There is a need for agents for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) which are able to modify the course of the disease, reduce the need for surgery and the need for long-term corticosteroids. Corticosteroids have major limitations in the treatment of inflammatory bowel disease . Most experience with immunomodulatory treatment has been with the purine analogues 6-mercaptopurine (6-MP) and azathioprine (AZA) [2,3]. There has been much less experience with methotrexate. It has been reserved for second-line immunomodulatory treatment of patients who are resistant or intolerant to AZA or 6-MP. This review seeks to determine if there is enough evidence to use methotrexate as a first-line immunomodulator.
Mode of action
Methotrexate is a folate analogue that was originally designed to inhibit dihydrofolate reductase. Reduced folate (tetrahydrofolate) is the proximal, single carbon donor in several reactions involved in the de-novo synthetic pathway for purines and pyrimidines, the formation of polyamines, and for transmethylation of phospholipids and proteins . In the treatment of cancer, the rationale for use of methotrexate is that malignant cells become starved of the purine and pyrimidine precursors of DNA and RNA that are required for proliferation. The rationale for low-dose treatment of other diseases such as psoriasis, rheumatoid arthritis and inflammatory bowel disease is less clear. The degree of anti-proliferative activity at the low doses used for the treatment of these diseases may be minimal. Blood levels are mostly below those that cause cytotoxic effects on lymphocytes. One potential mechanism for therapeutic activity is the inhibition of adenosine deaminase. Adenosine accumulates and is released into the extracellular space where it exhibits anti-inflammatory properties by decreasing polymorphonuclear chemotaxis. The release of some cytokines is decreased as well as other inflammatory mediators such as interleukins and eicosanoids, but the mechanism is not understood [4,5].
After a single dose, the drug is present in the circulation for a relatively short period. The elimination half-life is 5–8 h . It is taken up by tissues and converted to methotrexate polyglutamates. These are long-lived derivatives that retain biochemical and biological activity, especially the ability to inhibit dihydrofolate reductase. This explains why weekly dosing is effective. The slow build-up of methotrexate polyglutamates in the tissues may be required for therapeutic activity [6,7]. Methotrexate is absorbed from the proximal intestine by a folate specific transport mechanism. Folate supplements directly compete with methotrexate for uptake although this effect is modest. Oral absorption is highly variable. Average bioavailability from oral dosing is 70–80% of that from intravenous dosing, but may be as little as 25%. Subcutaneous dosing gives more consistent blood levels – the average bioavailability is 87% of intravenous dosing, which is equivalent to intramuscular dosing. Oral absorption is not reduced in patients with small bowel CD  and drug levels are not affected by meals or fasting . Bioavailability is lower at higher doses, but the effect is insignificant – there is a 13.5% reduction in bioavailability when the dose was increased from 7.5 to 20 mg weekly .
Less than 10% of the drug is metabolized to 7-hydroxymethotrexate. The majority of the drug is eliminated unchanged via the kidneys . This means that care is required in a clinical setting where there may be impaired renal clearance, such as dehydration or concomitant nephrotoxic drugs, although there is no clear interaction with non-steroidal anti-inflammatory drugs. Blood levels of methotrexate or 7-hydroxymethotrexate and erythrocyte levels of methotrexate do not predict response or toxicity . It is prudent to avoid co-administration of trimethoprim–sulfamethoxazole. This mixture inhibits bacterial dihydrofolate reductase, but case reports of pancytopenia following the combination of these drugs suggest that there may occasionally be some effect on human dihydrofolate reductase . The combination of methotrexate with sulfasalazine appears to be safe .
Methotrexate for rheumatoid arthritis: lessons for gastroenterologists
Low-dose methotrexate has become the most commonly prescribed disease-modifying agent for rheumatoid arthritis over the last 15 years . Pivotal short-term studies showing efficacy in rheumatoid arthritis were published in the 1980s. Approximately 50% of patients gained significant benefit [14,15]. Long-term observational studies subsequently showed a good safety profile and good long-term tolerability: 50–60% of patients chose to continue with methotrexate for at least 5 years. This is a much higher percentage than for any other disease-modifying agent [16,17]. Methotrexate appears to be more effective than AZA for rheumatoid arthritis. There was a significant difference or a clear trend in three comparative trials [18–20], although one study showed no difference .
