Does methotrexate induce mucosal healing in Crohnʼs disease?

To the Editor: Mucosal healing has been claimed to be 1 of the most relevant therapeutic endpoints in Crohn's disease (CD) as far as it seems to be associated with a longer clinical remission and lower likelihood of disease-related hospitalizations and intestinal resection.1 However, clinical indexes poorly correlate with endoscopic lesions. For this reason, endoscopic monitoring to assess mucosal healing has been proposed as an important tool in order to establish the real efficacy of drug therapies in IBD. Among the available maintenance therapies for CD, mucosal healing has only been assessed for infliximab and thiopurines.2,3 Methotrexate (MTX) has proven to be effective in inducing and maintaining clinical remission in chronic active CD.4 Despite that its efficacy seems to be similar to that of azathioprine, it remains a second-line drug. The lack of data showing its potential in inducing mucosal healing may be 1 of the reasons for its limited use in CD. In this perspective, we aimed to assess mucosal healing among patients with clinical response to MTX. CD patients treated with MTX for steroid-dependency who entered into clinical remission free of steroids after starting MTX were identified. Eight patients from whom 2 colonoscopies—before and after MTX—were available were included. Disease location was colonic in 4 patients, ileal in 2, and ileocolonic in the remaining 2. Three patients had undergone ileocecal resection in the past. Azathioprine had been initially prescribed for steroid-dependency, but had to be discontinued because of intolerance in 4 and therapeutic failure in the remaining 4 patients. No patient received biological agents. MTX was administered subcutaneously or intramuscularly at an initial dose of 25 mg/week, for a total 16 weeks; then the dosage was decreased to 15 mg/week as a long-term maintenance treatment. Patients were clinically inactive at the moment MTX was started, as far as they also received prednisone. Endoscopic reports of IBD patients in our center routinely describe the severity of Crohn's lesions by specifying the presence and location of ulcers, erosions, aphtae, stenosis, and mucosal friability and erythema. As previously used elsewhere, total endoscopic healing was defined by the disappearance of all endoscopic lesions, whereas persistence of minor aphthous ulcers or erosions in the setting of a clear endoscopic improvement was considered partial mucosal healing.3 Individual characteristics and endoscopic features of patients are shown in Table 1. After a median time of MTX treatment of 15 months (range, 6–60), mucosal healing was found in 5 out 8 patients (total healing in 3, and partial healing in 2), whereas 2 patients worsened mucosal lesions and no changes were seen in the remaining patient, despite achieving steroid-free clinical remission. Interestingly, those 3 patients with total mucosal healing had isolated colonic involvement. Patient Characteristics Patient Characteristics Early studies showed that a successful course of steroids resulted in total mucosal healing in only one-third of patients,5 and similar rates have been reported after induction of remission with enteral nutrition,6 or even infliximab.2 However, as far as the relevance of mucosal healing lies in its impact of long-term outcome, it should be more reasonable to assess it during maintenance therapies rather than after short-term treatments. In that setting, mucosal healing has been scarcely evaluated. D'Haens et al3 retrospectively analyzed endoscopic healing in 20 patients responding to azathioprine. After a median of 24 months of treatment the authors reported 70% of total mucosal healing in colon and 54% in terminal ileum. Rutgeerts et al7 in a substudy of the ACCENT-I trial reported a total mucosal healing rate about 50% in 26 patients receiving scheduled infliximab therapy for 1 year. Recently, a higher mucosal healing rate has been reported in 26 patients treated with azathioprine after inducing remission with 3 infliximab infusions. Fewer data are available with MTX. Kozarek et al,8 in 1989, suggested for the first time that MTX could induce clinical remission and reduce steroid requirements in chronically active CD. Among 11 patients with clinical response, 5 (45%), all of them with isolated colonic disease, achieved total mucosal healing. Panaccione,9 in a series of 17 CD patients with clinical response to a 40-week course of MTX, reported total and partial mucosal healing in 10 and 4 patients, respectively. Our data agree with those previously reported with MTX, suggesting that clinical response to the drug is associated with mucosal healing in up to 40%–50% of patients, similar to what has been reported with other maintenance therapies. Although larger, prospective studies are needed, these data provide additional arguments for the use of MTX in CD.