Methotrexate

Of all the disease-modifying anti-rheumatic drugs (DMARDs), methotrexate is the one rheumatology uses most. In rheumatoid arthritis it is one of the first treatments offered, in practice the most common choice, and it has a place in psoriatic arthritis, in juvenile idiopathic arthritis that carries on into adult life, and in a range of other inflammatory conditions, among them some forms of vasculitis and connective tissue disease. No other medicine anchors the specialty in quite the same way.

It holds that place because it changes the course of the disease as well as easing the symptoms. An overactive immune system drives inflammatory arthritis, and methotrexate turns that overactivity down: pain and swelling ease, and, more importantly, the joints are protected from the damage that unchecked inflammation does over the years. It does not kill pain, and it takes its time: on the full dose, up to twelve weeks may pass before anything changes, and the effect goes on building for several months after that, which is why a steroid is sometimes brought in to cover the gap. Our guide to DMARDs in rheumatology shows where methotrexate sits among the other medicines of its kind, and biologics and JAK inhibitors covers the options when it is not enough by itself.

Few worries about methotrexate come up more often, and the question deserves a straight answer. At doses many times higher, the identical molecule treats some cancers, and because the leaflet in the packet lists those uses, many people are alarmed before their first dose. In rheumatology the dose is small and weekly, and its aim is to damp down an overactive immune system, not to destroy cells. Taken this way it neither acts nor feels like chemotherapy, and day-to-day life on it bears no resemblance to what the word brings to mind. It shares its molecule and its name with the high-dose treatment; the dose and the experience are different.

Methotrexate is taken once every seven days; a dose every day is never right and never safe. The rule gets repeated so firmly wherever methotrexate is prescribed because it cuts against habit, most medicines being daily, and because taking it every day by mistake is dangerous. Pick a fixed day and build the routine around it. If you are not sure whether today's dose was taken, or think an extra one was, neither guessing nor doubling up is safe: ask the prescribing team, a pharmacist or NHS 111.

Folic acid, a vitamin, usually goes with it. Its job is to soften side effects such as nausea and mouth ulcers without costing you any of the benefit; your prescriber decides how and when it is taken within the same weekly routine, which normally means not on your methotrexate day.

Tablets are one form; the other is an injection under the skin, once a week, from a pre-filled pen that most people are soon using without help. Treatment usually begins with tablets. Where tablets cause nausea, or the response to them falls short, the injection is a useful alternative, and may work where tablets have not. The once-a-week rule applies to both.

The majority get on with methotrexate without much difficulty, though the early months commonly bring side effects. Top of the list is nausea, or a washed-out, fragile feeling the day after the dose. Others are tiredness, mouth ulcers, mild headaches and a little thinning of the hair. As the body adapts and the folic acid begins to work, they often recede. Should they persist, there is usually something that can be changed, whether the timing, the folic acid arrangements or the form of the medicine; nausea, for instance, settles for many people once they move from tablets to the injection. Raise any of these at a review; the change, if one is needed, is your prescriber's to make, so do not alter anything yourself.

Methotrexate is supervised because of its rare but serious side effects, and knowing them lets you act early. One of them is pneumonitis, an allergic-type inflammation of the lungs. It is rare, it usually comes in the first months of treatment if it comes at all, and it typically settles once the medicine is stopped, so a new or worsening dry cough or breathlessness needs a review from your rheumatology team, your GP or NHS 111 the same day (in pregnancy, breathlessness that comes on suddenly, or when you lie down, or with dizziness, is for your midwife or maternity unit straight away, or, before a first midwife appointment, your GP surgery or early pregnancy unit, or NHS 111 when they are closed), and breathlessness bad enough that you gasp, choke or are left without the breath to talk is a 999 or A&E emergency. It should not be confused with the slower lung scarring that some inflammatory conditions produce of their own accord. Methotrexate was once blamed for that scarring; it is no longer thought to cause it, and the question is kept under review rather than being a reason to avoid the medicine. Suppression of the bone marrow, where the blood cells are made, is another possibility, and it is the reason a persistent sore throat, a fever, or bruising or bleeding with no explanation needs a same-day call to your rheumatology team, your GP or NHS 111, for an urgent blood test, though the signs of sepsis under When to seek help, and coughing up blood, are a 999 or A&E emergency. The liver can come under strain as well, and as that usually produces no symptoms, the routine blood tests exist precisely to detect it.

