Methotrexate

01Purpose and principlesWhat the treatment does and how it fits into care.

Methotrexate is a conventional synthetic disease-modifying antirheumatic drug used across rheumatoid arthritis, psoriatic arthritis and selected inflammatory connective-tissue or skin disease. At low weekly doses, anti-inflammatory actions include intracellular polyglutamation and increased extracellular adenosine signalling; the treatment is not simply low-dose cancer chemotherapy. Clinical improvement usually takes four to twelve weeks, so a bridge may be needed while the DMARD takes effect.

Baseline review establishes marrow reserve, renal clearance and hepatic risk. Check FBC, platelets, ALT or AST, albumin, creatinine and eGFR; assess weight, alcohol, diabetes, obesity, previous liver disease, viral hepatitis risk, pregnancy, vaccines, infection and lung symptoms. A chest radiograph is not universally required in an asymptomatic person, but pre-existing respiratory disease or abnormal examination needs appropriate imaging and respiratory assessment.

Monitoring is shared but responsibility must be explicit. BSR 2025 supports risk-stratified monitoring; commonly, FBC, liver profile and renal function are checked every two weeks during initiation and dose changes until stable for six weeks, monthly for the next three months, then at least every twelve weeks in a stable lower-risk adult. Higher dose, renal impairment, liver risk, interacting treatment or prior abnormality requires closer review. Local shared-care thresholds govern withholding.

Kidney function is a major safety modifier because methotrexate and metabolites are renally cleared. Avoid in severe renal impairment under the product licence, reduce or seek specialist advice at lesser impairment, and pause during significant dehydration or acute kidney injury. NSAIDs, proton-pump inhibitors and penicillins can impair clearance in susceptible patients; this does not make all co-prescribing forbidden, but it makes dose, renal state and monitoring clinically important.

Methotrexate pneumonitis is uncommon but potentially severe and can occur independent of cumulative dose. New cough, dyspnoea or hypoxaemia requires immediate withdrawal and urgent evaluation for bacterial or opportunistic infection, pulmonary embolism, heart failure and inflammatory interstitial lung disease. Do not restart simply because antibiotics were given; respiratory and rheumatology review should decide causality.

Reproductive counselling precedes the first tablet. Methotrexate is teratogenic and abortifacient, incompatible with pregnancy and not recommended during breastfeeding. BSR advises women stop low-dose methotrexate at least one month before conception. If pregnancy occurs on treatment, stop it, commence folic acid 5 mg daily and arrange early fetal-medicine advice; paternal exposure at 25 mg weekly or less is considered compatible by BSR.

Key points

Low-dose methotrexate for rheumatic disease is taken once weekly, never once daily; write the day in words, keep tablet strength consistent and confirm understanding at every handover.
A usual adult starting dose is 7.5–15 mg once weekly orally or subcutaneously, increased in 2.5–5 mg steps according to response and monitoring to a usual maximum of 25 mg once weekly.
Co-prescribe folic acid at least 5 mg once weekly on a different day; increase or redistribute folate for adverse effects under the specialist plan without placing it on the methotrexate day.
Before treatment check FBC, ALT or AST and albumin, creatinine and eGFR, weight, pregnancy, alcohol and liver risk, lung history and hepatitis, HIV or TB risk as clinically indicated.
Initial monitoring is frequent and risk-adapted: commonly every two weeks until the dose is stable for six weeks, monthly for three months, then at least every twelve weeks when stable, following the agreed specialist protocol.
Trend matters more than a single normal-range result. Falling neutrophils or albumin, rising MCV or transaminases and declining filtration should trigger early review before an absolute stop threshold is crossed.
Never prescribe trimethoprim or co-trimoxazole with methotrexate unless a specialist deliberately manages an exceptional indication because severe and sometimes delayed marrow suppression can occur.
Hold methotrexate during a serious infection and obtain specialist advice about restart; mild self-limiting illness does not need an improvised prolonged interruption.
Methotrexate is incompatible with pregnancy and breastfeeding. BSR advises stopping low-dose treatment at least one month before planned maternal conception; paternal doses of 25 mg weekly or less are compatible.
If nausea, poor absorption or inadequate response limits oral treatment, split oral dosing over one day or change to once-weekly subcutaneous administration under specialist direction before declaring failure.

