Major side effects of low-dose methotrexate

Low-dose methotrexate is a once-weekly folate antagonist (usually 5–25 mg/week). In pooled RA cohorts (3463 patients, mean 8.8 mg/week, mean 36.5 months), adverse events were reported in 72.9% and 10.5% stopped permanently for toxicity. Most events are mild.

These are commonest (30.8%) and dose-related. On placebo folate, 35% had nausea and vomiting and 22% mouth sores. Folate reduces gastric effects and subcutaneous dosing may.

Raised enzymes come second: in 3808 pooled patients, 20.2% had at least one episode; about 13% of 883 exceeded twice the upper limit of normal (ULN) and 3.7% of 1799 stopped.

Elevations are often transient. Fibrosis or cirrhosis seems rare but data conflict: biopsies after a mean 4.1 years showed severe fibrosis in 1.3% and cirrhosis in 0.5% (0.3% before treatment); a meta-analysis of uncontrolled studies suggested 3% over 55 months. Alcohol, obesity, diabetes and viral hepatitis raise risk.

Stop for a confirmed ALT or AST above 3 times ULN; methotrexate may restart at a lower dose after normalisation. Adjust the dose if levels stay raised below that; consider NSAIDs, obesity and alcohol as causes.

Single-line cytopenia occurred in 5.2%; pancytopenia in 0.96–1.4% in retrospective studies.

Pneumonitis is an early hypersensitivity reaction, usually in the first year, seen in 0.43%. Fever, dry cough and dyspnoea can progress to respiratory failure; Pneumocystis can be hard to distinguish. Risk factors: age over 60, earlier DMARDs, hypoalbuminaemia, diabetes and prior lung disease. Treatment: withdrawal, supportive care and steroids.

Long-term RA data show no excess of serious infection (HR 0.91) or herpes zoster (HR 1.0). Yet a meta-analysis of 22 RA trials found more respiratory infections (RR 1.11), so evidence is mixed. Influenza, pneumococcal and shingles vaccines are advised.

Skin and hair effects occur in 8.9%, central nervous effects in 5.5%. Lymphoma risk is unresolved because RA itself raises it. The placebo-controlled coronary CIRT trial found more non-basal skin cancers.

At least 5 mg folic acid per week is strongly recommended. In a Cochrane review, folate cut transaminase rises by 77%, discontinuations for any reason by 61% and gastrointestinal effects by 26%. Efficacy was not impaired.

Baseline: risk factors including alcohol, ALT, AST, albumin, blood count, creatinine and chest X-ray; consider HIV and hepatitis B and C serology. Repeat ALT, creatinine and blood count every 1–1.5 months until the dose is stable, then every 1–3 months, with clinical review each visit. These are 2009 recommendations, and evidence on intervals is limited.

Kidney: 80–90% is excreted unchanged. Among 4618 adults aged 66 or over with eGFR below 60, a 90-day hospital visit with myelosuppression, sepsis, lung or liver toxicity occurred in 3.55% versus 1.73% on hydroxychloroquine (risk ratio 2.05). The ratio was 2.79 at eGFR below 45, 1.25 (not significant) at 45–59, 3.25 at 15–35 mg/week, and not significantly raised below 15 mg/week. Myelosuppression (4.40) and lung toxicity (2.28, most frequent) rose; sepsis did not significantly. The study is observational.

Methotrexate is contraindicated below eGFR 30; in milder CKD start low and monitor closely, especially the blood count. Advanced age and folate deficiency predispose to toxicity. In a series of 12 with severe marrow toxicity, all over 70, methotrexate was stopped and intravenous folinic acid given, and 11 survived; compared with other treated patients over 70 they had lower eGFR and more often took diuretics or proton pump inhibitors. Age over 70 was a frequent exclusion in RA trials.

Drugs: NSAIDs can reduce renal function; in registry data they raised serious adverse events, including renal failure and cytopenia. Treatment-dose trimethoprim-sulfamethoxazole should not be combined because of marrow toxicity; one review accepts prophylactic dosing three times a week. In older Ontario adults, adding it rather than a cephalosporin did not change 30-day mortality (RR 0.93) but raised hospitalisation (RR 1.49).

The MHRA records 11 UK Yellow Card reports of serious toxicity from inadvertent daily dosing between 2006 and July 2020. Overdose can cause cytopenias, mucositis, gastrointestinal ulceration and bleeding; some reports were fatal.

MHRA advice, for all ages: confirm the person can follow weekly dosing, weigh pill burden, write the weekday in full on the prescription, warn patient and carers that daily use is potentially fatal, advise prompt help after any excess, and use the patient card.