METHOTREXATE
Introduction :
Methotrexate is an immunomodulator used to induce and maintain remission of Crohn’s
disease and Ulcerative colitis in patients who have steroid dependent or refractory
disease, or who have been intolerant of either azathioprine or 6-Mercaptopurine.
Methotrexate inhibits the enzyme dihydrofolate reductase, essential for the synthesis of
purines and pyrimidines. Although unlicensed to treat inflammatory bowel disease,
methotrexate is widely used in Crohn’s disease (BNF section 1.5) and less commonly in
ulcerative colitis.
Dose and mode of administration :
Much of the evidence for the beneficial effects for methotrexate has been with the
intramuscular route of administration. The evidence for the efficacy and bioavailability of
oral methotrexate is limited in Crohn’s disease, although there is very good evidence for
its efficacy in the treatment of Rheumatoid Arthritis for over 50 years. Many
Gastroenterologists are now recommending oral therapy as it is more convenient for the
patient and easier to supervise.
Intramuscular route : 25mg once per week for up to 16 weeks, then reduced to 15mg
once a week.
Oral route : Intially 15mg once per week as a single dose, increasing to 20mg once per
week after 2 weeks and up to a maximum of 25mg once a week after a further 2 weeks as
tolerated and according to response.
A lower starting dose may be required for the elderly or frail or those with renal
impairment. Clinical response is usually evident in 4-6 weeks.
Folic acid treatment : Folic acid reduces the toxicity of methotrexate treatment and
improves continuation of therapy and compliance. Folic acid should be taken ONCE
weekly, but SHOULD NOT be taken on the same day as the methotrexate.
Recommended monitoring and precautions / interactions
Monitoring Schedule :
Pre-treatment assessment
British Society of Gastroenterology
recommendation
Avoid use in patients with known liver
disease (including fatty liver), alcohol
excess, obesity, diabetes or women trying
to conceive.
Monitoring
FBC, U&E, LFT’s
Pre-treatment Pulmonary Function Tests
and CXR may be considered for some
patients
FBC, U&E, LFT’S every 2 weeks after
the last dose change; thereafter monthly
until stabilised.
Monitoring frequency every 2-3 months if
patients results remain stable
Action to be taken :
WBC < 3.5 x 109/l
Neutrophils < 2.0 x 109/l
Platelets < 150 x 109/l
Withold treatment and recheck in 1 week
Discuss with Specialist team
Withold treatment and recheck in 1 week
Discuss with Specialist team
Withold treatment and recheck in 1 week
Discuss with Specialist team
MCV > 105fl
Check serum B12, folate & TFT and
Discuss with Specialist team
AST, ALT > 2 fold rise (from the upper
limit of the reference range)
Consider for liver biopsy when persistent
elevation occurs.
Discontinue treatment in patients with
abnormal LFT’s who decline liver biopsy
Monitor closely and consider need for
liver biopsy
Nausea occurs commonly & may be
reduced by changing timing of dose
(before bedtime), ensure adequate intake
of folic acid, & consider antiemetic at
time of weekly dose
Albumin – Unexplained fall in the
absence of active disease
Nausea
Rashes or oral ulceration, vomiting &
diarrhoea
Renal function – significant
deterioration compared to baseline or
upper limit of normal of reference
range
Severe sore throat, abnormal bruising
New or increasing dyspnoea or dry
cough
Withold treatment and recheck in 1 week
Discuss with Specialist team
Withold treatment and recheck results
Discuss with Specialist team
Immediate FBC and withhold until the
result of FBC is available
Withold treatment; CXR & pulmonary
function tests;
Discuss with Specialist team
The incidence of hepatotoxicity in patients with inflammatory bowel disease is very low
and particularly so, if the drug is only given to carefully selected patients – avoiding its
use in :
 In patients suspected of alcohol abuse;
 The Obese
 Patients with previously demonstrated fatty liver, pre-treatment abnormalities of
liver function and those with pre-existing liver disease
Liver biopsy should be considered when there is a persistent elevation of the
transaminases above baseline or a decrease in the albumin level below the reference
range when the inflammatory disease is inactive.
Methotrexate is contraindicated in patients with significant renal impairment because the
primary mode of excretion of the drug is via the kidneys. Renal toxicity occurs rarely
with methotrexate treatment, but cases of nephrotic syndrome and renal failure have been
described.
Pneumonitis has very rarely been reported in patients with IBD taking methotrexate
treatment. If respiratory symptoms develop whilst a patient is receiving methotrexate
treatment, a CXR and pulmonary function tests should be arranged urgently and the drug
discontinued.
Bone marrow suppression may occur as a result of methotrexate treatment. The risk is
greatest in the elderly and those with significant renal impairment. When a significant fall
in the indices has occurred the following should be arranged immediately :



Stop Methotrexate therapy
Give Folinic Acid Rescue – The initial dose should be at least 20mg given
intravenously. Subsequent doses of 15mg given orally at 6 hourly intervals until
the haematological abnormalities have improved (usually not more than 2 – 8
doses.
Consider immediate discussion with Supervising Specialist team / Medical On
Call team or the local Haematologist.
Pregnancy & Breast feeding :
Methotrexate is both teratogenic and is an abortofacient. Methotrexate may also be toxic
to sperm. Adequate birth control is therefore essential for both men and women.
Contraception (for both sexes) should be continued for at least 3 months after stopping
methotrexate therapy.
Methotrexate may be excreted in breast milk so breast feeding is contraindicated.
Should an inadvertent pregnancy occur, referral should me made to an Obstetrician.
Cautions :
 Patients with clinically significant renal impairment from any cause



Localised or systemic infection including hepatitis B & C and past history of TB
Unexplained anaemia or cytopenia associated with bone marrow failure
Immunisation with live vaccines should be avoided (pneumoccocal and Influenza
vaccinations can be given)
Drug interactions :
o Phenytoin, Co-trimoxazole, Trimethoprim – the antifolate effect of
methotrexate is increased
o Probenacid, Penicillin, Azapropazone, NSAID’s – Methotrexate excretion
is reduced (but a clinically significant interaction between methotrexate
and NSAID’s is rare
o Tolbutamide – serum concentrations of methotrexate may be increased
Duration of treatment
As for azathioprine, the duration for continuing treatment with MTX cannot be
recommended from current literature alone. If well-tolerated, the drug may be continued
for several years, under appropriate supervision. Hepatic fibrosis now seems relatively
uncommom in these IBD patients, and liver biopsy is no longer routinely recommended
after 1.5g intake. Serum markers of fibrosis are available in spcialist centres, if needed.
Again, informed discussion with the patient as to the uncertainties of long-term toxicity
are necessary, if therapy continues beyond 3-5 years without attempted withdrawal of the
drug.
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maintenance of remission in crohn’s disease.N.Engl.J.Med. 2000; 342: 1627-1632.
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refractory Crohn’s disease. Cochrane Database Syst. Rev. 2005; (1) : CD003459.
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9-10.
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