Department of Paediatric Gastroenterology, Bristol Royal Hospital for Children, Bristol, UK
Received 19 June, 2006
Accepted 19 December, 2006
Address correspondence and reprint requests to C.H. Spray, MD, Department of Paediatric Gastroenterology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ, UK (e-mail: email@example.com).
Background: The majority of children with Crohn disease (CD) are likely to need some form of immunomodulatory therapy to maintain remission and to avoid long-term corticosteroid usage. Although thiopurine agents are commonly used, some children are unresponsive or intolerant to these drugs. Biological agents like infliximab are being increasingly used in these circumstances, but long-term safety has yet to be established. Methotrexate has been shown to induce and maintain remission in CD in many adult studies, but pediatric data are limited. The present report describes our experience of using methotrexate in CD in children.
Patients and Methods: All children with CD treated with methotrexate were identified by the departmental database. Case records were reviewed for site of disease, Pediatric Crohn Disease Activity Index, medications, time to achieve remission, duration of remission, and complications.
Results: A total of 10 children received methotrexate, 7 of whom were female and 3 of whom were male. All of the children had colonic involvement and had active disease despite previous standard medical treatments. Seven children exhibited remission with methotrexate treatment. Median time to achieve remission was 12 weeks and median duration of remission was 21 months to the point of assessment. One child had transient increase of alanine aminotransferase levels and another developed neutropenia, which remitted with dose reduction. None needed discontinuation of methotrexate treatment.
Conclusions: Methotrexate is effective and well tolerated in children with CD. It should be considered in those patients who do not experience a remission with standard medications because it may avoid the use of biological agents and their potential uncertain long-term side effects.
Crohn disease (CD) accounts for 60% of inflammatory bowel disease (IBD) in childhood with a reported incidence of 3.1/100,000 children in the United Kingdom (1). The natural history is characterized by recurrent exacerbations. Although corticosteroids are highly effective in inducing remission, a substantial proportion of patients experience relapse when steroid treatment is withdrawn. Corticosteroid resistance occurs in as many as 20% of patients with CD, and 36% become steroid dependent (2,3). In pediatric practice the goal of treatment of CD is not only to induce and maintain remission but also to promote growth and development and to improve quality of life, which requires avoidance of prolonged corticosteroid treatment. To achieve this the majority are likely to need immunomodulatory agents to maintain remission. Azathioprine (AZA) and 6-mercaptopurine (6-MP) are found to be effective and remain the most widely used agents for this purpose (4). However, a significant minority are intolerant or unresponsive to these medications. Over the years, a number of medical therapies have become available for the treatment of CD. In particular, infliximab (anti–tumor necrosis factor-α antibody) is being more commonly used even though their long-term safety has yet to be established (5). Use of agents with well-established pharmacotherapeutic profiles should be considered to avoid the potential long-term and uncertain side effects of these biological agents. Several adult studies have shown weekly injection of methotrexate to be beneficial in inducing and maintaining remission in patients with CD, allowing steroid reduction (6–8). However, pediatric data are limited and published literature on the use of methotrexate for childhood CD is mainly in abstract form only (9–13). We report our experience with 10 children with CD treated with methotrexate in a single center.
PATIENTS AND METHODS
The pediatric gastroenterology unit at our institution offers tertiary-level service for children with IBD and other gastroenterological problems in the southwest region of the United Kingdom. The department maintains a database of all children diagnosed with IBD, from which children treated with methotrexate were identified. Data were collected for site of disease, Pediatric Crohn Disease Activity Index (PCDAI), concomitant medications, time to achieve remission, duration of remission, and complications. Remission was considered when clinical symptoms had resolved and inflammatory markers had returned to normal. Methotrexate was given weekly at a dose according to body weight: children with a body weight of 20 to 29 kg received 10 mg, those with a body weight of 30 to 39 kg received 15 mg, those with a body weight of 40 to 49 kg received 20 mg, and those with a body weight of ≥50 kg received 25 mg of methotrexate. All children received 5 mg of oral folic acid weekly, 1 day after the methotrexate dose. Full blood count and liver function tests were monitored regularly.