02Indications, selection and cautionsWho may benefit, who needs urgent treatment and important alternatives.

Therapeutic response

Improvement in swollen joints, stiffness, inflammatory markers, skin or organ activity and function over four to twelve weeks supports benefit and enables glucocorticoid reduction.

Mucosal and marrow toxicityRed flag

Painful oral ulcers, sore throat, fever, bruising, bleeding, pallor or profound fatigue may precede or accompany cytopenia and require same-day interruption and FBC.

Hepatic toxicity pattern

Persistent transaminase increase, falling albumin or jaundice requires assessment of methotrexate exposure, metabolic fatty liver, alcohol, viral hepatitis and other hepatotoxic medicines.

Pneumonitis patternRed flag

Subacute dry cough, breathlessness, fever, hypoxaemia and diffuse interstitial change during treatment is methotrexate pneumonitis until infection and other lung disease are excluded.

Renal accumulation riskRed flag

A previously stable patient who develops vomiting, diarrhoea, poor intake, oliguria or acute kidney injury can accumulate the next dose and become rapidly toxic.

Dosing misunderstanding

A patient cannot name the weekly day, alternates tablet strengths or takes folic acid and methotrexate together without a clear plan; treat this as a safety failure before renewal.

Red flags requiring action

Any confirmed or possible daily-for-weekly dosing error requires urgent assessment even when the patient initially feels well because cytopenia and mucositis may be delayed.
Fever, sore throat, mouth ulceration, bruising, bleeding or severe diarrhoea suggests marrow or mucosal toxicity and requires immediate withholding and blood counts.
New dry cough, dyspnoea, hypoxaemia or diffuse pulmonary shadowing may represent methotrexate pneumonitis, opportunistic infection or inflammatory lung disease.
Jaundice, marked transaminase rise, falling albumin or right-upper-quadrant symptoms requires interruption and assessment for drug, alcohol, metabolic and viral liver injury.
Vomiting, dehydration, oliguria or a sudden eGFR fall can turn a previously tolerated weekly dose toxic by reducing renal clearance.
Pregnancy or conception within the advised washout interval requires immediate cessation, folic acid 5 mg daily and urgent rheumatology, obstetric and fetal-medicine advice.

03Assessment before treatmentTests and checks that guide safe selection.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line baseline FBC, liver and renal profileFirst stepFirst line
Why
Confirm marrow reserve, liver status and renal clearance before the first dose.
Interpretation and limitations
Record WCC, neutrophils, platelets, MCV, ALT or AST, albumin, creatinine and eGFR; unexplained abnormalities need evaluation rather than a lower empirical dose.
02
Baseline infection and immunity assessment
Why
Identify chronic infection and vaccine needs before immune suppression.
Interpretation and limitations
Use hepatitis B, hepatitis C, HIV and TB testing according to risk and treatment pathway, establish varicella and vaccination history and investigate active infection before starting.
03
Pregnancy assessment
Why
Prevent embryo exposure and establish a contraception or conception plan.
Interpretation and limitations
Test when pregnancy is possible and timing uncertain, document counselling for both partners and arrange a compatible alternative before planned maternal conception.
04
Serial FBC, liver and renal monitoring
Why
Detect marrow suppression, hepatotoxicity and reduced clearance while dose and risk change.
Interpretation and limitations
Use frequent initiation and dose-change checks, then at least twelve-weekly monitoring in a stable low-risk adult; act on trends and the shared-care thresholds, not laboratory flags alone.
05
Respiratory assessment and imaging
Why
Distinguish pneumonitis, infection and background inflammatory lung disease when respiratory symptoms emerge.
Interpretation and limitations
Stop methotrexate, measure oxygenation and obtain chest imaging and microbiology urgently; high-resolution CT, lung function or bronchoscopy follows severity and specialist assessment.
06
Toxicity work-up
Why
Grade organ injury after dosing error, mucositis, cytopenia or renal decline.
Interpretation and limitations
Urgently repeat FBC, reticulocytes, renal and liver profiles, electrolytes and infection cultures; confirm total dose and timing and obtain toxicology or haematology advice about folinic acid.
07
Cause-specific liver assessment
Why
Clarify persistent biochemical abnormality rather than attributing every change to methotrexate.
Interpretation and limitations
Review alcohol, BMI, diabetes, viral hepatitis, other medicines and ultrasound or fibrosis assessment under hepatology advice; isolated transient values and progressive fibrosis require different decisions.

