Methotrexate: Uses, dosage and side effects

Methotrexate is typically used to treat certain cancers as well as autoimmune diseases like psoriasis and rheumatoid arthritis. Please find more information about methotrexate in the following text.

Mechanism of action

How does methotrexate work?

Methotrexate is a so-called folic acid antagonist. It is used as cytostatic agent in chemotherapy to treat different types of cancer. The word cytostatic comes from Greek and stands for “kytos” = cell and “stazio” =stand. Cytostatic drugs inhibit cell division and stop or reduce tumours from growing.

Methotrexate stops cell division

Methotrexate inhibits a very specific enzyme called dihydrofolate-reductase. This enzyme usually catalyses and accelerates the conversion of folic acid into tetrahydrofolic acid, which in turn, is important for the synthesis of nucleic acid, the carrier of genetic information inside the cell. By blocking dihydrofolate-reductase, methotrexate stops cell division and proliferation. In terms of chemotherapy, this means that cancer cells die, and that cancer growth is slowed down.

Methotrexate is also used as drug for the treatment of chronic inflammatory diseases like severe forms of rheumatoid arthritis and psoriasis (with and without joint involvement). Its active ingredient suppresses and changes the overactive immune system in these diseases. However, the exact mechanism of this immunosuppressive, anti-inflammatory effect of methotrexate has not yet been fully understood.

Methotrexate in Psoriasis

How do I use methotrexate for psoriasis?

Methotrexate is used to treat the moderate to severe form of psoriasis vulgaris when conventional therapies such as local or light therapy are not sufficiently effective or unsuitable. Combination therapies are also possible.

As an opponent of folic acid (vitamin B 9), methotrexate interferes with cell metabolism. In low doses, methotrexate has an anti-inflammatory and immunomodulatory effect and regulates the misdirected immune system, which is used for the treatment of autoimmune diseases.

In higher dosages, however, methotrexate inhibits cell division or growth. In this form it is used as a cytostatic agent in cancer therapy. Tablets and intravenous or subcutaneous injections are prescribed.

Not more than once a week

Methotrexate is usually used once a week, ideally it should always be the same day of the week. It is best to choose a largely relaxed day for this, for example at the weekend. The administration of 5 mg folic acid 24 hours after methotrexate is recommended by many doctors. This is to avoid side effects. However, the experts disagree on this recommendation.

If, for any reason, you have accidentally taken too much methotrexate, please notify your doctor immediately. There is an antidote (calcium folinate) that can be administered in case of overdose.

Pills and injections

Pills: It is recommended to take methotrexate tablets in the evening, preferably not with meals, with enough liquid (preferably water). If for any reason the single dose is too much for you, you can also divide the weekly dose into two or three individual doses at 12-hour intervals.

Subcutaneous injections: The syringes have relatively short and thin needles, like thrombosis needles. They are injected into the subcutaneous fatty tissue. You can choose between two injection areas: the abdominal fat or the thighs. Patients with affected skin in psoriasis chose to switch between these two sides.

Different dosages for cancer and autoimmune diseases

For treating moderate to severe psoriasis, it is recommended to start with 15 mg methotrexate once a week. This recommendation refers to intravenous and subcutaneous injections. If administered orally in tablet form, the initial dosage may be lower and the onset of effect slower.

The dosage may be increased up to 20mg per week, if the achieved success is not satisfactory but the medicine itself well tolerated. During the long-term therapy, a generally lower maintenance dose is wanted.

Results after 2-8 weeks

The time until you can see an improvement in psoriasis under methotrexate therapy can take two to eight weeks. This depends, among other things, on the type of therapy, dosage and severity of psoriasis.

Can I sunbathe with psoriasis despite taking methotrexate?

A combination of methotrexate and UV light is generally possible but must be used with caution. Some dermatologists even use artificial UV light therapy under methotrexate treatment in order to increase the effect of both therapies.

Anti-inflammatory effect of UV light

UV light itself has a beneficial effect on inflammatory processes and autoimmune reactions within the skin. This effect, which is known from natural sunlight, has been used in medicine for many decades, especially patients with psoriasis appreciate the positive effect of UV therapy. It consists of two light wave parts, UVA and UVB rays.

Increased photosensitivity with methotrexate

However, combining methotrexate with UV light therapy can also lead more frequently to a phototoxic reaction with acute worsening of psoriasis.

The increase in photosensitivity due to methotrexate is yet unpredictable and can vary in intensity. This depends, among other things, on the amount of UV light a patient has been exposed to. Therefore, special attention must be paid to UV dosage when combining methotrexate with phototherapy and or sunbathing.

Methotrexate pills and injections

What is better: Pills or injections?