A total of 10 children were identified, 7 girls and 3 boys, with a median age of 15.8 years (range, 12–16.9). Median age at diagnosis of CD was 11.4 years (range, 7.7–12.7). Table 1 summarizes patient characteristics, reason for starting methotrexate, PCDAI scores, and side effects. All 10 children had active disease despite previous standard medical management including enteral nutrition therapy, steroids, AZA, and mesalamine preparations for a median duration of 34 months (range, 14–69) before starting methotrexate. Two children did not tolerate AZA and the majority refused to restart steroid treatment because of cushingoid side effects.
Nine children received the methotrexate dose parenterally (intramuscular or subcutaneous) for the first 16 weeks before changing to the oral route. In 1 child who was started on a methotrexate regimen for ulcerating perianal disease, the oral route was adopted from the start. Significant improvement in clinical and biochemical parameters was seen in 7 children. In those children who exhibited a remission, median duration to remission was 12 weeks (range, 8–14). Mean PCDAI scores before starting methotrexate and after attaining remission were 34.7 and 6.4, respectively. None of the children required adjunctive steroid treatment after starting methotrexate. Median duration of remission to the point of assessment was 21 months (range, 18–32).
Methotrexate did not have a significant effect on the course of the disease in 3 children. Of these, 1 had severe pancolitis and small bowel fistula. His condition improved following ileostomy after failed infliximab treatment. Another child had orofacial, colonic, and perianal CD. Even though he subjectively felt better while receiving methotrexate, he did not exhibit remission clinically or biochemically. He also developed anaphylactic reaction to infliximab during the second infusion. The third child who was started on methotrexate for ulcerating perianal disease did not show any improvement and needed a colostomy.
One child had transient increase of alanine aminotransferase, which became normal within 1 month on continued methotrexate treatment. Another child developed neutropenia, which recovered after temporary cessation of treatment. A lower dose was subsequently well tolerated. One child reported symptoms of dry mouth and sore throat after oral methotrexate treatment.
Our experience shows that children with CD who are unresponsive to standard medical treatments with steroids and thiopurine drugs may benefit from methotrexate, both to induce and to maintain remission. Of 8 children with ongoing disease while receiving AZA, 5 responded favorably. Two children who were started on methotrexate as a result of AZA intolerance tolerated the drug well, with no untoward side effects during the follow-up period. These results are similar to those reported by Mack et al, who found methotrexate to be useful in paediatric patients with CD who did not benefit from 6-MP. Similar to their observations, it could be expected that AZA-intolerant patients may benefit from methotrexate because the 2 drugs exert their actions in a multifactorial manner involving cellular and anti-inflammatory actions (9).
Methotrexate is a competitive antagonist of folic acid, and in high doses it inhibits the enzyme dihydrofolate reductase, leading to impaired DNA synthesis and cell death (7). Although this mechanism is responsible for the antiproliferative and cytotoxic effects of high-dose methotrexate, it does not explain the antiinflammatory effects of methotrexate seen at lower doses. Low-dose methotrexate has no cytotoxic or antiproliferative effects at all, but instead is an immunomodulator (14). The mechanism is poorly understood but may be due to reduction in neutrophil activity, effect on adenosine metabolism (15), reduction of interleukin-1 production, and induction of apoptosis of selected T cell populations (16).
We used subcutaneous or intramuscular injections for at least the first 16 weeks because previous studies have shown that the parenteral route may be more beneficial in view of the erratic oral bioavailability of methotrexate, particularly at doses >10 mg/m2 (17). Kozarek et al, who first reported the use of methotrexate in IBD, used weekly intramuscular doses with conversion to oral methotrexate in those who responded favorably (18). However, recent reports in pediatric and adult patients suggest that there is no sound pharmacological basis for favoring parenteral administration of methotrexate (10,19).
