinusitis and cough productive of purulent sputum 9 weeks after initiating methotrexate therapy. Chest X-ray, CAT scan and pulmonary function tests suggested a pneumonia. The patient improved completely with antibiotics. Both cases were thought to be related to infection and not to methotrexate-induced pulmonary toxicity.

Two patients had elevated liver enzymes. One developed a 3–9-fold increase in their transaminases within 3 weeks of starting methotrexate. This resolved with discontinuation of therapy. The second patient (treated elsewhere) reported ‘elevated liver function tests’ from methotrexate that resolved with cessation of therapy. A liver biopsy was not performed in either patient.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

‘Low dose’ methotrexate has been used to treat rheumatoid arthritis, psoriasis and other chronic inflammatory diseases.20 Initial, uncontrolled trials of methotrexate for refractory Crohn’s disease showed improvements in clinical disease activity indices, induction of histological remission, decreased prednisone usage,8[9]–10 and improvement in disease activity for patients failing ciclosporin.21 Subsequent, controlled-trials substantiated these findings. The largest study (141 patients) by Feagan et al.12 reported that 39% of methotrexate-treated Crohn’s disease patients achieved remission and prednisone independence compared to 19% of placebo-treated patients. A small controlled trial of oral methotrexate described a trend towards a decrease in Crohn’s disease flares11 (46% vs. 80% in patients who received placebo). However, a larger Israeli study also comparing oral methotrexate with placebo did not show an advantage for attaining remissions, but did demonstrate significant reductions in steroid dose, improved well-being, and reduced abdominal pain.13

The efficacy of methotrexate in the maintenance of remission in Crohn’s disease has only very recently been reported in a randomized trial. As a follow-up study to their initial randomized trial of parenteral methotrexate in active Crohn’s disease,12 76 patients (23 from the randomized trial and 53 from open label experience) were randomized to intramuscular methotrexate 15 mg weekly or placebo for 40 weeks.14 Remission maintenance was seen in 65% of the 40 patients receiving methotrexate vs. 39% of the placebo group (P=0.01). Fewer patients who received methotrexate required prednisone for relapses (28% vs. 58%, P=0.01), and most (55%) of the relapse patients who were subsequently given parenteral methotrexate at a dose of 25 mg weekly were able to achieve remission and stop prednisone, vs. only 14% of those who did not receive the methotrexate after relapse. methotrexate was well tolerated, with no difference in the incidence of adverse events between methotrexate and placebo events, only one withdrawal from the methotrexate group (due to nausea), and both ‘serious adverse events’ occurring in the placebo group.

There are some important differences between this study and the current one. All patients in the randomized trial received parenteral methotrexate, as was the case in most (78%) of our patients. The weekly dose (15 mg) in the Feagan trial was lower than the mean (20 mg) and median (25 mg) doses reported here. Only 1% of patients in the randomized trial had previously been treated with purine analogues, compared to 85% of the patients in this present study. Thus, our population represented patients who were refractory or intolerant to both steroids and to the purine analogues that are often used as the ‘next step’ in Crohn’s disease management. While is not possible to directly compare the results of the two studies, due to the different designs, methodologies and patient populations, it is encouraging that the 40-week 65% remission rate of the randomized trial is consistent with the 80% maintenance rate that we reported at 52 weeks.

Another recently published uncontrolled study of 41 Crohn’s disease patients in remission for at least 6 months on either oral (44%) or parenteral methotrexate reported 1-, 2- and 3-year relapse rates of 29%, 41% and 48%, respectively.15 The authors did not separately report rates for oral vs. parenteral routes of delivery. These rates fell between those we showed for ‘all’ patients (Figure 3) and those receiving only parenteral therapy (Figure 4). Predictors of relapse were the presence of both small and large bowel disease (P=0.02) and female gender (P=0.04).

The side-effect rate of 49% in their study was similar to the 46% reported here. These authors performed liver biopsies in 11 patients for a variety of reasons, and reported ‘mild portal fibrosis’ and ‘slight periportal fibrosis’ in two. Our study also established the relative safety of methotrexate, while emphasizing the need for careful patient monitoring, including blood counts and liver chemistries. Although minor side-effects were fairly frequent, there were no serious, irreversible side-effects in our 76 patients. While liver biopsies were not obtained, a recent prospective analysis of liver biopsy findings in University of Chicago Crohn’s disease patients with at least 1.5 g of cumulative methotrexate dose suggested that hepatic fibrosis or cirrhosis is rare in inflammatory bowel disease patients without other risk factors for hepatic fibrosis (i.e. obesity, excessive ethanol use).26

There have been other published series in Crohn’s disease patients treated with methotrexate. In a controlled study of 27 patients who received oral methotrexate after an initial response to intramuscular methotrexate, only 49% demonstrated long-term benefit after 2 years,16 while in a similar uncontrolled study of 86 patients, 51% of patients receiving methotrexate maintenance therapy stayed in remission after 69 weeks.17 A retrospective review of 39 patients described 72% of patients achieving remission at 3 months, but only 42% were able to maintain in remission and remain off steroids over 12 months. Of those who achieved remission, 58% relapsed within 12 months.22 Similarly, in a recent retrospective study following 23 patients who initially achieved remission, 70% eventually relapsed18 and an analysis of 20 patients with steroid-refractory or dependent disease reported maintenance rates of 64%, 55% and 33% at 6, 9 and 12 months, respectively. At 6 months, steroids were tapered in 85% of patients, and discontinued in 60%.19

A comparison of the endpoints of different studies, such as ‘remission rates’, can be complicated by many factors, including study design, patient population and outcome measurements. This retrospective study did not gauge patient response and remission by standard disease activity scales, such as the Crohn’s Disease Activity Index, nor did it address quality of life issues. These are not possible to do in a retrospective manner, and as a result, this and similar studies must be interpreted with these limitations in mind.

