Immunomodulatory agents are well established in the maintenance treatment of Crohn disease (CD). Thiopurine analogues, azathioprine (AZA), and 6-mercaptopurine (6-MP) are the most widely used agents; however, intolerance or unresponsiveness to these drugs occur in 30% to 50% of patients (1). Two basic strategies have developed over time in patients unresponsive to an immunomodulator. The first is to select an alternative immunomodulator such as methotrexate (MTX), or to introduce a biologic treatment for remission and maintenance. Antitumor necrosis factor-alpha agents are often used in pediatric patients following failure on incomplete disease control with AZA/6-MP, and have shown clinical efficacy (2). Treatment with MTX was shown to be efficacious both for induction of remission and maintenance of remission in adult patients with CD (3–5). In children, limited data regarding MTX therapy in CD is available (6–8).
Therefore, we aimed to evaluate the efficacy and safety of MTX in maintenance of clinical remission in pediatric patients with active CD who failed thiopurine treatment.
PATIENTS AND METHODS
This is a retrospective longitudinal study of pediatric patients (<18 years of age) with CD treated with MTX between 1998 and 2006, from 5 pediatric gastroenterology centers. The diagnosis of CD was established based on endoscopic and radiological findings. All of the patients underwent colonoscopy and either upper gastrointestinal series with small bowel follow-through or abdominal CT-enterography.
All of the patients received treatment with purine analogues (oral AZA or 6-MP) before MTX treatment, and were intolerant, nonresponsive, or had lost response to treatment. Nonresponders were defined as patients treated with AZA/6-MP at the recommended doses (2–2.5 mg/kg for AZA and 1–1.5 mg/kg for 6-MP) for more than 16 weeks with no clinical improvement, no steroid withdrawal or need for escalation of therapy to biological treatment.
MTX was administered subcutaneously once per week by a nurse, or given orally once weekly. Oral 5 mg folic acid was supplemented daily (8).
Monitoring of liver profile, complete blood count with differential and erythrocyte sedimentation rate was performed within 2 weeks of MTX initiation, every 2 to 4 weeks for the first 2 months and every 6 to 8 weeks thereafter. Office visits and physical examination of the patient were performed every 2 weeks in the first month and every 4 to 12 weeks along the treatment period.
Data extraction included demographic and disease characteristics, dosing of MTX and steroids, results of blood tests, and adverse drug reactions.
Outcome variables included MTX efficacy, steroid withdrawal, and adverse reactions. MTX efficacy was the proportion of patients achieving steroid-free remission or a partial response. Remission was defined as clinical remission by Harvey-Bradshaw (HB) score (≤4) (9), steroid withdrawal lasting more than 3 months, and no need for escalation in therapy, such as infliximab. Response was defined as a decrease in the HB index by at least 2 points, and a decrease of corticosteroids of at least 50%. In addition, and despite the retrospective nature of the study, it was possible to calculate the Pediatric Crohn Disease Activity Index (PCDAI) before and during MTX therapy. Remission was defined as PCDAI less than or equal to 10, and response as a drop of at least 10 points in PCDAI within 8 to 12 weeks after MTX initiation.
HB activity index and PCDAI were calculated using data from the time of MTX initiation and at 8 to 12 weeks, 6 months, and at 6 months intervals of follow-up.
Adverse reactions requiring cessation of MTX and time to development of toxicity were evaluated.
Analysis of demographic parameters and relevant clinical parameters was performed using biomedical data package (10). Pearson χ2 test or Fisher exact test (where appropriate) were applied to analyze discrete variables. Continuous variables were compared using the Mann-Whitney nonparametric U test. A P value of less than or equal to 0.05 was considered significant.
Twenty-five pediatric patients with CD treated with MTX were identified. The number of patients recruited from each center was 10, 6, 4, 3 and 2 from Safra, Carmel, Schneider, Asaf-Harofe, and Wolfson, respectively. Patient characteristics are shown in Table 1. The mean age of CD diagnosis was 11.1 ± 3.1 years (range −3.1 to 16.0 years), and the mean age of MTX initiation was 14.5 ± 3.1 years (range 4–18 years). Nineteen patients received parenteral and 6 patients received oral treatment. Patients receiving oral treatment were from 3 centers (3/10 Safra, 2/4 Asaf-Harofe, 1/3 patients Schneider), and the reason was refusal to receive injections. The median MTX dose was 12.5 mg/m2, range 9.0–21.5 mg/m2.
Mean duration of MTX therapy was 13.1 ± 8.7 months (range 0.5–36 months, median 12 months).
Disease activity: Remission was achieved in 16 patients (64%) and response in 6 patients (24%). Time to remission or response was 6 to 10 weeks (median 8 weeks). The duration of remission and response was 10.8 ± 8.8 months (median 12 months, range 1.5–32 months). Eighteen patients (72%) received MTX treatment for longer than 6 months. Of those, 15 patients (83%) continued to be in remission or response after 12 months of treatment. Remission rate in relation to length of MTX treatment is presented in Figure 1. Three patients discontinued therapy after less than 3 months, 2 of them due to adverse effects and 1 due to severe disease exacerbation requiring treatment escalation.