The usual practice in the treatment of rheumatoid arthritis is to start at a low dose of 5–7.5 mg weekly and then increase slowly up to 25 mg weekly (perhaps by 5 mg every 2 months). Gradual dose escalation probably decreases the risk of significant bone marrow toxicity. There is a clear dose–response relationship for methotrexate treatment of rheumatoid arthritis . Combination treatments have become common in clinical practice. Agents commonly prescribed in addition to methotrexate have been low-dose prednisolone, hydroxychloroquine, or sulfasalazine . More recently, combinations with biological treatments such as etanercept and infliximab have been explored .
Methotrexate for Crohn's disease
Induction of remission
The encouraging results from the treatment of rheumatoid arthritis in the 1980s led to studies in CD. Preliminary data, published in 1989, showed that methotrexate had some efficacy for the treatment of both CD and UC . Symptomatic improvement was noted in two thirds of the patients as well as a steroid sparing effect. This led to the North American Crohn's Study Group trial which assessed 141 patients with chronically active CD who were treated with 25 mg methotrexate (intramuscular) weekly or placebo over a 16 week period . After 16 weeks, 39% of the methotrexate group were in remission compared to 19% in the placebo group (P = 0.025). The withdrawal rate in the methotrexate treatment group was 17%.
Several large centres have reviewed their data on methotrexate. Although these data are retrospective and not placebo controlled, these studies have all shown that methotrexate is able to induce remission in a high proportion of patients. The Oxford group reviewed 70 patients (48 with CD) . The remission rate was 62% for those patients who completed more than 3 months’ treatment and, for all patients, the remission rate was 45% . The Chicago experience in 76 steroid refractory patients with CD reported treatment for a mean duration of 55 weeks at a mean dose of 20 mg (mostly given parenterally) . Sixty-four per cent improved and 37% were able to discontinue steroids. In Paris, out of 49 patients with refractory CD given methotrexate, 41 patients (84%) achieved remission . Similar results have been reported in other small studies [29–34]. A Belgian study of 20 steroid refractory patients reported that only 33% remained in remission on methotrexate after 12 months, although steroid tapering was possible in 85%, and 60% discontinued steroids completely at 6 months .
Both the dose and route of administration of methotrexate may be important factors in the induction of remission . Oral dosing and a relatively low dose of 12.5 mg weekly may be the explanation for a negative, placebo controlled study by Oren et al. . The issue of finding the appropriate dose was addressed by Egan et al. in a small randomized trial comparing 15 mg weekly with 25 mg weekly . There was no difference in the remission rates (which were surprisingly low for both groups). However, after the 16-week trial was completed, four of 11 patients improved significantly when the dose was increased from 15 to 25 mg weekly. A retrospective study subsequently found that a higher dose (mg/kg) was associated with increased chance of remission .
Maintenance of remission in Crohn's disease
The North American Crohn's Study Group has now presented results of maintenance treatment with methotrexate . Seventy-six methotrexate responders, who had achieved remission on 25 mg/week (intramuscular) were randomized to receive intramuscular methotrexate 15 mg or placebo every week. After 40 weeks, 65% of the patients given methotrexate were in remission compared with 39% in the placebo group. The treatment appeared to be well tolerated as only one patient was withdrawn from the study because of side effects. There are several retrospective studies of long-term remission rates (with up to 3 years of follow-up data) for methotrexate treatment in patients with CD (Table 1) [26–28]. Long-term tolerability has also been shown by Kozarek et al., who reported that 51% patients started on methotrexate were still continuing the drug after 69 weeks .