The goals of the current study were to determine the long-term efficacy and safety of methotrexate in a large clinical practice of Crohn’s disease patients, and to determine the impact of the dose and method of delivery of the medication. The resulting remission rate of 37–40% (the latter if the patients were on steroids at the time of initiation of methotrexate) compared closely with the 39% remission rate reported from the controlled trial by Feagan et al.12 Although the 40% remission rate might not appear impressive, 85% of the 68 patients had failed treatment with, or were allergic to, either 6-mercaptopurine or azathioprine. In addition, the mean times to improvement and remission were approximately 2 and 5 months, respectively, slightly lower than the often quoted ‘3–6 months’ for azathioprine and 6-mercaptopurine.

This study also addressed the method of drug delivery and dose as important treatment variables. Patients who received parenteral methotrexate were more likely to improve, and enter and maintain remission than those who received the drug orally. In previous studies of methotrexate, the dose and delivery of the drug often varied. The regimen first proposed by Kozarek of weekly 25 mg intramuscular injections (i.m.) for the first 12 weeks, followed by oral dosing and a gradual decrease to at least 7.5 mg was purely ‘arbitrary…based on clinical experience…with rheumatoid arthritis’,8 but was adopted by many of the aforementioned investigators.9, 16, 22 Other weekly dosing regimens utilized in the trials include 25 mg i.m.,12, 18 25 mg i.m. for the initial 12 weeks, then lowered to 12.5 mg i.m.,19 25 mg subcutaneously, 15 mg orally, gradually introduced over four weeks,10 and 15 mg orally, dosed as 5 mg three times weekly.11 A paediatric trial dosed subcutaneously 10–25 mg initially, with 2–20% dose reductions after 3 to 6-month intervals.23 Subcutaneous (s.c.) administration of methotrexate has been shown to be effective in treating Crohn’s disease in adults24 and children.25

The benefits of parenteral methotrexate compared to oral therapy may in part be due to the variable oral bioavailability (50–90%), as compared to the linear pharmacokinetic profile of the parenteral form.8, 20 The uncertainties with absorption of oral methotrexate may be important in Crohn’s disease patients with impaired intestinal absorptive capabilities. Differences in patient adherence to prescribed regimens may also account for the difference in efficacy, whereby it may be more likely for a patient to successfully dose themselves once weekly (as in the case of parenteral methotrexate) rather than multiple times a week (as with oral methotrexate). The likelihood of adherence, however, may be greater for oral dosing than for an injection.

Another interesting finding from this series was the comparative success of methotrexate therapy in younger patients. Improvement rates ranged from 67% to 75% for those under 30 years or aged 30–40, respectively, compared to only 42% for patients more than 40 years old. It remains to be explained why remission rates were four to five times higher for the younger patients. The paediatric experience with methotrexate in Crohn’s disease has been less extensive. A recent uncontrolled study of 14 children (11 on steroids) with extensive Crohn’s disease refractory (n=11) or intolerant (n=3) to 6-mercaptopurine described initial improvement in all patients, and remission rates of 57% and 54%, respectively, at 1 and 3 months.23 Ten of the patients were continued on methotrexate, and steroid reduction was eventually realized in 10/11 patients, but with elimination of steroids in only two cases. Thus, most of the patients ‘in remission’ were, in fact, still on steroid therapy, and most had increased steroid intake during the initial 8 weeks of the study.

The interpretation of these data and application to the adult experience is thus somewhat limited; the results from the current study, however, also suggest that patients treated concurrently with steroids at the time of methotrexate initiation had better outcomes. This is supported by the findings in the controlled trial by Feagan et al.,12 where subanalysis of the remission data suggested that only patients receiving at least 20 mg of prednisone prior to randomization had a significant remission (39%) over placebo (10%; P=0.003). The patients who were increased to 20 mg of prednisone at the time of the trial did not achieve remission benefit (40% vs. 35.3% for placebo, P=0.92). The current series also identified benefits from concomitant antibiotic use, an observation that has not been described by previous researchers.

In conclusion, methotrexate is a safe, effective, steroid sparing agent for patients with refractory Crohn’s disease, particularly in patients younger than 40 years of age. It may be beneficial to start the methotrexate while the patient is still on steroids, and to taper off the steroids over time while maintaining the methotrexate dose. Its maintenance effects begin to wane after approximately 1 year, although some patients do achieve prolonged remissions.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography

We would like to acknowledge Ronald Thisted, PhD, for his assistance with the statistical analyses in this study.

This research supported by the Reva and David Logan Gastrointestinal Clinical Research Center at the University of Chicago and the University of Chicago Pritzker School of Medicine Summer Research Program.

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. Bibliography
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