Sirs, We read with interest the article by Paoluzi et al., who evaluated methotrexate, followed by daily folate supplementation, in patients with steroid-dependent or steroid-resistant ulcerative colitis.1 They found methotrexate to be effective and safe in patients who did not tolerate azathioprine for the maintenance of remission. Although parenteral methotrexate in Crohn's disease has been successfully employed in various studies (for an overview, see Fraser et al.2 and Lichtenstein3), comprising one multi-centre, placebo-controlled trial,4 its role in ulcerative colitis is still unclear and is a matter for ongoing debate. This might be due to the different doses and routes of delivery used.5
We would like to supplement the data by Paoluzi et al. by reporting four patients with ulcerative colitis (one left-sided, three pancolitis) who were treated with methotrexate for the induction and maintenance of remission. All patients were switched from treatment with azathioprine for different reasons: allergic exanthema in one patient, elevated liver enzymes in one and treatment failure in two. All but one patient received methotrexate, 25 mg intramuscularly, once per week, followed by 10 mg of folate orally on the day after injection. One patient received 15 mg of methotrexate, with the dose being adjusted to 25 mg following increased activity of colitis. This patient and two of those described above have been in remission on this medication for 2 and 3 years, respectively. In one patient, the treatment had to be discontinued because of an increase in aspartate aminotransferase/alanine aminotransferase levels despite dose reduction and prophylactic supplementation of folate.
In comparison with Paoluzi et al., our patients received a higher dose of parenteral methotrexate, with the additional administration of 10 mg of folate once weekly on the day after the injection of methotrexate, instead of a daily intake. Thus far, we have not observed any major side-effects apart from the elevation of liver enzyme levels in one patient, as mentioned above. In the rheumatological literature, larger trials have found folate supplementation to reduce the risk of hepatic but not other side-effects. Of interest is the potentially impaired immunosuppressive effect of methotrexate with folate supplementation.6 In comparison with our therapeutic regimen, Paoluzi et al. observed a beneficial effect of parenteral methotrexate in ulcerative colitis despite employing a lower dose and daily folate supplementation. Hence, further studies to address this issue, as well as to determine the optimal dose and route of delivery of methotrexate in patients with ulcerative colitis, are needed.
We certainly agree with the findings of Paoluzi et al., whose study adds further evidence to the effectiveness and safety of methotrexate for patients who cannot tolerate or do not respond to azathioprine.