Nineteen patients received MTX as subcutaneous (SC) injections, and 6 patients received oral treatment. There was no significant difference between those patient groups in the dose/m2, pretreatment disease activity, disease location and remission or response rate. Duration of treatment and duration of remission or response were longer in the oral treatment group (Table 2).
No relation was found between inflammatory or stricturing disease behavior and between disease location and remission or response. Age of diagnosis and duration of disease before MTX initiation were not related to remission or response to MTX treatment.
Steroid requirement: Steroid cotherapy (≥1 mg/kg) was used in 16 patients at MTX initiation. Complete steroid withdrawal was possible in 12 patients (75%) within 1 to 6 months (median 3 months) of MTX therapy. The steroid-free period was 12.4 ± 7.5 (median 12) months.
Infliximab therapy was used in 14 patients before MTX treatment, in conjunction with thiopurine analogues. In 11 patients infliximab was discontinued before MTX initiation due to lack of response. Three patients continued infliximab treatment at the same dose and intervals during MTX treatment for 3 to 4 months. Of those patients, 2 were MTX treatment failures, and 1 patient had a response for 18 months.
A total of 6 patients (24%) experienced adverse effects, and in 4 of them MTX was discontinued. Nausea and vomiting occurred in 3 patients (12%), requiring treatment discontinuation in 1 patient. Two patients (8%) had persistently elevated hepatic enzymes up to 5 times the upper limit of normal within 6 weeks and 20 months, and MTX was stopped. Pancreatitis appeared in 1 patient after 5 months, and although direct relation to MTX could not be proved, treatment was discontinued.
The main goal in the treatment of pediatric patients with CD is the control of the inflammatory process, allowing long-term steroid-free remission and enabling normal growth. AZA/6-MP treatment is widely used in children with CD and is efficacious in maintaining remission; however, treatment failure due to drug intolerance or lack of response is common (11). In the present study, we show that MTX is effective for maintaining remission and avoiding steroid use in pediatric patients with CD following AZA/6-MP treatment failure.
Large randomized placebo-controlled studies evaluating the benefit of MTX treatment in adult patients with CD showed a steroid-free remission rate of 36% to 65% in luminal and perianal disease (3,4). Uncontrolled data in adults confirmed the effectiveness and long-term benefit of MTX, reporting 52% remission in 3-year follow-up (5,12). In children, a limited number of studies examined the role of MTX in CD treatment. The first 2 studies (6,13) followed only 14 and 10 patients, respectively, showing effectiveness of MTX treatment in 64% to 70% of children. Recently, a French retrospective multicenter study (7) of 61 children with AZA/6-MP treatment failure found a response or remission rate of 80% in MTX-treated patients, with steroid withdrawal in 73%, and a 12-month full remission rate of 45%. A similar North American retrospective multicenter study (8) evaluated 60 MTX-treated pediatric patients with CD following unsuccessful thiopurine therapy. Forty-two percent were in clinical remission without steroids in both 6 and 12 months of therapy, and in a median 3-year therapy one-third of patients did not require escalation of therapy. In the present study, 78% of patients improved and 53% achieved steroid-free remission with MTX therapy. Of 18 patients treated for more than 6 months, 83% were still in remission or response at 12 months of treatment. These response and remission rates are comparable and even higher than previous studies. The results of the pediatric studies, including the present study, suggest a better effectiveness for MTX than in adult patients.
We observed a similar effectiveness of MTX in treatment of small bowel and colonic disease and in different disease types, similar to the French study results, in which no difference was found between disease behavior and response pattern to MTX (7).
In the present study, we included patients cotreated with infliximab before MTX therapy. Most patients stopped infliximab before MTX initiation due to lack of response or side effects. Three patients continued treatment with no change in dose and schedule. Both the French and North American studies included infliximab-naïve patients. It has been a common practice of pediatric gastroenterologists to treat uncontrolled disease while administering thiopurine drugs, with infliximab cotherapy. The efficacy of infliximab in children with active CD despite previous immunomodulatory treatment is evident from the recent REACH study (2). The relatively short time for induction of remission achieved by infliximab and the limited controlled data about MTX therapy in CD has led to its widespread use as a step-up option, before a trial of MTX. Inclusion of the infliximab-treated patients reflects the daily clinical practice. These patients in our study had failed thiopurines-infliximab cotherapy and, therefore, their clinical improvement can be attributed to MTX. Although it has not been an aim of the present study, our results indicate that MTX may be effective even in children with CD with infliximab intolerance or failure. Further studies are needed to define the role of MTX in children after thiopurine-infliximab treatment failure.
