Methotrexate

Methotrexate (MTX) is an immune‑modulating medicine used at low weekly doses to treat Crohn’s disease and some other autoimmune conditions. In Crohn’s it is mainly used as a steroid‑sparing maintenance drug and sometimes together with biologic therapies. Regular blood and safety monitoring are essential because methotrexate can affect the liver, bone marrow, and, rarely, the lungs and pregnancy.

Key Takeaways

• In Crohn’s disease, parenteral methotrexate 15–25 mg once weekly is an option for steroid‑dependent or steroid‑responsive moderate‑to‑severe disease, especially when thiopurines are not suitable. (journals.lww.com)

• Evidence for methotrexate in ulcerative colitis is weak, and current data do not support routine use for inducing or maintaining remission. (pubmed.ncbi.nlm.nih.gov)

• Methotrexate is taken once a week, never daily, and is usually combined with folic acid supplements to limit side effects without reducing effectiveness. (academic.oup.com)

• Regular blood work (CBC, liver enzymes, kidney tests) is needed before treatment, every few weeks early on, then every 2–3 months long term. (sps.nhs.uk)

• Methotrexate is strongly contraindicated in pregnancy, so reliable contraception and advance planning for pregnancy are critical for anyone who could become pregnant or father a pregnancy. (drugs.com)

What is methotrexate?

Methotrexate is an immune‑modulating drug that interferes with folate, a B‑vitamin needed for cells to copy their DNA. At very high doses it is used for some cancers. In inflammatory diseases such as Crohn’s, it is given at much lower, once‑weekly doses to calm an overactive immune system.

For inflammatory bowel disease (IBD) it is available as tablets and as injections given under the skin or into a muscle. Because oral absorption can be unpredictable, especially when the small bowel is inflamed, many IBD teams prefer the injectable form for Crohn’s disease. (academic.oup.com)

Role of methotrexate in Crohn’s disease

Guidelines from the American College of Gastroenterology (ACG) and the European Crohn’s and Colitis Organisation (ECCO) list parenteral methotrexate as an option for moderate‑to‑severe Crohn’s disease that has responded to steroids, especially when a person is steroid‑dependent or cannot tolerate thiopurines. (journals.lww.com)

Induction (getting disease under control).
In classic trials, steroid‑dependent Crohn’s was treated with 25 mg methotrexate given intramuscularly once weekly along with a steroid taper. More patients on methotrexate reached clinical remission than on placebo, although the evidence quality is moderate and anti‑TNF or other biologics are now more common first‑line advanced therapies. (academic.oup.com)

Maintenance (staying in remission).
After remission has been induced with steroids and methotrexate, lowering the dose to 15 mg by injection once weekly can maintain remission in a substantial proportion of patients, outperforming placebo in steroid‑dependent Crohn’s. (academic.oup.com)

Combination with biologics.
Lower‑dose methotrexate (often 12.5–15 mg once weekly, sometimes oral) is also used together with anti‑TNF biologics. The aim is to reduce antibody formation against the biologic and help keep drug levels stable, which can prolong effectiveness. (journals.lww.com)

Methotrexate works slowly. Full benefit often appears after about 8–12 weeks, so it is not usually used alone as an emergency rescue medicine. (journals.lww.com)

Methotrexate in ulcerative colitis

For ulcerative colitis (UC), methotrexate has been disappointing. Several randomized trials using both oral and injectable methotrexate have not shown clear benefit over placebo or standard drugs for inducing remission or maintaining steroid‑free remission. (pubmed.ncbi.nlm.nih.gov)

Because of this, current evidence does not support methotrexate as a routine treatment for UC. It is used far less often than in Crohn’s disease and is usually reserved for research settings or very selected situations.

How methotrexate is taken

For Crohn’s disease, methotrexate is always scheduled weekly, on a fixed “methotrexate day.” Daily dosing can be dangerous and has caused severe toxicity in other conditions.

Common adult IBD dosing patterns include:

• Induction: 25 mg once weekly by subcutaneous or intramuscular injection.

• Maintenance: 15 mg once weekly by injection if remission is stable.

