What is methotrexate?
Methotrexate is a medication used in low doses to treat inflammatory skin conditions such as psoriasis. It is also prescribed for rheumatoid arthritis, psoriatic arthritis, and increasingly, other inflammatory disorders (off-label). In much higher doses, it is sometimes used as a chemotherapy agent for leukaemia and some other forms of cancer.
Methotrexate can cause side effects that occasionally can be serious, so it is important that the medication is prescribed by a doctor experienced in its use and that the treatment is monitored carefully. If you have been prescribed methotrexate, refer to consumer medicine information* for more information.
Which skin diseases respond to methotrexate?
Methotrexate has been used in the treatment of moderate to severe psoriasis for many years. It is now used in suitable patients that have other extensive or troublesome skin conditions. These include:
- Atopic dermatitis
- Pityriasis rubra pilaris
- Pompholyx and other forms of chronic hand dermatitis
- Pityiasis lichenoides (PLC) and pityriasis lichenoides et varioliformis acuta (PLEVA)
- Chronic urticaria
- Immunobullous diseases such as bullous pemphigoid and pemphigus
- Morphoea (localised scleroderma)
- Cutaneous lupus erythematosus
Methotrexate has mainly been used in adults, but it appears to be well tolerated in children over 3 years of age.
How quickly does the skin condition improve on methotrexate?
For responding skin diseases, methotrexate usually shows some benefit within 6 to 8 weeks. Maximum effects are achieved within 3 to 6 months. In chronic plaque psoriasis, about 50-60% of patients see a good result (a reduction in PASI score of 75%).
How does methotrexate work?
There are several mechanisms that may explain the effect of low-dose methotrexate in skin diseases.
- Methotrexate is an antimetabolite. This means it reduces the speed that skin cells proliferate, because it antagonises the B vitamin, folic acid. It reduces pyrimidines, purines and methylation of DNA.
- Methotrexate has anti-inflammatory properties, perhaps through an increase in intracellular adenosine, a purine nucleoside.
- Methotrexate also has weak immune suppressive effects.
Contraindications to methotrexate
Avoid methotrexate in pregnancy and when breastfeeding
Methotrexate is FDA pregnancy category X. It is known to cause birth defects and may cause miscarriage or stillbirth, especially in the first 3 months of pregnancy. Pregnant or breastfeeding women must not take methotrexate, and women of childbearing age must not become pregnant while taking methotrexate. Adequate contraceptive measures are necessary during therapy and for at least three months thereafter (as methotrexate may persist in the tissues for some weeks). Consult your doctor before considering pregnancy.
Males on methotrexate must ensure contraception too
Males are advised not to father children while they are on methotrexate or for at least 3 months afterwards because it has been reported to cause a reduction in sperm count. The risks to the fetus are uncertain.
Other health concerns
Methotrexate should not be taken by patients with low blood counts (anaemia, leukopaenia, thrombocytopaenia). It is unsuitable for patients with severe liver disease, particularly if it is caused by methotrexate.
It should be taken with caution by patients with mild liver disease, kidney disease, infections, obesity or diabetes.
Illness can increase the risk of methotrexate
Dehydration from fever, vomiting, diarrhoea, or decreased fluid intake can be dangerous. Excessive thirst may be a symptom of dehydration. Notify your doctor if these symptoms develop before you take the next dose of methotrexate.
Dehydration or any other reason for reduced kidney function may prevent normal excretion of methotrexate resulting in toxic accumulation of the medication. The excessive methotrexate can in turn damage the kidneys further.
Avoid alcohol while on methotrexate
Alcoholic beverages (including beer and wine) may increase some of the side effects, including the chance of liver damage, and should be severely restricted or avoided altogether.
A general guideline would be to halve the so-called 'safe' quantities of alcohol imbibed each week. See guidelines of The Alcohol Drug Association of New Zealand, The Alcohol Advisory Council of New Zealand (ALAC), or similar.
How to take methotrexate
Methotrexate is available as 2.5mg and 10mg tablets, and as a solution for injection.
Most people are prescribed tablets. The most common dose is 15 mg each week, but it varies from 2.5 mg to 30 mg each week depending on kidney function, side effects experienced, and efficacy in treating the skin disease. The doctor may decide to start with a low dose such as 2.5 to 5mg and then gradually build it up to the full dose over several weeks. A low dose should be prescribed if there is reduced renal function (kidney disease).