Methotrexate can be administered in different ways. For the treatment of psoriasis, three dosage forms are used: oral pills, intravenous injections and subcutaneous injections.

Subcutaneous injections are carried out like insulin injections or anti-thrombosis injections. After a brief instruction by your doctor, you can easily perform this type of injection yourself at home. Intravenous injections, on the other hand, must always be carried out by your doctor.

Fewer side effects with injections

Methotrexate is absorbed much better when given in form of intravenous and subcutaneous injection compared to tablets. Also, it is often tolerated better than the oral medication. Plus, gastrointestinal side effects like nausea, vomiting and diarrhoea occur less frequently and the onset of action is faster.

It is important to take additional 5mg of folic acid in tablet form the day after your weekly methotrexate dosage (i.e. after 24 hours) in order to avoid side effects.

Injection pens

For some patients, a methotrexate pen may be more suitable than the normal subcutaneous injection needle as an injection instrument. Ask your doctor. It works like the insulin pens used by diabetics. This subcutaneous form of injection enables uncomplicated self-medication, especially for more anxious people. You press a button at one end and the needle is automatically inserted into the skin.

Rheumatic Arthritis: What happens if I stop taking methotrexate?

If you take methotrexate for your rheumatic arthritis and stop it, the arthritis may relapse, and your symptoms may worsen. The desire to "get off" this medicine is understandable, but you should not make this decision on your own. Always talk to your doctor about this.

Serious side effects are rare

The most common reason why patients want to stop taking methotrexate are its side effects and the fear of side effects. It is important to know that methotrexate is a very safe and frequently prescribed drug for the treatment of rheumatic diseases. Serious side effects are rare, whereas the positive impact on treating the disease is usually high.

Many of the side effects may also improve over time if you follow some rules like taking extra folic acid. An exception are allergic reactions and other severe side effects like skin rashes, difficulty breathing, fever, cramps, shortness of breath, dizziness, bleeding or blurred vision.

Side effects & toxicity

What are typical side effects of methotrexate?

Common side effects of methotrexate include nausea, vomiting, diarrhoea, hair loss and skin rash. Other side effects, that occur less frequently include changes in white blood cells or platelets, lung, and liver function. Yet, blood tests should be taken at regular intervals when taking this medicine.

Since methotrexate affects the immune system, some patients become more susceptible to infections. Patients on methotrexate should therefore be cautious when seeing friends or people who suffer from severe infections like chickenpox or shingles, for example.

Please notify your treating physician, if you experience any of the symptoms listed above or any of the following problems: Sore throat, chills, fever, unusual bruising or bleeding, severe fatigue, impaired vision, dizziness, cramps, shortness of breath, yellowish discoloration of the skin or eyes.

Folic acid can reduce side effects

Many studies have shown that methotrexate is better tolerated when folic acid is administered at the same time. When and how much folic acid you should take, you should discuss with your doctor.

Since methotrexate can have side effects on your liver function, your doctor may recommend being careful with alcohol and to reduce your intake to a minimum to avoid any liver damage.

Furthermore, pre-existing illnesses and conditions as well as other medications can reinforce side effects and lead to interactions between different medicines.

Fewer side effects with injections

If you are taking methotrexate as a tablet and suffer from severe gastrointestinal problems, it may be helpful to spread your pills over the day instead of taking them in one single dose. Yet, always talk to your doctor prior to changing your medication.

Also, switching from pills to injections may reduce side effects. Although some patients fear self-injections, they can relieve stomach and intestines considerably.

What else you should pay attention to

When taking methotrexate, you cannot get vaccinations based on live vaccines.

Contact your doctor immediately if you develop the following symptoms during therapy: acute fever, cough, shortness of breath, acute blue discoloration of the skin and mucous membranes.

Contraceptive measures are mandatory for women and men during and up to six months after the end of methotrexate therapy.

Can methotrexate damage liver and kidneys?

Although methotrexate is used in lower doses to treat autoimmune diseases like psoriasis or rheumatoid arthritis, compared to cancer treatment, it can still compromise liver or kidneys. Therefore, methotrexate requires regular controls of blood samples including liver and kidney function, among others.

Side effects due to cytotoxic action

Parts of the side effects are due to the cytostatic mechanism of action of methotrexate. It inhibits cell division and grows not only in cancer cells (s. above) but also in body cell that divide frequently and rapidly like the cells of the gastrointestinal tract, for example. These undesired side effects occur more frequently when treating cancers with higher doses compared to treating autoimmune diseases with lower doses.

What are contraindications for methotrexate?

Since methotrexate can be potentially harm liver and kidneys, it should be used with caution. The risk depends not only on the dosage, but also on personal risk factors.

