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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

Background : We performed an audit of methotrexate for ulcerative colitis, because efficacy is unclear.

Aim : To investigate the role of methotrexate in the management of ulcerative colitis.

Methods : Patients with ulcerative colitis treated with oral methotrexate at the inflammatory bowel disease clinics of Oxford and Wycombe General Hospital, UK, were evaluated. Efficacy was defined by remission (complete steroid withdrawal for >3 months) and response (good, partial or nil, proportionate reduction of steroids).

Results : There were 50 patients (42 ulcerative colitis alone; eight had rheumatoid arthritis associated with ulcerative colitis and were analysed separately). Indications for methotrexate in ulcerative colitis alone were azathioprine intolerance (31 of 42) and lack of benefit from azathioprine (11 of 42). The mean dose of methotrexate in ulcerative colitis alone was 19.9 mg/week for a median of 30 weeks (range: 7–395). Remission occurred in 42%. The response was good in 54% and partial in 18%. Side-effects occurred in 23%; 10% stopped treatment because of side-effects. Of those treated with methotrexate because of treatment failure with azathioprine, three of 11 achieved remission, but four came to colectomy within 90 days of starting methotrexate. The colitis remained in remission in seven of eight of those with RA treated with methotrexate and ulcerative colitis (mean dose 15.0 mg/week).

Conclusion : Oral methotrexate (approximately 20 mg/week) is well-tolerated and moderately effective in steroid-dependent or steroid-refractory patients with ulcerative colitis.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

The role of methotrexate (MTX) in the management of ulcerative colitis (UC) remains unclear. Given that up to 28% of patients with inflammatory bowel disease (IBD) will be intolerant of thiopurines,1 it is crucial that an effective, safe alternative is available to patients with steroid-refractory or -dependent disease. There is evidence for alternative immunomodulators in Crohn's disease, such as infliximab or MTX,2–9 unlike UC. Studies on MTX for UC tend to be small, use varying doses or routes of administration and have inconsistent outcomes.10–13 There is, however, some evidence of efficacy from retrospective studies, which suggest a potential role for MTX in the management of UC.14 It seems unlikely that large, randomized, placebo-controlled studies to establish the role of MTX in the management of UC will ever be carried out. Retrospective case series will therefore play a determining role in the assessment of MTX in the management of UC.

Patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

All the case notes of approximately 2000 UC patients attending the IBD clinic over the last 10 years at the John Radcliffe Hospital, Oxford and approximately 350 attending the general gastroenterology clinic at Wycombe Hospital, High Wycombe over the last 5 years were reviewed. In addition, pharmacy records were reviewed and all clinic letters were screened for the term ‘Methotrexate’ at both hospitals. All patients with UC who were treated with MTX were included in the study, including a group of eight patients in whom the primary indication was rheumatoid arthritis. These patients were analysed separately. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white cell count at initiation of MTX therapy and between 3 and 6 months after this was recorded from the notes.

Definitions

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

Remission was defined as the lack of treatment with steroids (either prednisolone or budesonide) for 3 months or more. Continued use of other medications such as 5-aminosalicylic acid (5-ASA) compounds orally or as a local preparation was allowed within the definition of remission. Efficacy was assessed by retrospective review of case notes and defined as good, partial or ineffective. Good efficacy was defined as stopping steroid therapy and tolerating MTX with no side-effects. Partial efficacy was defined as a reduction in the steroid dose without achieving remission. Patients in whom MTX was ineffective had no improvement in their clinical condition, or a reduction in their dose of steroids. Relapse was defined as the need for further oral or intravenous (IV) steroids, or surgery. Azathioprine (AZA) intolerance was defined as stopping AZA treatment because of side-effects. AZA ineffective patients were defined as AZA showing no clinical improvement despite being treated with AZA for at least 3 months.