It is interesting to note that in our observation, in children who responded to methotrexate, mean duration to achieve remission was 12 weeks (range, 8–14). This is comparable to data seen with AZA and 6-MP, which have a delayed onset of action, with several studies showing clinical benefit after 2 to 3 months of treatment (20). Even though the only head-to-head study comparing methotrexate with AZA was not powered to address the question of rapidity of onset of action (21), there was a suggestion that methotrexate may provide clinical benefit earlier than AZA/6-MP (22).
The most common adverse effects of low-dose methotrexate for IBD include gastrointestinal symptoms (nausea, vomiting, abdominal pain), increased aminotransferase levels, and infections. Most of these are transient and resolve with continuation of treatment or dose reduction (14). No child in our group had any major gastrointestinal side effects. One child reported symptoms of dry mouth and sore throat for 24 to 48 hours after the oral methotrexate dose. For reasons not known, she did not have these symptoms with parenteral dosing. One child reported frequent viral upper respiratory tract infections. One child developed neutropenia, which resolved after temporary discontinuation of the drug. Therapy was restarted at a lower dose without recurrence of neutropenia. Reversible bone marrow suppression in patients treated with low-dose methotrexate for CD is estimated to be somewhat lower at 1.3%, compared with those with rheumatoid arthritis, in whom it was reported to occur in a maximum of 5% (14). Most are mild and resolve with dose reduction or temporary discontinuation.
One of the concerns about long-term methotrexate treatment is the potential for hepatic fibrosis and cirrhosis, first noted in patients with psoriasis (7). A meta-analysis has shown a 7% overall risk of cirrhosis after low-dose methotrexate in psoriasis (23), but a much lower risk of approximately 1% in rheumatoid arthritis (24). The Psoriasis Task Force suggests a liver biopsy pretreatment and, if on long-term treatment, after a cumulative dose of 1.5 g (23). However, the risk appears to be much lower in patients with IBD. In adult patients with IBD, data suggest that low-dose methotrexate has no significant hepatotoxicity (25,26). Increased aminotransferase levels as high as 3 times the normal level occur in approximately 8% of patients during treatment. Abnormal chemistry values are a poor indicator of severity of histopathologic liver changes and are of concern only if the changes persist (14). In our group, 1 child developed transient, isolated increase of alanine aminotransferase levels (to 3 times the normal value) in the first 4 weeks after the initiation of methotrexate treatment, which became normal in the next 4 weeks on continuation of treatment and remained normal throughout subsequent follow-up. No patient needed liver biopsy.
Another potential life-threatening side effect is interstitial pneumonitis, which can occur at any stage of treatment. Fortunately this is rare. A survey of patients with IBD treated with methotrexate showed only 2 cases of this complication among 457 patients. Development of cough and dyspnea should prompt further respiratory evaluation, and discontinuation of treatment should be considered (14).
There are no data or recommendations regarding optimal duration of methotrexate treatment for CD. Limited data suggest that relapse is frequent after stopping methotrexate treatment. Deslanders, in a study of 10 children receiving methotrexate for CD, reported that 3 cases of relapse occurred 3 weeks to 4 months after discontinuation of methotrexate (11). Adult data suggest that after stopping treatment with methotrexate, relapse is frequent and occurs usually within 1 year (27). In female patients teratogenic potential of methotrexate should be taken into consideration before treatment is started.
In conclusion, our study suggests that methotrexate is effective in inducing and maintaining remission CD and is well tolerated. Treatment with this agent should be considered in patients who do not show a response to standard first- and second-line treatment. This may avoid the use of biological agents and their potential uncertain long-term side effects, particularly in light of recent unpublished reports of hepatosplenic T cell lymphoma with nearly universal fatal outcomes in a few patients treated with infliximab and azathioprine (data on file, Centocor, Inc, Malvern, PA).
1. Sawczecko A, Sandhu BK, Logan RFA, et al. Prospective survey of childhood inflammatory bowel disease in the British Isles. Lancet 2001; 357:1093–1094.
2. Hanauer SB. Inflammatory bowel disease: drug therapy. N Engl J Med 1996; 334:841–848.
3. Munkholm P, Langholz E, Davidsen M, et al. Frequency of glucocorticoid resistance and dependency in Crohn's disease. Gut 1994; 35:360–362.