The most accepted administration practice is SC weekly MTX administration. The bioavailability of MTX was reported to be better with SC than oral treatment (14–18), although others have reported a comparable drug bioavailability during oral and SC chronic MTX treatment (19). The French group included only patients receiving SC treatment. In the present study, no difference in remission or response rate and steroid-sparing period was found in SC versus oral treatment; however, the number of patients in the oral treatment group was too small to allow conclusions. Similar results were reported in the North American study, but despite a lower disease activity index at MTX initiation in the oral group, a better steroid-sparing effect at 1 year was achieved with SC therapy. A decision about the preferred route of MTX administration can be made only after a prospective study.
The median MTX dose used in the present study was lower than in the other pediatric studies (12.5 mg/m2 versus 13.8 mg/m2 and 17 mg/m2 in the North American and French studies), and yet the remission and response rates were similar. No difference in dosage was found between patients in remission, response, or treatment failures. There are no data for pediatric dosing, but the common pediatric practice used by us is 10 mg for patients weighing 20 to 29 kg, 15 mg for 30 to 39 kg, 20 mg for 40 to 49 kg, and 25 mg for 50 kg and heavier (8).
In addition to its efficacy, MTX treatment was safe in the present study. No infectious or hematological complications were reported. The most common side effect was nausea (9.3%), followed by persistently elevated transaminases (6.2%). The rate of adverse events was lower than reported by others (7,8).
The efficacy and safety of MTX induction of remission in comparison to AZA was examined in a small randomized, investigator-blind study (20) of 54 patients, and was found to be comparable to AZA at 6 months of treatment. With the proven efficacy of MTX in prior pediatric studies as well as the present study, first-line MTX therapy may be considered in pediatric patients with CD in whom teratogenicity is less of a concern than in young adults. Concomitant use of MTX and infliximab, long-term results with MTX therapy, and first-line MTX treatment need to be further studied.
We conclude that MTX is effective and safe for the treatment of pediatric patients with CD and is well tolerated. MTX can be used as an alternative treatment in patients with AZA/6-MP failure, and should be considered before the introduction of biological therapy. MTX may have a beneficial effect even after infliximab treatment failure.
1. Teml A, Schaeffeler E, Herrlinger KR, et al
. Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. Clin Pharmacokinet 2007; 46:187–208.
2. Hyames J, Crandall W, Kugathasan S, et al
. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology 2007; 132:863–873.
3. Feagan BG, Rochon J, Fedorak RN, et al
. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med 1995; 332:292–297.
4. Feagan BG, Fedorak RN, Irvine EJ, et al
. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. N Engl J Med 2000; 342:1627–1632.
5. Lemann M, Zenjari T, Bouhnik Y, et al
. Methotrexate in Crohn's disease: long-term efficacy and toxicity. Am J Gastroenterol 2000; 95:1730–1734.
6. Mack DR, Young R, Kaufman SS, et al
. Methotrexate in patients with Crohn's disease after 6-mercaptopurine. J Pediatr 1998; 132:830–835.
7. Uhlen S, Bellbouab R, Narebski K, et al
. Efficacy of methotraxate in pediatric Crohn's disease: a French multicenter study. Inflamm Bowel Dis 2006; 12:1053–1057.
8. Turner D, Grossman AB, Rosh J, et al
. Methotrexate following unsuccessful thiopurine therapy in pediatric Crohn's disease. Am J Gastroenterol 2007; 12:2804–2812.
9. Harvey RF, Bradshaw JM. A simple index of Crohn's-disease activity. Lancet 1980; 1:514.
10. Dixon WJ, Chief ed. BMDP statistical software. Los-Angeles: University of California Press; 1993.
11. Kirshner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology 1998; 115:813–821.
12. Soon SY, Asari A, Yanez M, et al
. Experience with the use of low-dose methotrexate for inflammatory bowel disease. Eur J Gastroenterol Hepatol 2004; 16:921–926.
13. Ravikumara M, Hinsberger A, Spray CH. Role of methotrexate in the management of Crohn's disease. J Pediatr Gastroenterol Nutr 2007; 44:427–430.
14. Hoekstra M, Haagsma C, Neef C, et al
. Bioavailability of higher dose methotrexate comparing oral and subcutaneous ad ministration in patients with rheumatoid arthritis. J Rheumatol 2004; 31:645–648.
15. Jundt JW, Browne BA, Fiocci GP, et al
. A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. J Rheumatol 1993; 20:1845–1849.
16. Teresi ME, Crom WR, Choi KE, et al
. Methotrexate bioavailability after oral and intramuscular administration in children. J Ped 1987; 110:788–792.
17. Balis FM, Savitch JL, Bleyer WA. Pharmacokinetics of oral methotrexate in children. Cancer Res 1983; 43:2342–2345.
18. Sun JH, Das KM. Low-dose oral methotrexate for maintaining Crohn's disease remission: where we stand. J Clin Gastro 2005; 39:751–756.
19. Stephens MC, Baldassano RN, York A, et al
. The bioavailability of oral methotrexate in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2005; 40:445–449.
20. Ardizzone S, Bollani S, Manzionna G, et al
. Compaison between methotrexate and azathioprine in the treatment of chronic active Crohn's disease: a randomized, investigator-blind study. Dig Liver Dis 2003; 35:619–627.