Side-effects

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

Antiproliferative side-effects were considered to be gastrointestinal (GI) upset and leucopaenia, whilst later toxicity such as abnormal liver function tests was considered to be due to accumulation of metabolites of MTX.15

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

A total of 50 patients were analysed. Demographic data and patient's UC characteristics are shown in Table 1. Forty-two patients had UC solely and a further eight had rheumatoid arthritis in addition to UC. In the 42 patients with UC, the primary indication for immunomodulatory therapy was steroid dependency (69%), steroid-refractory disease (12%) and frequent relapses (19%). The primary indication for MTX was AZA intolerance in 31, AZA failure in 11 and rheumatoid arthritis in eight (Table 2). Mercaptopurine (MP) was given to three of 31 AZA-intolerant patients. Patients with rheumatoid arthritis and UC are considered separately.

Table 1.  Demographic data and ulcerative colitis (UC) characterization
Number50
Male/female18/32
Mean age at diagnosis (years, range)41.7 (13–67)
Duration of disease when MTX started (years)8.4 (0.1–37.1)
Disease extent 
 Rectal 7
 Left-sided23
 Hepatic flexure5
 Total colitis15
Extra intestinal manifestations13
Concomitant oral 5-aminosalicylic acid (5-ASA) use13
Rectal 5-ASA or corticosteroids use 7
Table 2.  Indication for methotrexate use
Indication for methotrexateNumberMean dose of AZA ± S.E.M. (mg/kg)Duration of AZA treatment [median (range), weeks]Mean dose of methotrexate  ± S.E.M. (mg/kg)Duration of methotrexate treatment [median (range), weeks]
Azathioprine (AZA)-ineffective111.91 ± 0.2248.7 (18.6–157.1)0.30 ± 0.0724 (4–72)
AZA-intolerant311.64 ± 0.304.1 (0.6–179.2)0.32 ± 0.0944 (6–364)
Rheumatoid arthritis8N/AN/A0.20 ± 0.05140 (68–656)

There were no significant differences in the mean dose of AZA given. The duration of treatment, however was longer in the AZA-ineffective group compared with the AZA-intolerant group (median 48.6 weeks vs. 4.1 weeks, mean 70 ± 15.4 weeks vs. 15.4 ± 6.5 weeks, P < 0.001). There was no significant difference in the duration of MTX treatment between the groups. All MTX was given orally once weekly. The mean maintenance dose of MTX in UC only patients was 19.9 mg (range: 10–40).

Overall efficacy

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

Efficacy was assessed from a review of patient case notes as being good (no steroids, no MTX side-effects) in 54%, whilst a further 18% had a partial response (reduction in the dose of steroid without remission). Overall, remission was achieved in 42% of patients and sustained for more than 6 months in 38%.

Efficacy in azathioprine ineffective patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

Mean dose of AZA was 1.91 mg/kg and all these patients were on AZA for at least 18 weeks. Only three patients had a good response to MTX. One patient was restarted on a higher dose of AZA and achieved long-term remission. Five of 11 patients in whom AZA was ineffective had a colectomy vs. 5 of 31 patients who were intolerant of AZA (P < 0.05). Four of five patients who had a colectomy and for whom AZA was ineffective were on MTX for <90 days. Only one of these patients had a partial response to MTX.

Efficacy of MTX in azathioprine-intolerant patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

The most common reason for not tolerating AZA was GI upset (18 of 31). The efficacy of MTX was good in 58% of these patients with remission achieved in 45%. Mean CRP was decreased 3 months after starting MTX (32.5 ± 11.9 vs. 6.7 ± 0.5, P = 0.051). Mean ESR and white blood cell (WBC) showed no significant differences (ESR: 21.2 ± 7.3 vs. 11.3 ± 1.8, P = 0.198, WBC: 9.99 ± 0.7 vs. 9.12 ± 0.9, P = 0.39). Seven patients stopped MTX as a result of lack of efficacy. Five of seven of these patients had a colectomy (all the colectomies were carried out within 6 months of starting MTX). MTX was tolerated by 27 of 31 (87%) patients who had been unable to tolerate AZA. Four patients stopped MTX because of side-effects and two stopped because they wished to become pregnant. One patient became pregnant whilst taking MTX and had a medical termination of pregnancy.