4. Hawthorne AB. Methotrexate: a useful alternative in Crohn's disease. Gut 2001; 49:9–10.
5. Homan M, Baldassano RN, Mamula P. Managing complicated Crohn's disease in children and adolescents. Nat Clin Pract Gastroenterol Hepatol 2005; 2:572–579.
6. Kozarek RA, Patterson DJ, Geland MD, et al. Methotrexate induces clinical and histological remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110:353–356.
7. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn's disease. N Engl J Med 1995; 332:292–297.
8. Alfadhi AA, McDonald JW, Feagan BG. Methotrexate for induction of remission in refractory Crohn's disease. Cochrane Database Syst Rev 2003; 1:CD003459.
9. Mack DR, Young R, Kufman SS, et al. Methotrexate in patients with Crohn's disease after 6-mercaptopurine. J Pediatr 1998; 132:830–835.
10. Stephens MC, Baldassano RN, York A, et al. The bioavailability of oral methotrexate in children with inflammatory disease. J Pediatr Gastronterol Nutr 2005; 40:445–449.
11. Deslanders C. Methotrexate—an alternative treatment in pediatric Crohn's disease. J Pediatr Gastroenterol Nutr 1999; 29:520.
12. Rosh J, Youssef N, Schuckalo S, et al. Efficacy of methotrexate as a maintenance agent in pediatric Crohn's disease. J Pediatr Gastroenterol Nutr 2003; 37:392.
13. Uhlen S, Belbouab R, Narebski K, et al. Efficacy of methotrexate in the treatment of pediatric Crohn's disease. J Pediatr Gastroenterol Nutr 2006; 42:E44.
14. Shroder O, Stein J. Low dose methotrexate in inflammatory bowel disease: current status and future directions. Am J Gastroenterol 2003; 98:530–537.
15. Cronstein BM, Naime D, Ostad E. The anti-inflammatory mechanism of methotrexate. J Clin Invest 1993; 92:2675–2682.
16. Seitz M. Molecular and cellular effects of methotrexate. Curr Opin Rheumatol 1999; 11:226–232.
17. Balis FM, Miro J, Reaman GH, et al. Pharmacokinetics of subcutaneous methotrexate. J Clin Oncol 1988; 6:1882–1886.
18. Kozarek RA, Patterson DJ, Geland MD, et al. Methotrexate induces clinical and histological remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110:353–356.
19. Kurnik D, Loebstein R, Fishbein E, et al. Bioavailability of oral vs subcutaneous low dose methotrexate in patients with Crohn's disease. Aliment Pharmacol Ther 2003; 18:57–63.
20. Aberra FN, Lichtenstein GR. Monitoring of inflammatory bowel disease. Aliment Pharmacol Ther 2005; 21:307–319.
21. Ardizzone S, Bollani S, Manzionna G, et al. Comparison between methotrexate and azathioprine in the treatment of chronic active Crohn's disease: a randomised, investigator blind study. Dig Liver Dis 2003; 35:619–627.
22. Feagan BG, Alfadhi A. Methotrexate in inflammatory bowel disease. Gastroenterol Clin North Am 2004; 33:407–420.
23. Roenigk HH Jr, Auerbach R, Maibach H, et al. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol 1988; 19:145–156.
24. Kremer JM, Alarcon JS, Lightfood RW Jr, et al. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. Arthritis Rheum 1994; 37:316–328.
25. Kozarek RA, Bredfeldt JE, Rosoff JE, et al. Does chronic methotrexate cause liver toxicity when use for refractory inflammatory bowel disease: Gastroenterology 1991; 100:A223.
26. Te HS, Schiano TD, Hanauer HJ, et al. Hepatic effects of long term methotrexate use in the treatment of inflammatory bowel disease. Am J Gastroentrol 2000; 95:3150–3156.
27. Fraser AG, Morton D, McGovern D, et al. The efficacy of methotrexate for maintaining remission in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16(4):693–697.
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