Dose for maintenance therapy
The dose of methotrexate may be an important determinant of maintenance of remission. The maintenance study of Feagan et al. showed 15 mg weekly to be effective maintenance treatment for patients who had been induced into remission with 25 mg weekly. Importantly, 12 of the 22 patients who relapsed were brought back into remission on 25 mg weekly, suggesting that maintenance treatment at 25 mg weekly may have been more appropriate. These data suggest that for many patients dose reduction for maintenance will not be successful in the long term .
Relapse after stopping treatment
There are limited data on relapse rates after cessation of treatment. In one study 15 out of 19 patients (79%) had relapsed within 12 months . For the placebo arm of the maintenance study by Feagan et al. (where remission had been induced by methotrexate) 61% of patients had relapsed after 40 weeks .
Methotrexate treatment of ulcerative colitis
There have been few studies of the efficacy of methotrexate for the treatment of UC. The initial report by Kozarek et al. in 1989 showed that methotrexate induced remission in five of seven patients with UC . Oren et al. studied 67 patients with UC who were randomized to oral methotrexate 12.5 mg weekly or placebo for 9 months. This study showed no difference in the induction or maintenance of remission . However, a review of 22 patients with UC found that the remission rates and the maintenance of remission to be similar to that found in 48 patients with CD treated with similar doses of methotrexate .
Comparison with azathioprine
How effective is methotrexate compared to other immunosuppressive treatment, in particular, AZA or 6-MP? There are few comparative data. Mate-Jimenez et al. reported that methotrexate had similar efficacy to AZA for the treatment of CD, but that AZA appeared to be more effective for the treatment of UC . The incidence of side effects was similar for both drugs. Oren et al. compared 12.5 mg of methotrexate and 50 mg of 6-MP with placebo over a 9 month period . Disappointingly, neither treatment was better than placebo, either for induction or maintenance of remission, but doses of both drugs would now be considered suboptimal. More comparative studies are required before any conclusions can be drawn.
In the absence of head-to-head studies, other ways of comparing thiopurines and methotrexate are to consider long-term efficacy, treatment failures and results in other diseases. The baseline response to methotrexate as first-line immunomodulatory therapy can be derived from the trials by Feagan et al., since only two patients had previously received thiopurines [25,37]. Retrospective studies of methotrexate are composed mainly of patients with severe and refractory CD who have failed or not tolerated AZA therapy [26–28]. Despite this selected patient group, the long-term efficacy data appear to be satisfactory (Table 1). The 3 year remission rate for methotrexate in the Oxford series was 51% , which compares well with data on AZA from the same centre (69% 3 year remission rate for AZA ). It is notable that methotrexate has been preferred to AZA for the treatment of rheumatoid arthritis because it is considered to have a more rapid clinical effect, greater efficacy and superior long-term tolerability [13,18–21].
Remission rates after withdrawal of immunomodulatory treatment also offer an insight into the comparative efficacy of thiopurines and methotrexate. A study by O'Donoghue et al.  of 52 patients in remission on AZA, randomized to continue AZA 2 mg/kg or placebo showed similar results to the methotrexate maintenance study by Feagan et al. . After 1 year the remission rates were 42% in the AZA group and 6% in the placebo group . In the methotrexate withdrawal trial the 40 week remission rate was 65% on methotrexate and 39% on placebo . The difference in placebo response may reflect more severe disease and higher threshold for immunomodulation in the earlier (1978) AZA study. There is anecdotal evidence for a more rapid onset of action with methotrexate, but few comparative data. Improvement on methotrexate for active disease occurred at a mean of 3 months , but it is difficult to determine if this is more rapid than that with AZA or 6-MP. Response will depend on dosing and route of administration for each drug. One study comparing intravenous methotrexate and oral AZA found no difference in onset of action . Combinations of treatment with methotrexate are a potentially important field of study. Methotrexate combined with infliximab has established benefit for rheumatoid arthritis and initial experience in CD suggests a similar benefit [23,43–45].