MTX for patients with rheumatoid arthritis and UC

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

The primary indication for MTX in eight cases was rheumatoid arthritis rather than control of their UC. Six of eight of these patients had a good response to MTX, with five of them achieving a sustained remission of >6 months. Two patients had a colectomy carried out, but one of these was for a GI MALToma. The starting dose of MTX was significantly lower in keeping with rheumatological practice (8.8 ± 1.8 mg vs. 19.6 ± 0.7 mg, P < 0.001) as was their maintenance dose (15.0 ± 1.7 mg vs. 19.9 ± 1.0 mg, P < 0.03) when compared to patients without rheumatoid arthritis.

Toxicity

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

Methotrexate was well-tolerated by 78% of patients overall (Table 3). Five (10%) patients stopped MTX treatment because of side-effects. Two had nausea, one severe stomatitis, one depression (he was on concurrent high-dose prednisolone) and one stopped because of deranged liver function tests. None of these patients was on folic acid supplements. About 18 patients (36%) were given folic acid supplements. Overall, the use of folic acid was not associated with the prevention of side-effects. However, if antiproliferative side-effects are considered rather than cumulative side-effects (such as deranged liver function tests), folic acid reduced the incidence of side-effects (16 of 39 vs. 0 of 8, P < 0.05). One patient had an episode of herpes zoster, which resolved with oral acyclovir.

Table 3.  Side-effects of methotrexate
Side-effectsTotal (n = 50)
  1. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Nil39
Raised ALT/AST > x23
Nausea/vomiting2
Stomatitis1
Diarrhoea1
Fatigue1
Sepsis1
Photosensitive rash1
Depression1

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References

Our data suggest that oral MTX has a role in the management of UC and if administered with folic acid, is well-tolerated with few side-effects. About 72% of patients derived some benefit from MTX, with 42% achieving remission.

The only randomized-controlled trial of oral MTX in UC showed no benefit of MTX in UC.10 Oren et al. used oral MTX at a dose of 12.5 mg/week, with no folic acid. This dose matched the use of MTX in rheumatoid arthritis or psoriasis, rather than the higher doses used in studies of MTX for IBD.3, 12 This may account for the disappointing efficacy as well as the lack of side-effects in the Oren et al.10 study. An open, prospective study by Paoluzi et al.8 studied eight patients who were intolerant of AZA and two in whom AZA was ineffective. They were treated with MTX 12.5 mg/week intramuscularly, with six of 10 gaining good, sustained remission, whilst four improved. These results are similar to our data, although they did not distinguish between patients who were intolerant of AZA and those in whom AZA was ineffective. The numbers in this arm of the Paoluzi et al.8 study were small, but MTX appeared to be at least comparable with AZA in terms of efficacy. Mate-Jimenze et al.11 compared the efficacy of MP (1.5 mg/kg/day), MTX (15 mg orally once per week with no folic acid supplementation) and 3 g/day of 5-ASA in IBD patients to induce and maintain remission in steroid-dependent IBD. In the UC patients, seven of 12 (58%) were in remission at 30 weeks, however, only one (14%) remained in remission at 76 weeks, compared with seven of 11 of the MP patients (P < 0.015). This may suggest that patients with UC require either higher oral doses of MTX or parental administration to be effective when compared with Crohn's disease patients.

Most studies report side-effects leading to a withdrawal of MTX treatment in 10–18% of patients,11, 14 whilst the incidence of minor side-effects is up to 22%. Our data show that the use of folic acid significantly decreases the incidence of antiproliferative side-effects. There is some evidence from rheumatology patients that folic acid can increase the dose requirement of MTX, but reduces the incidence of side-effects.16 This was not seen in our data. Forty-two of our patients had been unsuccessfully treated with AZA previously. In this group of patients, any treatment which improves the tolerability of MTX without diminishing its efficacy15 is particularly important in order to maximize the chances of medically controlling their UC. It is notable that 87% of patients who stopped AZA due to side-effects were able to tolerate MTX. Only three of 31 patients intolerant to AZA were given MP, which reflects previous practice when MP was not routinely used for patients who experienced nausea/vomiting with AZA. All three experienced the same side-effect with MP that they had with AZA.17, 18 The importance of adequate contraception and counselling in woman of child-bearing potential is emphasized by one patient who had a medical termination as she became pregnant whilst taking MTX.

