Efficacy in Crohn’s disease
Our results show that 60% patients with Crohn’s disease who previously failed thiopurine therapy show a clinical response to MTX. This is the first study which shows that benefit is similar in thiopurine intolerant and refractory patients, in contrast to a previous report.17 It confirms that methotrexate is an effective and well tolerated treatment for the management of inflammatory bowel disease. In addition, MTX appears to provide some steroid sparing effect.
The current report was intended to evaluate the efficacy of MTX in inducing clinical response rather than as a maintenance strategy. In our series, 15 of the 99 patients with CD were receiving concurrent Infliximab. A possible synergistic effect must be acknowledged in light of the recent COMIT data.19 The induction dose of MTX 25 mg/week (combination of parenteral and oral administration) followed by a maintenance dose of MTX 15 mg/week may, in part, explain the response rates achieved in our study. Our results are consistent with findings in a recent retrospective study of 39 CD patients in whom remission was achieved in 71% at 16 weeks.20 Also, consistent with our findings, a paediatric study of 61 CD patients previously on thiopurine therapy reported a clinical response rates of 68.9% at 6 months, although in contrast to our findings, the reason for stopping thiopurine therapy was predominantly because of nonresponse (68.9%).21 Furthermore, response rates of at 6 months were seen in 10 of 20 patients either azathioprine resistant or intolerant treated with parenteral MTX.22
Efficacy in ulcerative colitis
In patients with ulcerative colitis, we observed an overall clinical response in 22 of 32 patients (68%). In addition, MTX also appeared to provide a steroid sparing effect. Similar high response rates have been reported in published studies; a retrospective study of 50 patients either intolerant or nonresponsive to azathioprine using oral MTX (20 mg/week) reported a response rate of 72% and a remission rate of 42%.14 Thus, our series suggests that MTX is effective in patients who have failed thiopurine therapy for lack of response as well as intolerance. This contrasts with a recent series from Oxford;14 but, in both studies, the numbers of patients with UC is relatively small (nine thiopurine intolerant patients in the current study and 11 patients respectively in the Oxford cohort) and hence the data must be interpreted with caution.
The mechanism by which MTX improves inflammatory bowel disease remains uncertain, despite an understanding of its cellular effects. Putative mechanisms include enhanced concentrations of adenosine,23 the inhibition of cellular proliferation, a decrease in the production of inflammatory mediators such as interleukins and eicosanoids and the induction of apoptosis.24, 25 At high doses, MTX antagonizes dihydrofolate reductase leading to inhibition of DNA, RNA and protein synthesis. At lower doses, inhibition of other folate dependent enzymes may be responsible for the action of MTX.26 In addition, the onset of peak activity of MTX is achieved after 12 weeks of treatment.9
Data from our study suggest that MTX therapy is well tolerated and safe with appropriate monitoring. The incidence of side effects was 17.4%; withdrawal of MTX was required in 8.3%, slightly less than reported in previous studies, in which withdrawal of treatment rates range between 10 and 18% of patients.27, 28 The most common minor side effects of methotrexate are gastrointestinal, including nausea, vomiting and diarrhoea. This was seen only in three patients in our study which may relate to the use of concomitant folic acid supplementation29 and parenteral administration of MTX during induction in a large proportion of patients. Interestingly, the incidence of side effects seen with MTX was considerably lower than in a recent study of 217 patients treated with azathioprine, in which 39% withdrew because of adverse effects with 15.7% suffering gastric intolerance.4
In a controlled study of MTX for the induction of remission in CD,9 patients were excluded for a number of pre-existing conditions including hepatic disease (biopsy proven cirrhosis, chronic active hepatitis, serum aspartate aminotransferase, bilirubin, or alkaline phosphatise at least twice upper limit of normal), renal dysfunction (serum creatinine concentration greater than 1.7 mg per decilitre (150 μmol per liter), clinical important lung disease, systemic infection, pregnancy, previous cancer, high alcohol consumption, hypersensitivity to MTX, erythrocyte macrocytosis, body weight 40 percent higher than normal, diabetes mellitus or NSAID use. Data relating to alcohol consumption were not obtained. In our series, 27 patients (20.4%) had co-morbidities that would have excluded them from the published controlled trial.9 Although, we did not find that patient’s pre-existing conditions influenced side effects, these factors should be considered before starting MTX.
With the doses of MTX used in inflammatory bowel disease, many serious side effects such as bone marrow suppression are seldom seen. We found only one case of osteomyelitis as consequence of bone marrow suppression.
In our study, 4 of 8 patients who developed abnormal liver function tests had to stop MTX. Hepatotoxicity is an important consideration for patients on long-term MTX because of the risk of liver fibrosis and, in the past, guidelines suggested routine liver biopsy after a cumulative dose of Methotrexate. Kozarek et al. performed liver biopsies in six patients who had been treated with MTX for a mean of 34 months with a mean cumulative dose of 1733 mg. Normal histology was seen in all specimens except in one patient who had received a cumulative dose of methotrexate of 2500 mg and had minimal periportal fibrosis.30 In a case series of 20 patients with IBD treated with MTX after receiving a cumulative dose of 1.5–5.4 g over 1–5 years, liver histology showed hepatic fibrosis in one patient in the absence of abnormal liver function tests.31 Hepatoxicity of MTX may vary according to the underlying condition. In psoriasis, the risk of cirrhosis is estimated at 3%, with recommendations for liver biopsy at 1–1.5 g.32 At present, it would appear reasonable to monitor liver function tests in patients on Methotrexate every 2–3 months.33
There are a number of limitations to our study being retrospective, most importantly in the definition of clinical response and the heterogeneity of the population.34 Clinical response included not only the physician’s assessment of improvement at 6 months but also steroid withdrawal and normalization of CRP. However, given that not all patients were on corticosteroids at baseline and similarly not all patients had elevated CRP at baseline, a combination of the end-points was used. Normalization of CRP was seen in a small proportion of subjects in comparison with physician’s assessment of improvement, which, in part, may be due to the study design and in part reflect that CRP does not always correlate with disease activity scores. The response for each end-point has been shown and in addition, the numbers of patients achieving one, two and three end-points. We acknowledge the need for caution in assessing results, although retrospective assessment of clinical response has been well established in other studies of immunosuppressive therapy in inflammatory bowel disease.14, 16, 27
In conclusion, MTX appears effective in both Crohn’s disease and ulcerative colitis in patients who fail to respond to or are intolerant to thiopurine therapy with no difference between the two groups. MTX is well tolerated in the majority of individuals.