Early toxicity from methotrexate is primarily gastrointestinal (nausea, vomiting, diarrhoea and stomatitis) and this is due to its antiproliferative activity. The later toxicity, such as liver disease, may result from accumulation of methotrexate polyglutamates in the tissues. In three retrospective reviews treatment was discontinued in 10–18% of patients because of side effects [26–28]. Folate supplements are able to decrease the gastrointestinal side effects without a decrease in the therapeutic efficacy (data from treatment of rheumatoid arthritis). Folic acid 5 mg once per week given 2 days after methotrexate dosing or folic acid 1 mg daily for 5 days has similar efficacy to folinic acid [46,47]. Nausea after the weekly dose may require dose reduction, night-time administration or switching to a parenteral route. Pancytopenia has been reported in 1–2% of patients, but may be less frequent with the routine use of folate supplements (Table 2) . Methotrexate should not be prescribed to a woman of child-bearing potential because of the risk of teratogenicity (unless the patient is prepared to accept termination of pregnancy if contraception fails) .
Methotrexate induced liver disease
The initial clinical experience with low-dose methotrexate was in patients with psoriasis. Liver fibrosis was observed in a significant number of patients. Roenigk and co-workers in the Psoriasis Task Force developed a classification of liver biopsies, which has now been modified and expanded. The risk and rate of progression of fibrosis has been difficult to determine. There is a surprisingly high rate of baseline abnormalities of liver biopsies (up to 50%) in psoriasis and patients with psoriasis may have other risk factors for liver disease. These include a high alcohol intake (> 100 g per week), the use of non-steroidal anti-inflammatory drugs, diabetes and obesity, in addition to a cumulative dose of methotrexate > 4 g . It is clear that fibrosis does not progress after stopping treatment. If treatment is continued the progression of fibrosis is slow compared to alcoholic liver disease.
The incidence of liver disease in methotrexate treated rheumatoid arthritis appears to be much lower than in psoriasis . Several long-term studies have shown that none of the patients have developed severe fibrosis or cirrhosis although mild fibrosis is relatively common (0–50%). A survey of US rheumatologists identified 25 patients treated with methotrexate who had cirrhosis or liver failure. These rheumatologists estimated that they have treated approximately 16 600 patients with methotrexate for more than 5 years and 1700 patients for more than 10 years. This gave a (somewhat tenuous!) estimated 5 year incidence of 1:1000 . There is no obvious reason for different susceptibility to methotrexate induced liver disease between psoriasis and rheumatoid arthritis. There may have been greater attention to risk factors in recent years [52,53], so that patients at high risk are not started on methotrexate. The result has been a conservative approach to liver biopsy for patients with rheumatoid arthritis treated with methotrexate. Surveillance liver biopsies, based on cumulative dose, do not appear to be warranted [54,55].
There are even fewer data on liver histology in patients with inflammatory bowel disease treated with methotrexate. In one study 31 patients who had received more than 1500 mg of methotrexate were reviewed (mean cumulative dose of 2673 mg) . Eighteen patients underwent liver biopsies and the grading of fibrosis by Roenigk's criteria was grade I for 15 patients and grade II for two patients. One patient had grade IIIB changes, but this patient had additional risk factors of obesity and diabetes. Twelve patients had mild to moderate elevation of liver enzymes. These changes were present prior to the initiation of treatment in eight patients and there was no correlation between liver enzyme abnormalities and liver histology. The limited data on liver biopsy findings from other studies are shown in Table 2. It is clear that liver biopsy is not commonly performed in practice. Liver enzyme elevations are common, particularly in the first few months, and can be followed unless there is a persistent elevation of alanine transaminase [51,57].
The incidence of serious lung disease with methotrexate treatment appears to be low. The prevalence has been estimated to be 2–3 cases per 100 patient-years of exposure, but many large series have not reported any cases [58,59]. Pneumonitis has rarely been reported in series of inflammatory bowel disease patients (Table 2) [26–28,37]. Nevertheless, pneumonitis can develop at any time during treatment although it usually presents in the first year. Patients present with shortness of breath, dry cough and fever. The chest radiograph usually shows bilateral interstitial infiltrates . Bronchoscopy is recommended to exclude opportunistic infections. The risk of pneumonitis may be higher with age, diabetes and be highest in those with rheumatoid arthritis, because of the potential for rheumatoid lung involvement. Most patients make a complete recovery, despite a reported mortality of up to 17% . Chronic lung disease does not occur .