• Add‑on to biologic: 12.5–15 mg once weekly, often oral, to reduce immunogenicity. (journals.lww.com)

Folic acid with methotrexate

Because methotrexate blocks folate, folic acid supplementation is standard. Randomized trials in arthritis show that folic or folinic acid:

• Greatly reduce mouth sores, nausea, and abnormal liver tests

• Do not meaningfully reduce methotrexate’s benefit at usual doses (pubmed.ncbi.nlm.nih.gov)

IBD and pediatric Crohn’s guidance commonly suggest either 5 mg folic acid once weekly, 24–72 hours after methotrexate, or 1 mg daily on most days of the week, with small variations across centers. (academic.oup.com)

Safety, side effects, and pregnancy

At Crohn’s doses, common side effects include:

• Nausea or stomach upset, often around injection day

• Fatigue the following day

• Mild hair thinning

• Headache and mouth ulcers

Many of these improve with folic acid or by switching from tablets to injections. (pubmed.ncbi.nlm.nih.gov)

More serious but less common risks include:

• Liver injury (persistent elevation of liver enzymes or, rarely, scarring)

• Bone marrow suppression (low white cells, red cells, or platelets)

• Lung inflammation causing cough or shortness of breath

• Serious infections

• Possible higher rates of some non‑melanoma skin cancers, although studies conflict (journals.lww.com)

Because lung toxicity is rare but important, some clinicians obtain a baseline chest X‑ray or lung function tests before starting methotrexate, especially in people with current or past smoking or known lung disease. (verywellhealth.com)

Pregnancy and fertility

Methotrexate is strongly teratogenic. Obstetric and pharmacology references agree that it increases the risk of miscarriage and major birth defects, so it is contraindicated in pregnancy and generally avoided in breastfeeding. (drugs.com)

Most experts recommend stopping methotrexate several months before conception. A common approach is at least 3 months for people who may become pregnant and at least 3 months for those who may father a pregnancy, with some clinicians preferring up to 6 months. (drugs.com)

Alcohol and frequent use of non‑steroidal pain medicines (such as ibuprofen) can add to liver strain. Many IBD teams recommend avoiding binge drinking and reviewing any regular alcohol or pain‑medicine use when methotrexate is planned. (verywellhealth.com)

Lab monitoring for methotrexate

Careful blood monitoring is central to safe methotrexate use. Serious complications are uncommon but are often signaled early by changes in routine labs.

Baseline tests before starting

Before the first dose, typical tests include:

• Complete blood count (CBC)

• Liver function tests (ALT, AST, bilirubin, albumin)

• Kidney function (creatinine and estimated GFR)

• Pregnancy test for anyone who could become pregnant (pmc.ncbi.nlm.nih.gov)

Clinicians also review other medicines, alcohol use, and any history of liver, kidney, or lung disease.

Ongoing monitoring schedule

National pharmacy and rheumatology guidance, used widely in inflammatory disease, suggest patterns like:

• CBC, liver enzymes, and kidney function at weeks 2, 4, 8, and 12 after starting or changing the dose

• Then every 2–3 months while the dose and disease are stable (sps.nhs.uk)

A simplified view:

More frequent tests are often used in higher‑risk situations, such as older age, kidney disease, other immunosuppressive drugs, or a history of abnormal labs. (sps.nhs.uk)

If blood counts drift downward or liver enzymes trend upward, clinicians commonly repeat labs sooner, adjust the dose, hold methotrexate, or involve specialists such as hepatologists or hematologists. (sps.nhs.uk)

FAQs

How long does methotrexate take to work in Crohn’s?

Clinical trials and guidelines suggest that methotrexate often needs about 8–12 weeks at a stable dose before its full benefit is clear. Steroids or other fast‑acting treatments are usually used in the meantime for symptom control. (journals.lww.com)

Why are lab tests needed even when symptoms are quiet?

Methotrexate‑related liver or bone‑marrow problems can appear in blood tests before a person feels unwell. Regular CBC, liver, and kidney tests allow teams to adjust or stop the drug early and avoid serious harm. (sps.nhs.uk)

Can methotrexate be stopped once Crohn’s is in remission?

Stopping or reducing methotrexate is a shared decision that weighs disease history, other treatments, pregnancy plans, and risk tolerance. Evidence is limited, so many teams taper cautiously and monitor symptoms and biomarkers closely if methotrexate is withdrawn.