04Treatment approachPreparation, options, escalation and aftercare.

01First-line initiationMake weekly dosing unambiguousFirst stepFirst lineMethotrexate is selected as a conventional DMARD and baseline safety assessment is satisfactory.

1Agree one weekly day, prescribe 7.5–15 mg once weekly using one tablet strength where possible and provide written plus verbal schedule confirmation.
2Prescribe folic acid at least 5 mg once weekly on a different day and document contraception, vaccines, alcohol and infection advice.
3Arrange named responsibility for early FBC, liver and renal monitoring and a contact route for mouth ulcers, fever, bruising, dyspnoea or dosing error.

02Dose optimisationTitrate response before classifying failureMonitoring remains satisfactory but inflammatory disease is not controlled after the initial dose.

1Increase by 2.5–5 mg weekly-dose increments according to specialist and shared-care timing, usually to no more than 25 mg once weekly.
2Check adherence and consider split oral dosing over one day or once-weekly subcutaneous administration for nausea, absorption or higher-dose bioavailability problems.
3EscalationAfter an adequate maximum-tolerated trial, escalate according to the disease guideline rather than continuing an ineffective dose or chronic glucocorticoid bridge.

03Abnormal-monitoring branchWithhold, repeat and explainSymptoms, a concerning trend or a local absolute threshold suggests marrow, liver or renal toxicity.

1Withhold methotrexate and contact the responsible specialist on the same day when toxicity is clinically important; manage severe symptoms or cytopenia in hospital.
2Repeat and investigate the abnormality, including infection, nutritional deficiency, alcohol, liver disease, dehydration, interacting drugs and disease activity.
3Restart only after recovery and an explicit specialist dose and monitoring plan; do not compensate for a missed dose by doubling the next.

04Emergency toxicityRespond before counts reach their nadirDaily dosing, overdose, severe mucositis, bleeding, sepsis, renal failure or pneumonitis is suspected.

1Stop methotrexate, document exact tablet strength and timing and arrange urgent acute assessment with blood counts and organ profiles.
2Treat infection, hypoxia, bleeding and kidney injury and seek toxicology or haematology advice about folinic-acid rescue and enhanced elimination.
3After survival, correct prescribing-system, dispensing and education failures before any future antifolate treatment is considered.

05Reproductive pathwayChange treatment before conceptionA patient taking methotrexate plans pregnancy, becomes pregnant or wishes to breastfeed.

1For planned maternal conception, stop low-dose methotrexate at least one month beforehand and establish disease control on pregnancy-compatible treatment.
2For exposure in pregnancy, stop immediately, prescribe folic acid 5 mg daily and arrange urgent rheumatology and fetal-medicine counselling rather than assuming a single outcome.
3Avoid methotrexate while breastfeeding; reassure that paternal doses up to 25 mg weekly are compatible under current BSR guidance.

05Regimens, contraindications and interactionsTreatment details and the circumstances that modify them.

Anchor conventional DMARD for rheumatoid arthritis and an option in several other inflammatory rheumatic diseases.

Methotrexate oral

Start 7.5–15 mg orally once weekly on one named day; increase by 2.5–5 mg steps according to response and laboratory monitoring to a usual maximum of 25 mg once weekly.

Never daily. Avoid pregnancy, breastfeeding and severe renal or hepatic disease; monitor marrow, liver, kidney, infection and lung toxicity and avoid trimethoprim or co-trimoxazole.

Improves bioavailability and can reduce gastrointestinal intolerance when oral therapy is inadequate or poorly absorbed.

Methotrexate subcutaneous

Give the total prescribed dose subcutaneously once weekly on one named day, usually using the same milligram weekly dose as oral treatment when switching, with specialist titration up to 25 mg weekly.

The injection remains systemic methotrexate with the same marrow, hepatic, renal, pulmonary, infection and reproductive risks; train handling and sharps disposal and prevent oral duplication.