Patients in whom AZA has been unsuccessful with chronic severe colitis represent a challenging clinical problem. Five of 11 patients in this group had a colectomy carried out, albeit the MTX may not have had sufficient time to have reached its full efficacy. Our data suggests that switching to MTX in this situation will have limited effect with only three of 11 having any response. The majority of these patients were treated more than 5 years ago, and current practice would be to increase the dose of AZA more aggressively,19 before changing therapy.

In the absence of properly powered, randomized-controlled studies, the evidence for the use of MTX in UC will come from case series such as this study. We believe that there is sufficient evidence now for the use of oral MTX at a dose of at least 20 mg once per week with folic acid supplementation in UC patients who are intolerant of thiopurines. Whilst thiopurines remain the immunomodulators of first choice in the management of UC, oral MTX offers patients an easily administered, effective and safe alternative.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Patients
  6. Definitions
  7. Side-effects
  8. Statistics
  9. Results
  10. Overall efficacy
  11. Efficacy in azathioprine ineffective patients
  12. Efficacy of MTX in azathioprine-intolerant patients
  13. MTX for patients with rheumatoid arthritis and UC
  14. Toxicity
  15. Discussion
  16. Acknowledgement
  17. References
  • 1
    Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30-year review. Gut 2002; 50: 4859.
  • 2
    Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators. N Engl J Med 2000; 342: 162732.
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    Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med 1995; 332: 2927.
  • 4
    Egan LJ, Sandborn WJ, Tremaine WJ, et al. A randomized dose-response and pharmacokinetic study of methotrexate for refractory inflammatory Crohn's disease and ulcerative colitis. Aliment Pharmacol Ther 1999; 13: 1597604.
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    Chong RY, Hanauer SB, Cohen RD. Efficacy of parenteral methotrexate in refractory Crohn's disease. Aliment Pharmacol Ther 2001; 15: 3544.
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    Lemann M, Zenjari T, Bouhnik Y, et al. Methotrexate in Crohn's disease: long-term efficacy and toxicity. Am J Gastroenterol 2000; 95: 17304.
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    Lemann M, Chamiot-Prieur C, Mesnard B, et al. Methotrexate for the treatment of refractory Crohn's disease. Aliment Pharmacol Ther 1996; 10: 30914.
  • 8
    Paoluzi OA, Pica R, Marcheggiano A, et al. Azathioprine or methotrexate in the treatment of patients with steroid-dependent or steroid-resistant ulcerative colitis: results of an open-label study on efficacy and tolerability in inducing and maintaining remission. Aliment Pharmacol Ther 2002; 16: 17519.
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    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: 61927.
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    Oren R, Arber N, Odes S, et al. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Gastroenterology 1996; 110: 141621.
  • 11
    Mate-Jimenez J, Hermida C, Cantero-Perona J, et al. 6-Mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid-dependent inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000; 12: 122733.
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    Kozarek RA, Patterson DJ, Gelfand MD, et al. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110: 3536.
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    Baron TH, Truss CD, Elson CO. Low-dose oral methotrexate in refractory inflammatory bowel disease. Dig Dis Sci 1993; 38: 18516.
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    Fraser AG, Morton D, McGovern D, et al. The efficacy of methotrexate for maintaining remission in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16: 6937.
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    Fraser AG. Methotrexate: first-line or second-line immunomodulator? Eur J Gastroenterol Hepatol 2003; 15: 22531.
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    van Ede AE, Laan RF, Rood MJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2001; 44: 151524.
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    Bowen DG, Selby WS. Use of 6-mercaptopurine in patients with inflammatory bowel disease previously intolerant of azathioprine. Dig Dis Sci 2000; 45: 18103.
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    Boulton-Jones JR, Pritchard K, Mahmoud AA. The use of 6-mercaptopurine in patients with inflammatory bowel disease after failure of azathioprine therapy. Aliment Pharmacol Ther 2000; 14: 15615.
  • 19
    Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 2001; 48: 6426.