Journal of Crohn's and Colitis, 2015, 303–304
doi:10.1093/ecco-jcc/jjv038
Editorial
Editorial
Methotrexate in IBD: The Return of the Prodigal Son
Twenty years ago, Brian Feagan and colleagues proved the efficacy of parenteral methotrexate [MTX; 25 mg per week] as an
induction therapy in steroid-dependent Crohn’ disease [CD].1 Five
years later, they showed that MTX also maintains remission in
patients who had reached remission with this drug.2 Since then,
the efficacy of MTX has been somewhat eclipsed by the compelling advent of biologics. However, safety and cost of CD therapies remain key issues. Biologics are cost-prohibitive and have a
strong impact on healthcare expenditures. In this context, there is
a need for alternative, safe and inexpensive drugs in CD as well as
in ulcerative colitis [UC]. In these respects, MTX is competitive.
MTX has been used for decades in the treatment of Wegeners’ disease, psoriasis, and rheumatoid arthritis. Its safety profile is well
known. Side effects of MTX include nausea, vomiting, fatigue,
diarrhea leukopenia, liver fibrosis, hypersensitivity pneumonitis,
and teratogenicity. Oral folic acid [5 mg per week] can reduce the
severity of side effects, particulary leukopenia and gastrointestinal
symptoms. Yet, it is fair to say that many patients have nausea and
fatigue, even after the maintenance dose has been reduced and
split. Nonetheless, severe side effects are rare. The risk of cancer
associated with methotrexate therapy has been assessed in patients
with rheumatoid arthritis [RA] and most studies have found that
it was not increased.3 These results compare favorably with those
observed with thiopurines (alone or combined with anti-tumor
necrosis factor [anti-TNF]),4,5 which increase the risk of lymphoma, non-melanoma skin cancer, and acute myeloid leukemias
and myelodysplastic syndromes.6,7,8
Methotrexate is inexpensive. Inflammatory bowel disease [IBD]
incidence continues to rise, particularly in countries of southern and
eastern Europe as well as in the Middle East, North Africa, India,
and Brazil.9,10,11,12 Not all these countries will be able to afford the
cost of biologics.
Recent papers, including two published in this issue of JCC, and
ongoing studies renew the interest in MTX in IBD. The paper by
Haisma et al. is based upon a multicenter retrospective cohort of
130 paediatric patients who had failed thiopurines and were prescribed MTX as a maintenance therapy. Twelve months after initiation of MTX, 52% of the patients were relapse free, decreasing to
29% after 24 months. There was no difference in efficacy between
children who were intolerant and those who failed to respond to
thiopurines. The paper by Colman et al. is based upon a retrospective chart review of 88 IBD patients who received a combination
therapy consisting in anti-TNF and methotrexate at a dose of
15–25 mg/week or less than ≤ 12.5 mg/week. The 46 patients who
had reached clinical remission were followed up. The relapse rate
was significantly higher in patients who had received the low dose
as compared with those who had received the high dose of MTX.
The rate of adverse events leading to discontinuation of MTX was
similar in the two groups. Analogous results have been observed in
rheumatoid arthritis.13
The recently published COMMIT trial compared the efficacy
of infliximab + placebo versus infliximab + MTX in patients with
CD. There was no difference between the two groups as regard to
clinical efficacy [primary endpoint].14 It is possible that the highdose steroids prescribed in all included patients confounded the
beneficial effect of combotherapy. Yet, COMMIT did show that
patients randomized to the MTX + infliximab arm had a lower
rate of immunogenicity and higher trough levels of infliximab.
Prevention of immunization against the drug is crucial in patients
who receive anti-TNF.
Most studies concerning MTX in inflammatory bowel disease
were performed in CD patients, and very few were conducted in
UC. Until recently, no controlled trial had tested parenteral MTX
at the dose of 25 mg/week in UC patients. The METEOR trial
(NCT00498589), a European prospective, placebo-controlled, randomized trial, did so in steroid-dependent patients. The study has been
completed and the results will be submitted soon. The MEthotrexate
Response In Treatment of Ulcerative Colitis trial (MERIT-UC
[NCT01393405]) is a US prospective, placebo-controlled, randomized trial that tests the efficacy of MTX as a maintenance treatment in UC patients who have responded to MTX. The study is still
enrolling patients.
MTX is a safe and inexpensive drug. In CD patients, it is
an efficient drug in monotherapy and it prevents immunization
when associated with an anti-TNF. It can be prescribed to CD
patients who have failed or become intolerant to thiopurines. It
is now recommended as a first-line immunosuppressive therapy
in Epstein-Barr virus- [EBV-] naive CD patients [ECCO malignancy consensus 2015, in preparation]. Due to its safety profile, it
can also be employed as the first-line immunosuppressive, either
alone or in combination with biologics, in women and men who
do not wish to conceive. Results concerning UC patients will be
published soon.
Thibaut Vaysse and Franck Carbonnel
Service de Gastroentérologie, Hôpital universitaire de Bicêtre,
Université Paris Sud, Assistance Publique-Hôpitaux de Paris, le
Kremlin Bicêtre, Paris, France
Corresponding author: Franck Carbonnel; Email: fcarbonnel7@
gmail.com
Conflict of interest
None declared.
Copyright © 2015 European Crohn's and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For
permissions, please email: [email protected]
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References
1. 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;332:292–9.
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;342:1627–32.
3. Mariette X, Cazals-Hatem D, Warszawki J, et al. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective
study in France. Blood 2002;99:3909–15.
4. Nyboe Andersen N, Pasternak B, Basit S, et al. Association between tumor
necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA 2014;311:2406–13.
5. Osterman MT, Sandborn WJ, Colombel J-F, et al. Increased risk of malignancy with adalimumab combination therapy, compared with monotherapy, for Crohn’s disease. Gastroenterology 2014;146:941–9.
6. Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders
in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009;374:1617–25.
7. Peyrin-Biroulet L, Khosrotehrani K, Carrat F, et al. Cesame Study
Group. Increased risk for nonmelanoma skin cancers in patients who
receive thiopurines for inflammatory bowel disease. Gastroenterology
2011;14:1621–8
T. Vaysse and F. Carbonnel
8. Lopez A, Mounier M, Bouvier AM, et al. CESAME Study Group.
Increased risk of acute myeloid leukemias and myelodysplastic syndromes
in patients who received thiopurine treatment for inflammatory bowel disease. Clin Gastroenterol Hepatol 2014;12:1324–9
9. Ng SC, Bernstein CN, Vatn MH, et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut 2013;62:630–
49.
10.Baumgart DC, Bernstein CN, Abbas Z, et al. IBD around the world:
comparing the epidemiology, diagnosis, and treatment: proceedings of
the World Digestive Health Day 2010 Inflammatory Bowel Disease Task
Force meeting. Inflamm Bowel Dis 2011;17:639–44.
11.Ahuja V, Tandon RK. Inflammatory bowel disease in the Asia-Pacific area:
a comparison with developed countries and regional differences. J Dig Dis
2010;11:134–47.
12.Parente JML, Coy CSR, Campelo V, et al. Inflammatory bowel disease in
an underdeveloped region of Northeastern Brazil. World J Gastroenterol
2015;21:1197–206.
13.Burmester G-R, Kivitz AJ, Kupper H, et al. Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised
CONCERTO trial. Ann Rheum Dis 2014; Feb 18. doi: 10.1136/annrheumdis-2013-204769. [Epub ahead of print].
14.Feagan BG, McDonald JWD, Panaccione R, et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in
patients with Crohn’s disease. Gastroenterology 2014;146:681–8.