Reduces gastrointestinal and hepatic toxicity and supports persistence with low-dose methotrexate.

Folic acid

Prescribe at least 5 mg orally once weekly on a day different from methotrexate; specialist plans may use 5 mg on additional non-methotrexate days when adverse effects persist.

Do not place it on the methotrexate day unless a specialist protocol explicitly does so; ordinary folic acid does not replace folinic-acid rescue for overdose or severe toxicity.

Rescues healthy cells from folate antagonism after significant overdose or severe low-dose methotrexate toxicity.

Folinic acid rescue

Dose and duration are determined urgently by toxicology or haematology from the ingested dose, time, renal function, counts and clinical toxicity; repeated intravenous or oral doses may be required until recovery.

Do not delay specialist advice while waiting for a methotrexate level, which is often unhelpful in delayed low-dose toxicity; continue sepsis, marrow and organ support.

A prescribing prohibition rather than a co-treatment: both medicines can add antifolate marrow suppression and alter methotrexate handling.

Trimethoprim and co-trimoxazole avoidance

Do not initiate trimethoprim or co-trimoxazole in a patient taking methotrexate except under deliberate specialist management of an exceptional indication.

Severe pancytopenia may be delayed and can occur after one drug is stopped; use a culture-directed non-antifolate alternative where possible and arrange urgent counts if exposure occurred.

06Complications, monitoring and follow-upAdverse effects, response and longer-term review.

During initiation and each dose increase, use the agreed FBC, liver and renal schedule; a common sequence is every two weeks until stable for six weeks, monthly for three months, then at least every twelve weeks in stable lower-risk care.
Review trends alongside absolute values and contact the specialist early for falling cell lines or albumin, rising MCV or transaminases, or a creatinine increase even before a formal stop threshold.
At each prescription ask the patient to state the tablet strength, number, weekly day and folic-acid day; this short teach-back is a core monitoring intervention.
Record disease activity and function at eight to twelve weeks and after dose optimisation, including whether steroid exposure has reduced; laboratory tolerance without clinical benefit is not success.
Ask about oral ulcers, sore throat, fever, bruising, bleeding, nausea, diarrhoea, cough, breathlessness, alcohol, pregnancy intention and new medicines, particularly antibiotics and NSAIDs.
Review monitoring frequency after acute kidney injury, infection, dose change, interacting medicine or transfer between teams, and state who may authorise restart after a hold.

07Special situationsVariants, exceptions and circumstances that change the usual approach.

One day can contain a split dose

Dividing the weekly oral total over twelve hours can improve absorption, but both portions still belong to one weekly treatment day.

Toxicity can follow stable years

Ageing kidneys, dehydration or a new interacting antibiotic can abruptly change exposure even when the prescribed weekly dose has not changed.

Macrocytosis needs a cause

An increasing MCV may reflect folate or B12 deficiency, thyroid disease, alcohol, liver disease or marrow toxicity and should not be dismissed as expected.

A drug level rarely reassures

Serum methotrexate concentrations guide high-dose oncology protocols but may not correlate with delayed toxicity from chronic low-dose exposure.

Pneumonitis is a diagnosis of exclusion

The medicine is stopped immediately, while infection and inflammatory interstitial lung disease are investigated in parallel rather than sequentially.

Paternal and maternal advice differs

Current BSR guidance considers paternal doses up to 25 mg weekly compatible, while maternal exposure requires withdrawal before conception.

08Common pitfallsFrequent interpretation and management errors.

01
Writing once weekly without naming the day or allowing mixed 2.5 mg and 10 mg tablet strengths to obscure the total dose.
02
Prescribing trimethoprim for a presumed urinary infection without checking methotrexate on the repeat-medication list.
03
Continuing treatment through severe vomiting or acute kidney injury because the last scheduled blood result was normal.
04
Treating a new cough empirically and restarting methotrexate without excluding pneumonitis or opportunistic infection.
05
Responding to a rising MCV by adding folate without checking B12, thyroid, alcohol, liver and other marrow causes.
06
Monitoring laboratory tolerance while failing to measure disease response, function and the ability to withdraw bridging glucocorticoid.