Methotrexate

Randomised controlled trials support the use of methotrexate as both induction and maintenance therapy in patients with Crohn’s disease who have required at least one course on corticosteroids. It is normally used in patients who are steroid-dependent or thiopurine refractory. It is also used to reduce immunogenicity of biologic agents, although there is limited evidence to support this use.

Active disease

  • In patients with steroid dependant active Crohn’s disease, methotrexate 25mg im once weekly induced steroid free remission in 39% compared to 19% placebo treated patients
  • A systematic review supports it use in this setting

Case series have been published that report benefit of methotrexate in patients with ulcerative colitis. However, the 2 published randomised controlled trials showed no significant advantage over placebo for induction of remission. A Cochrane review (prior to the second RCT) reports that there is insufficient evidence to support its use.

Active disease

  • An Initial randomised controlled trial compared low dose (12.5mg) oral methotrexate once weekly to placebo and reported no benefit
  • The GETAID METEOR randomised controlled trial compared 25mg im or sc once weekly to placebo and showed no significant benefit in the primary endpoint (steroid free remission at week 16)

Maintaining remission

  • There is very little controlled data available on which to base recommendations for maintenance therapy
  • A Cochrane review reported that there was insufficient evidence to support its use as a maintenance therapy

Prevention of post-surgical recurrence

Not applicable for patients with ulcerative colitis

Stopping therapy

  • Case series suggest withdrawal of methotrexate is associated with high relapse rates (up to 80% at 12 months)
  • As there is no controlled data, no recommendation can be given

Dosing, administration and monitoring

Before treatment

Dosing

  • Despite the limited evidence and guidelines above MTX is occasionally used for patients with UC
  • 25 mg is provided weekly PO/SC/IM to induce remission, normally over 8 -12 weeks (IM administration may be more effective)
  • 15mg weekly PO as maintenance therapy, switching to parenteral administration if ineffective
  • Provide 5 mg folic acid PO supplementation on day after MTX

Follow-up

  • Monitor patients regularly (blood count, LFT, U∓E) every 2 weeks for 2 months and then every 2-3 months
  • Recommend stopping therapy and urgent blood tests if unexpected bleeding, bruising or fever
  • Stop drug and consider pulmonary function tests if a patient has unexplained cough or dyspnoea
  • Stop drug for unexplained increase in LFT (3x upper limit of normal)
  • Surveillance liver biopsy is no longer recommended

Red flag interactions

  • It is unsuitable for those of child-bearing age due to teratogenicity
  • Use with caution in patients who have risk factors for steatohepatitis
  • For further information see guideline for the use of Methotrexate in IBD

Adverse effects

  • Side-effects prevent persistent treatment in ≈ 15%
  • Early toxicity causes nausea, vomiting, diarrhoea, and stomatitis (consider an anti-emetic)
  • Myelosuppression occurs and requires blood monitoring
  • Delayed toxicity includes pneumonitis (2/100 patient-years exposure) and hepatotoxicity
  • The drug is teratogenic and pregnancy is contraindicated
  • Exercise caution with co-administration of anti-folate medications (e.g. Trimethoprim)
  • Caution in patients with diabetes mellitus, fatty liver or alcohol abuse
  • National Formulary should be consulted to review adverse drug reactions and drug interactions

Special situations

Pregnancy

  • Methotrexate is teratogenic and embryotoxic (reliable form of contraception essential during and 3-6 months after treatment)
  • Women should stop 3-6 months before conception, men at least 4 months beforehand (allowing for 6 week washout of toxic metabolites and 2.5 months for spermatogenesis)
  • Healthy pregnancies have occurred in women taking MTX so abortion is not mandatory, but should be discussed
  • If pregnancy is to continue, stop MTX and provide high dose folic acid (15mg daily) for a minimum of 6 weeks

Breastfeeding

  • Methotrexate is contraindicated in breast-feeding mothers

Surgery

  • There is no evidence to allow comment on the safety of methotrexate in patients undergoing surgery for ulcerative colitis

Paediatrics

  • There is no evidence that supports the use of methotrexate in paediatric patients with ulcerative colitis