Methotrexate is taken weekly, rather than daily.
This is different from most medications. The importance of this weekly schedule cannot be overestimated. It is taken either as a single or divided dose each week. Taking methotrexate more often or changing the dose schedule in any way can result in serious side effects.
If doses are taken too often, notify your doctor at once. If an accidental overdose occurs, folinic acid injections may be necessary. The antidote must be given as early as possible.
If methotrexate tablets cause nausea, your doctor may recommend splitting the dose, taking it after meals or at bedtime on one or two days a week. Rarely, a tiny daily dose may be prescribed (and very carefully monitored).
If oral treatment is unsuccessful, intramuscular or subcutaneous injection may be tried.
Tests before starting methotrexate
Laboratory tests should normally include a full blood count with differential (CBC), kidney function tests (creatinine) and liver function tests. Hepatitis B and C serology, varicella serology and tuberculosis testing may be considered in patients at risk of these infections. Fasting blood sugar and blood fats may be measured.
Pretreatment liver biopsy is rarely necessary, but may be considered if there is existing liver disease or high risk of liver disease.
A chest X-ray is appropriate for patients with lung disease such as asthma, bronchitis or smoker's cough.
Pregnancy test may be done in sexually active women of childbearing age.
Tests after starting methotrexate
Blood tests should be arranged to monitor blood count, liver function and kidney function initially every few weeks and later at intervals of perhaps 3 months long-term while on methotrexate. The tests are best done 5 days after a dose of methotrexate and before the next dose.
P3NP collagen testing
In many regions, a blood test measuring pretreatment type 3 procollagen amino terminal propeptide (P3NP collagen) may be requested in adults before treatment with methotrexate, and repeated every 3 to 6 months while on methotrexate.
P3NP collagen measurement can be used to assess hepatic fibrosis in patients on long term methotrexate. If the result is in the normal range, it is very unlikely that methotrexate is causing liver fibrosis. However, elevated levels may be due to any condition in which there is enhanced collagen deposition, not only hepatic fibrosis, for example:
- Myocardial infarction (heart attack)
- Trauma (injury)
- Hypertension (high blood pressure)
- Heart disease
- Liver disease for other reasons
- Inflammatory arthritis
Testing in childhood is not warranted, because normal growth leads to rises in P3NP collagen.
Transient elastography scan
Some patients may be offered a liver ultrasound scan using transient elastography (FibroScan®), which measures the stiffness of the liver and may reveal fibrosis or cirrhosis due to longstanding liver disease or methotrexate toxicity.
It may be necessary to take a small specimen of liver tissue with a needle (liver biopsy). Liver biopsy findings may be reported using Roenigk classification:
- Class 1: normal or mild fatty change
- Class 2: more severe fatty change and portal tract inflammation
- Class 3: fibrosis
- Class 4: cirrhosis.
Side effects of methotrexate
Side effects can occur at any time during treatment but are most common in the first few weeks. Folic acid supplements are thought to reduce some of the side effects of methotrexate and may be prescribed. However, these supplements may reduce how well methotrexate controls the skin disease. The best dose of folic acid is unknown.
If the side effects described below or other problems trouble you, or should you develop any signs of infection or unusual bleeding, notify your doctor promptly and before your next dose of methotrexate is due.
Gastrointestinal side effects
The most common side effects of methotrexate are loss of appetite, nausea, diarrhoea and mouth ulcers (stomatitis). These side effects are usually temporary, but changes in dose may be required, and/or supplemental folic acid tablets. If you have gastroenteritis (stomach upset), do not take methotrexate until you have recovered.
Blood count abnormalities
An overdose of methotrexate or deficiency of the vitamin folic acid may result in anaemia (decreased haemoglobin count), leucopaenia (reduced white cell count risking serious infections) and thrombocytopaenia (low platelet count resulting in bruising and bleeding). Methotrexate should not be taken unless the blood count is normal or near-normal prior to the next dose. Low blood counts are more likely in people with kidney disease, existing haematological disorders or taking other medications (particularly sulfonamides).