Risk of malignancy and infections
The risk of malignancy complicating methotrexate monotherapy is thought to be low or absent, because methotrexate does not react with, or become incorporated into, nucleic acid. No carcinogenic effects at the relatively low doses used for non-malignant conditions have been demonstrated [61–63]. A large European study of malignancy and immunosuppressive treatment in patients with rheumatoid arthritis showed that there was an increased risk of lymphoma for AZA, but not with methotrexate treatment . These data are not necessarily applicable to patients with inflammatory bowel disease, but for whom there are no long-term data on methotrexate. Opportunistic infections are rare .
Overall mortality on methotrexate
In a cohort of 1240 patients with rheumatoid arthritis (mean follow-up 6 years), 588 had methotrexate treatment. During follow-up 191 patients died. The mortality hazards ratio for patients treated with methotrexate was 0.4 (CI 0.2–0.8, after adjusting for the more severe disease in those patients treated with methotrexate) . Other disease modifying drugs (sulfasalazine, penicillamine, hydroxychloroquine) did not influence mortality. The benefit was attributable to a reduction in cardiovascular mortality, but there was also a trend for non-cardiovascular mortality to be reduced. There was no dose-dependent effect. This is an important study, because undue attention can focus on a particular adverse event that might be fatal, when there is a larger unexpected benefit (in this case a favourable effect) on overall mortality. The authors of this study speculate that methotrexate could inhibit some of the mechanisms in the formation of atheroma. This is speculative, but of interest to patients with inflammatory bowel disease when the atherogenic potential of corticosteroids is considered.
Duration of methotrexate maintenance therapy
Given the rapid relapse rate after stopping treatment, both the patient and physician need to consider carefully the safe duration of treatment. The questions are: what treatment will be offered as an alternative should the methotrexate be discontinued and how long is safe treatment? These questions cannot be answered by available data. Retrospective reviews confirm satisfactory long-term rates of remission after 3 years’ treatment. Modigliani, in a useful review of the appropriate duration of immunosuppressive treatment, has suggested that methotrexate treatment can be continued for 3–4 years . This is similar to the often quoted figure of 3–4 years for AZA treatment [2,3]. Perhaps even more uncertain is the time to start immunomodulatory treatment. The experience from the treatment of rheumatoid arthritis would suggest that better remission rates and better long-term outcomes are obtained with earlier immunomodulatory treatment [66–68]. Whether this applies to inflammatory bowel disease is entirely unclear.
Methotrexate has proven efficacy for the treatment of CD. It has an acceptable toxicity profile that is different to AZA, but similar overall tolerability. Methotrexate has gained wide acceptance by rheumatologists as the preferred first-line disease modifying treatment, but has not been widely used by gastroenterologists. Future treatment in rheumatoid arthritis appears to lie in beneficial combinations of treatment, with methotrexate as the mainstay.
There is not enough evidence to compare the efficacy of methotrexate with AZA or 6-MP in inflammatory bowel disease. Such data as are available suggest that methotrexate is unlikely to be more effective in a direct comparison study. Although the route of methotrexate administration is still debated, it is reasonable to start with oral dosing, gradually increasing to 25 mg/week. Parenteral treatment achieves more reliable drug levels and should be considered if oral dosing fails. The most convenient parenteral route is subcutaneous. Folic acid 5 mg per week (either as a single dose or 5 × 1 mg daily over 5 days) should be part of the routine protocol. At present there is insufficient evidence to recommend methotrexate for UC but there are patients who have responded well. On the other hand, methotrexate should be encouraged as a second-line treatment for CD and the usual treatment duration increased, at least up to 4 years.
• Of special interest
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