QuestionSBA
QuestionChoice
Methotrexate increased the risk of blood dyscrasias, liver cirrhosis and blood dyscrasias. Bloods should be checked every 1-2 weeks until dosing stabilised and then every 2-3 months.
50176
a
FBC, U&E and LFTs every 1-2 weeks until stabilised
QuestionChoice
Methotrexate is teratogenic and may also reduce fertility. It is therefore recommended that effective contraception is used during treatment and for 6 months afterwards for both men and women. Despite this, pregnancy prevention programmes are not routinely used in methotrexate therapy.
50178
c
Pregnancy prevention programme
QuestionChoice
Methotrexate is not known to cause any cardiac adverse reactions. An ECG is therefore not routine in the monitoring of methotrexate therapy.
50179
d
ECG before starting
QuestionChoice
Methotrexate level is not used in the monitoring of methotrexate therapy.
50180
e
Methotrexate level every week
QuestionChoice
Although Methotrexate is a folate antagonist, Haematinics (B12, folate, ferritin and intrinsic factor) are rarely monitored. Folic acid is instead taken weekly, to prevent deficiency.
50177
b
Haematinics every 1-2 weeks until stabilised
Concept
Chapter
# Summary

Methotrexate is one of several conventional disease-modifying anti-rheumatic drugs (DMARDs) used in a variety of autoimmune diseases. It is an inhibitor of dihydrofolate reductase, one of the key enzymes involved in purine and pyrimidine (and therefore DNA) synthesis. It is an immunosuppressive treatment that has several significant side effects, including hepatotoxicity, bone marrow suppression and pneumonitis. Folic acid should be co-prescribed with methotrexate as this reduces mucosal and gastrointestinal side effects (but should be taken on a different day as it reduces methotrexate's efficacy). Patients require regular monitoring with blood tests (full blood count, renal and liver function) and for women with the potential to become pregnant, highly effective contraception should be advised as methotrexate is teratogenic.

# Definition

Methotrexate is a conventional DMARD that inhibits DNA synthesis by inhibiting the enzyme dihydrofolate reductase. It has both immunosuppressive and cytotoxic effects and so is used in both autoimmune diseases such as rheumatoid arthritis, Crohn's disease and psoriasis, as well as in cancer treatment (e.g. as part of chemotherapy regimens for lymphoma).

# Side Effects

- Gastrointestinal upset (e.g. nausea, diarrhoea, abdominal pain)
- Stomatitis and mucosal ulcers
- Anorexia
- Headache
- Hair loss
- Fatigue
- Increased risk of infection; may reactivate latent infections
- Teratogenicity 
- Myelosuppression with subsequent anaemia, leukopenia and thrombocytopenia
- Hepatotoxicity including liver cirrhosis
- Renal toxicity
- Pulmonary toxicity especially pneumonitis; increased risk in rheumatoid arthritis
- Photosensitivity reactions - may present with blistering or papular rashes and swelling of affected skin

# Investigations

**Baseline tests prior to starting methotrexate:**

- Blood pressure
- Weight and height
- Pregnancy testing if appropriate 
- Full blood count (FBC)
- U&Es for renal function (dose reduction may be needed; avoid methotrexate in severe impairment)
- Liver function tests (avoid if baseline hepatic impairment)
- Hepatitis B and C and HIV serology
- Consider screening for tuberculosis and other lung disease e.g. with a chest X-ray

**Monitoring whilst on treatment:**

- FBC, U&Es and LFTs should be checked every 2 weeks until the dose of methotrexate is stable
- They should then be checked monthly for 3 months, then at least every 3 months thereafter
- More frequent monitoring may be required in patients at increased risk of toxicity

**Ensure no contraindications are present, for example:**

- Active infection - methotrexate should be paused during acute infections
- Immunodeficiency syndromes
- Ascites or significant pleural effusion (increases the risk of methotrexate accumulation unless drained)
- Significant hepatic or renal impairment
- Current peptic ulceration
- Pregnancy or breast-feeding
- Co-administration of another anti-folate medication e.g. co-trimoxazole

**Consider cautions, such as:**

- Excess alcohol intake (increases hepatotoxicity risk)
- Renal impairment (may need to reduce dose)
- Pre-existing haematological abnormalities e.g. anaemia, thrombocytopenia
- Chronic respiratory disease
- History of recurrent infections (e.g. urinary tract infections, chronic obstructive pulmonary disease exacerbations)
- Frail or elderly patients (may require dose reduction)
- Dehydration - may need to pause treatment e.g. if the patient develops diarrhoea or vomiting

# Management

- Methotrexate is usually taken as a weekly tablet, on the same day each week
- Folic acid 5mg should be co-prescribed to be taken once weekly on a different day
- Patients should receive the following vaccines:
- Annual influenza vaccine
- One-off pneumococcal vaccine (ideally prior to starting methotrexate)
- Covid vaccination as per national guidelines
- If aged 50+, the recombinant shingles vaccine (Shingrix, which is not a live vaccine)
- Advise patients to avoid contact with people with chickenpox and shingles, and seek urgent medical advice if exposed
- Advise patients that live vaccines (e.g. yellow fever) are contraindicated whilst on methotrexate
- All patients should be under a specialist team (e.g. rheumatology), usually with a shared care agreement for prescribing and monitoring in primary care
- A patient card should be provided with safety information and to show to other healthcare professionals
- Medication interactions are important to be aware of, including:
- NSAIDs increase the risk of methotrexate toxicity by decreasing renal excretion
- Trimethoprim or co-trimoxazole may cause severe bone marrow suppression
- Anti-epileptic medications may reduce effectiveness of methotrexate
- Theophylline clearance may be reduced by methotrexate
- Folic acid (may be included in multivitamin supplements) reduces effectiveness of methotrexate if taken together
- Ensure women of childbearing age are advised of the risk of teratogenicity in pregnancy
- Highly effective contraception is recommended
- Methotrexate should be stopped at least 3-6 months before conception 
- Breastfeeding is also contraindicated
- There is no strong evidence to suggest men need to stop methotrexate whilst trying to conceive, however the BNF suggests waiting 6 months after stopping methotrexate
- Patients should be warned regarding the risk of photosensitivity reactions and advised to use sunscreen, protective clothing and avoid UV light exposure
- If there are significant abnormalities in monitoring blood tests (e.g. thrombocytopenia, ALT or ALT > 100) or clinical signs or symptoms of complications (e.g. unexplained bruising suggestive of bone marrow suppression), hold methotrexate and arrange urgent specialist review 
- In cases of methotrexate toxicity, folinic acid (e.g. as calcium folinate) can be given to counteract methotrexate's folate-antagonist mechanism of action

# NICE Guidelines

[NICE CKS - DMARDs](https://cks.nice.org.uk/topics/dmards/)

# References

[BNF - Methotrexate](https://bnf.nice.org.uk/drugs/methotrexate/)

[Specialist Pharmacy Service - Methotrexate monitoring](https://www.sps.nhs.uk/monitorings/methotrexate-monitoring/)
427
2775
Methotrexate
Topic
9
Internal Medicine
10083
Case Presentation:  A 36-year-old female patient attends the outpatient rheumatology clinic.  He is due to commence treatment on methotrexate for rheumatoid arthritis. Weight 63kg.


**PMH**
Depression

**DH**
Cerazette, 1 tablet daily
Citalopram, 20mg OD

Question: Which of the following is the most appropriate monitoring of a patient starting methotrexate?
a