For example, people with (insulin-dependent) diabetes mellitus or obesity have an increased risk of permanent liver damage when taking methotrexate. In those cases, the therapy option with methotrexate must be considered carefully. Simultaneous intake of liver-damaging drugs and alcohol can also have a negative effect. In case of pre-existing liver disease or hepatitis, a different therapy should be considered.

Avoid NSAIDs

It is also strongly advised not to take so-called non-steroidal anti-inflammatory drugs (NSAIDs) together with methotrexate. They include aspirin, diclofenac, or ibuprofen, for example. Particularly in the case of renal dysfunction, simultaneous administration of NSAIDs and methotrexate can be dangerous.

Don´t worry!

Despite all the side effects mentioned above, methotrexate is usually a very safe and potent drug. It has been used for many decades and different diseases and can be given for years if blood tests and organ function are monitored regularly.

Do coffee and caffeine affect methotrexate?

Caffeine can reduce the absorption of methotrexate by influencing the so-called adenosine, an endogenous substance that influences biochemical processes in our body. Thus, excessive intake of coffee, black tea or caffeinated cold drinks like coke and other soft drinks may influence the effect of methotrexate.

If you have been taking methotrexate for a long time without any problems despite drinking caffeine, you can of course continue to enjoy your beloved morning coffee.

However, if you have already tried various therapies without success and methotrexate is not working properly, you should consider whether you could reduce your caffeine consumption. It would be worth a try in this case.

Pregnancy, fertility and breast feeding

Does methotrexate affect pregnancy, fertility, and breast feeding?

Yes, all of it. Methotrexate affects cell division of all body cells, particularly the ones that divide rapidly. Therefore, it can be used to stop cancer cells from proliferating and growing.

Since also human germ cells like sperms and egg cells divide rapidly, methotrexate can have negative effects on both. This can then lead to sperm not being produced correctly, thus containing "false" genetic information. Thus, methotrexate can lead to a possible damage to the genetic material. A side effect that must be taken very seriously.

Contraceptive measures necessary up to 6 months after stopping methotrexate

Methotrexate can harm genetic material in men and women. If you are a man receiving methotrexate, you should not have a child both during the treatment and three to six months after it. Also, since treatment with methotrexate can lead to infertility, it may be advisable to think about sperm freezing before starting treatment.

As a woman, you are not allowed to become pregnant during and up to six months after the end of the therapy as well. Methotrexate can lead to malformations and organ damage of the unborn child and even to miscarriage.

Do not breastfeed while taking methotrexate

Methotrexate passes into breast milk and can cause toxic and harmful effects in breastfed babies. Thus, you must stop breastfeeding before starting methotrexate.

Do I have to stop methotrexate before a planned pregnancy?

Treatment with methotrexate during pregnancy and lactation is prohibited since methotrexate can cause malformations in the unborn child. As an antidote to folic acid, methotrexate can damage genetic cell material and lead to variable malformations during pregnancy.

• Possible malformations include, for example:
• Malformations of the cranial bones (cranial bone dysplasia)
• Brain abnormalities
• Malformations of arms and legs
• Very rarely also: complete absence of the brain (anencephaly)
• Birth control in men and women h4

For this reason, it is important to exclude a pregnancy before starting methotrexate, and a safe contraceptive method is essential during the treatment with this drug to prevent unexpected pregnancies. This applies females and males. The safety interval between discontinuation of the methotrexate and conception lies around several months. Therefore, consult your rheumatologist or other specialist at an early stage if you are planning a pregnancy. You should also tell your gynaecologist about previous methotrexate treatments. Also, be sure to take enough folic acid before becoming pregnant.

Do I need to abort a pregnancy that occurred during methotrexate therapy?

Treatment with methotrexate of rheumatoid arthritis, psoriasis or cancer is prohibited in pregnant patients. Physicians and experts underline how important save contraceptive measures are when taking methotrexate. Nevertheless, it does happen that this potentially harmful drug is taken during an unnoticed pregnancy.

Prenatal diagnostics

However, usually there is no reason for an immediate abortion. Indeed, studies have shown that such an accidental methotrexate intake in the "lower, rheumatism dosage" does not pose a significant risk of malformation for the unborn child. Nevertheless, the treatment should be changed immediately, and the condition and development of the child must be observed closely including specialized ultrasound tests.

Talk to your treating physicians – the gynaecologist, rheumatologist, or other doctor – about your situation and discuss with them what would be the best for you in your individual case. And be sure to take enough folic acid.

Authors: Dr. Hubertus Glaser, Dr. Julia Spengler & Dr. med. Sonia Trowe