Methotrexate

Methotrexate is a successful and popular medicine used for treating severe psoriasis and some other serious or extensive 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 is also used to treat some forms of arthritis, especially rheumatoid arthritis and psoriatic arthritis. In much higher doses, it is sometimes used as a chemotherapy agent for leukaemia and some other forms of cancer.

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%).

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.

Methotrexate has mainly been used in adults, but it appears to be well tolerated in children.

If you are taking methotrexate, please ask your doctor to explain your treatment. Each skin specialist tends to follow a slightly different regime.

How does it work?

Low-dose methotrexate is now thought to work in skin diseases such as psoriasis and eczema because it has anti-inflammatory properties. The precise mechanism of action is not understood, but it may relate to an increase in intracellular adenosine, a purine nucleoside that has anti-inflammatory effects. Methotrexate also has weak immune suppressive effects.

Methotrexate also reduces the speed in which skin cells proliferate, a particularly useful property in psoriasis because the skin cells are proliferating very quickly. Methotrexate is a folate antagonist – this means it prevents the action of an essential B vitamin, folic acid, on cellular function resulting in reduction in pyrimidines, purines and methylation of DNA.

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 as antidote and 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 this is unsuccessful, intramuscular or subcutaneous injection may be tried.

Contraindications to methotrexate

Methotrexate must be avoided in pregnancy and 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 three months thereafter (as methotrexate may persist in the tissues for some weeks). Consult your doctor before considering pregnancy.

Males must take precautions 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.

Other medicines may interfere with methotrexate.

Several medications may result in an increase in side effects or a decrease in 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, colchicine, dipyridamol, phenytoin, sulfonylureas, frusemide / furosemide and thiazide diuretics. Ask your doctor's advice if you take any of these medicines.

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.

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.

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.

Keep this medicine safely

Methotrexate should be kept out of the reach of children. Do not give this medication to other people.

How should treatment be monitored?

Close medical supervision is essential. If you are on methotrexate, to make sure the treatment is safe, 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.

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 while on methotrexate. The tests are best done 5 days after a dose of methotrexate and before the next dose.

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. Liver biopsy may be recommended if there is suspicion of liver toxicity or other reasons for liver disease.

PIIINP collagen testing

In many regions, a blood test measuring pretreatment type III procollagen amino terminal propeptide (PIIINP collagen) may be requested in adults before treatment with methotrexate, and repeated every 3 to 6 months while on methotrexate.

PIIINP 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 PIIINP collagen.

Side effects of methotrexate

Side effects can occur at any time during treatment but are most common in the first few weeks. Regular blood tests (as advised by your doctor, perhaps monthly) and sometimes other types of tests are necessary for the safe use of methotrexate. Your co-operation is essential. A vitamin supplement, folic acid, is thought to reduce some of the side effects of methotrexate without preventing its good effect on the skin disease. Dermatologists often recommend one tablet is taken on several days each week. 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 (but rarely vomiting), diarrhoea, or sores or ulcers in the mouth (stomatitis). These side effects are usually temporary, but changes in dose may be required, and/or supplemental folic acid tablets. Methotrexate may be unsuitable if you have peptic ulceration or ulcerative colitis. 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).

Liver disease
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. Regular blood tests should monitor liver function. Your doctor will look out for persistent transaminase rises and if available, will measure P3NP collagen, which detects liver fibrosis. If the P3NP collagen is unavailable, or is abnormal, transient elastography may be available to test for fibrosis (this is a special liver ultrasound scan). At times it may be necessary to take a small specimen of liver tissue with a needle (liver biopsy) to determine whether scarring is present. If, and when, to do a liver biopsy should be discussed with your physician. Liver biopsy findings may be reported as Roenigk Class 1 (normal or mild fatty change), Class 2 (more severe fatty change and portal tract inflammation), Class 3 (fibrosis) or Class 4 (cirrhosis).

Lung disease
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 (which can become severe). 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.

Serious infections
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 untreated tuberculosis or acquired immunodeficiency (e.g., HIV infection).

Cutaneous side effects
Methotrexate rarely causes skin problems. However, reported effects include:

• Photosensitivity (easy sunburn): this is uncommon, but it's sensible to cover up and use sunscreens when outdoors. Many patients on methotrexate can be safely treated by cautious phototherapy (usually UVB), if required.
• Ulceration, particularly in overdose (mouth, lips, skin especially psoriasis plaques)
• Diffuse alopecia (hair loss), uncommon when methotrexate is used for psoriasis but quite frequent in patients receiving larger doses for cancer treatment

Although classified as a cytotoxic drug, methotrexate appears to have a very low risk of causing cancer even when taken for many years. However, patients with psoriasis do tend to have a higher risk of developing skin cancer than average, probably because of excessive exposure to the sun and phototherapy. A small increased chance because of methotrexate treatment cannot be ruled out, but on the other hand, methotrexate has antiproliferative effects and might even reduce the risk of skin cancer. Skin cancer can usually be treated successfully.

Other side effects
Some patients have headaches, dizzinesss, fatigue and mood changes, especially when first starting on methotrexate.