Methotrexate is stored by the liver. Transaminase liver enzyme levels may rise for a few days after treatment but they quickly return to normal and the next dose may be taken safely. It's best to do blood tests at least 5 days after a dose or just prior to the next dose.
Long term therapy for two years or more may cause scarring (fibrosis or cirrhosis) of the liver. This is more common in patients with other reasons for liver disease such as viral hepatitis, alcoholism, diabetes, hyperlipidaemia, fatty liver or obesity.
Methotrexate can rarely cause a lung reaction similar to pneumonia called acute pneumonitis. The symptoms are usually fever, cough (often dry and hacking), and shortness of breath. Should you develop such symptoms, stop taking methotrexate and notify your doctor promptly. A chest X-ray may reveal diffuse white patches.
Slowly progressive lung fibrosis associated with methotrexate is rare. It has usually affected patients with rheumatoid arthritis.
Although uncommon, methotrexate may rarely result in reactivation of tuberculosis or opportunistic bacterial, fungal or viral infections. Shingles (herpes zoster infection) and cold sores (herpes simplex) may be more severe in those taking methotrexate. It is unwise to take methotrexate if there is immunodeficiency, untreated tuberculosis or HIV infection.
Cutaneous side effects of methotrexate
Methotrexate may rarely causes skin problems.
- Photosensitivity (sunburn): as a precaution, cover up and use sunscreens when outdoors. Phototherapy may be safe but should be undertaken cautiously
- Ulceration of skin and mucous membranes (especially in overdose)
- Diffuse hair loss may occur if high doses are prescribed, e.g. in the treatment of leukaemia.
Other side effects
Some patients taking methotrexate have headaches, dizzinesss, fatigue and mood changes, especially when first starting on methotrexate.
Refer to datasheets and prescribing information for a full list of risks and side effects.
Drug interactions with methotrexate
Several medications may increase side effects or decrease the effectiveness of methotrexate or the other drug. Tell your doctor all the medicines you are taking, whether they are prescription or non-prescription medicines. If you are having an operation with a general anaesthetic, tell the anaesthetist you are on methotrexate.
Do not begin or change the dosage of any medicine without first checking with your doctor. This is especially true of antibiotics and anti-inflammatory agents.
Like methotrexate, antibiotics that contain the drug trimethoprim or sulfonamides such as cotrimoxazole antagonise folate. Taking them at the same time as methotrexate could result in unexpected and dangerous toxicity. Penicillins, sulfonamides, minocycline and ciprofloxacin may also increase methotrexate toxicity.
Aspirin and aspirin-like drugs (nonsteroidal anti-inflammatory medicines) may reduce how much methotrexate is eliminated by the kidneys. This could potentially result in a toxic build-up of methotrexate in the blood stream. Anti-inflammatories can often be taken safely but you should have regular blood tests if you start these medicines or others, as advised by your doctor. Alternatively, you could take paracetamol (acetominophen), as this does not interfere with methotrexate.
Other drugs that may increase methotrexate toxicity include barbiturates, proton pump inhibitors (pantoprazole, omeprazole, esomeprazole, lansoprazole, rabeprazole), colchicine, dipyridamol, phenytoin, sulfonylureas, frusemide / furosemide and thiazide diuretics. Ask your doctor's advice if you take any of these medicines.
Vaccination on methotrexate
Live vaccines may be ineffective in those taking methotrexate or cause allergic reactions.
Killed vaccines are safe and are often advisable to reduce the impact of infection – arrange annual influenza vaccination.
Methotrexate should be kept out of the reach of children. Do not give this medication to other people.
Close medical supervision is essential if you are on methotrexate. It is important that you carry out your doctor's instructions faithfully and promptly report any side effects or symptoms you may develop to him or her.
- Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 4. Guidelinesof care for the management and treatment of psoriasis with traditional systemic agents. Journal of the American Academy of Dermatology. Volume 61, Issue 3, September 2009, Pages 451-485 doi:10.1016/j.jaad.2009.03.027
- Shen S, O'Brien T, Yap LM, Prince HM, McCormack CJ. The use of methotrexate in dermatology: a review. Australas J Dermatol. 2012 Feb;53(1):1-18. doi: 10.1111/j.1440-0960.2011.00839.x. Epub 2011 Dec 29.