Elderly

  • There are no specific additional points for elderly patients (see above)

Maintaining remission

  • After inducing remission, 65% of patients taking 15 mg intramuscular MTX remain in remission after 40 weeks (c.f. 39% taking placebo)
  • Corticosteroid withdrawal was achieved in 39% of patients whilst maintaining remission
  • A Cochrane review confirms that 15 mg per week of intramuscular methotrexate is significantly more effective than placebo in maintaining remission in CD(RR 1.67, 95% CI 1.05-2.67

Prevention of post-surgical recurrence

There is no controlled trial data to support the use of methotrexate as therapy to prevent Crohn’s disease recurrence after surgery

Stopping therapy

  • Case series suggest withdrawal of methotrexate is associated with high relapse rates (up to 80% at 12 months)
  • However, the lack of controlled trial data means that no recommendation can be given
  • Stopping methotrexate will depend on the previous disease course and prognostic factors

ECCO statement 6G (CD 2016)

For patients in long term remission on thiopurine maintenance therapy, cessation of treatment may be considered in the absence of objective signs of inflammation [EL2]. No recommendation can be given for the duration of treatment with methotrexate. Prolonged use of anti-TNF agents may be considered if needed [EL3]

Dosing, administration and monitoring

Before treatment

Dosing

  • 25 mg is provided weekly PO/SC/IM to induce remission, normally over 12-16 weeks (IM administration may be more effective)
  • 15mg weekly as maintenance therapy
  • The higher dose may be continued for a longer time periods and oral therapy may be attempted.
  • Provide 5 mg folic acid PO supplementation on day after MTX

Follow-up

  • Monitor patients regularly (blood count, LFT, U∓E) every 2 weeks for 2 months and then every 2-3 months
  • Recommend stopping therapy and urgent blood tests if unexpected bleeding, bruising or fever
  • Stop drug and consider pulmonary function tests if a patient has unexplained cough or dyspnoea
  • Stop drug for unexplained increase in LFT (3x upper limit of normal)
  • Surveillance liver biopsy is no longer recommended

Red flag interactions

  • It is unsuitable for those of child-bearing age due to teratogenicity
  • Use with caution in patients who have risk factors for steatohepatitis
  • For further information see guideline for the use of Methotrexate in IBD

Adverse effects

  • Side-effects prevent persistent treatment in ≈ 15%.
  • Early toxicity causes nausea, vomiting, diarrhoea, and stomatitis (consider an anti-emetic)
  • Myelosuppression occurs and requires blood monitoring
  • Delayed toxicity includes pneumonitis (2/100 patient-years exposure) and hepatotoxicity
  • The drug is teratogenic and pregnancy is contraindicated
  • Exercise caution with co-administration of anti-folate medications (e.g. Trimethoprim)
  • Caution in patients with diabetes mellitus, fatty liver or alcohol abuse
  • National Formulary should be consulted to review adverse drug reactions and drug interactions

Special situations

Pregnancy

  • Methotrexate is teratogenic and embryotoxic (reliable form of contraception essential during and 3-6 months after treatment)
  • Women should stop 3-6 months before conception, men at least 4 months beforehand (allowing for 6 week washout of toxic metabolites and 2.5 months for spermatogenesis)
  • Healthy pregnancies have occurred in women taking MTX so abortion is not mandatory, but should be discussed
  • If pregnancy is to continue, stop MTX and provide high dose folic acid (15mg daily) for a minimum of 6 weeks

Breastfeeding

  • Methotrexate is contraindicated in breast-feeding mothers

Surgery

  • There is no evidence to allow comment on the safety of methotrexate in patients undergoing surgery for Crohn’s disease

Paediatrics

  • Methotrexate is recommended as an option for the maintenance of steroid free remission in paediatric patients with Crohn’s disease either as the primary therapy or in the setting on thiopurine intolerance.
  • Paediatric patients should be prescribed 15mg/m2 (body surface area) sub cut, up to 25mg ONCE WEEKLY
  • Dose reduction to 10mg/m2 sub cut once weekly is appropriate

Elderly

  • There are no specific additional points for elderly patients (see above)

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