Regular blood monitoring follows from all of this; it is part and parcel of the treatment, not an add-on you can take or leave. The tests follow the blood counts, the liver and the kidneys, often at first, while treatment is started or changed, and less often once everything is steady. Most of what the tests find is mild and reversible, and a pause or an adjustment is often all it needs; the problems that do harm are the ones that are not watched. What each test measures, and why, is explained in our guide to rheumatology blood tests.

Alcohol deserves a word of its own, because the liver has to cope with it and with methotrexate, and each can affect it. The limit is practical rather than a ban: 14 units a week at most, spaced out rather than saved up, is acceptable for most people on methotrexate, and many drink less than that. Neither heavy drinking nor bingeing goes with methotrexate. Be accurate with your team about what you drink, because the liver test is read against it.

Infections are somewhat more likely on methotrexate, and can run harder than they otherwise would, because the immune system has been quietened. When you are unwell, get advice early rather than late, from your rheumatology team, your GP or NHS 111, though the signs of sepsis under When to seek help are a 999 or A&E emergency; and make sure that anyone treating you knows about the methotrexate. Live vaccines are generally avoided while you are on it. Four vaccines are not live and are actively recommended: the injected flu vaccine, and those against COVID-19, pneumococcal infection and shingles. Shingles needs a separate mention: the vaccine of earlier years was live, and best avoided on methotrexate; the current one is not live, and it is offered to those who are eligible. All of this, including what to do about the medicine itself while you are ill, is covered by our guide to infections and arthritis medicines. Our guide to vaccinations in rheumatology sets out which vaccines suit you and how to fit them around methotrexate.

Make it a reflex to say that you are on methotrexate to any prescriber, dentist or pharmacist you deal with, without exception. Some antibiotics react with methotrexate and are avoided alongside it wherever possible; two of them, trimethoprim and co-trimoxazole, are not taken with it at all. The safest rule is to treat any new medicine, over-the-counter products included, as something to run past a pharmacist first. A monitoring booklet or a current medicines list, kept in a bag or wallet, does that job for many.

Pregnancy is no place for methotrexate: it is unsafe. Stopping it well before any attempt to conceive is essential, with a pregnancy-compatible treatment planned in its place. One month before planned conception is the minimum the UK rheumatology guideline sets, and many teams advise three months; the minimum is a floor, and the right timing is agreed with your specialist team, which is one more reason never to stop or change anything on your own initiative. A pregnancy that may already have begun while you are on methotrexate is a reason to contact the rheumatology team without delay. Nor is breastfeeding recommended while you are taking it. For men the position is reassuring: a man's ability to father a healthy child is not thought to be affected by low-dose weekly methotrexate, although it should be mentioned when a family is planned. Our guide to arthritis, autoimmune conditions and pregnancy fills in the wider picture, including the treatments that can safely carry on through pregnancy.

Severe illness with suspected sepsis, a high fever with shaking, confusion, rapid breathing, or feeling dramatically worse over hours, for example, is a 999 or A&E emergency, and so is breathlessness that is severe, with gasping, choking or no breath to get words out, as is coughing up blood. With a fever or feeling unwell, a rash that does not fade when you press it, a stiff neck with eyes that cannot bear bright light, or skin, lips or tongue turning blue, grey, pale or blotchy is a 999 or A&E emergency too, since these can be signs of meningitis or sepsis; on black or brown skin the rash and the change of colour may be easier to see on the palms of the hands or the soles of the feet. Chest pain that is crushing, tight or like a pressure, that spreads to an arm, the jaw, the neck, the stomach or the back, that comes with breathlessness, sweating, feeling sick or feeling light-headed, or that came on suddenly and does not go away, is a 999 or A&E emergency. A face that droops on one side, sudden weakness or numbness down one side of the body, or speech that slurs or will not come can be a stroke, as can sudden confusion, a sudden severe headache or a sudden loss of sight: each is a 999 or A&E emergency, on methotrexate or not, and even if it stops after a short time; so is a seizure. Lips, mouth, throat or tongue that suddenly swell, a throat that feels tight, very fast breathing or a struggle to breathe or to swallow, skin, tongue or lips turning blue, grey or pale (on black or brown skin this may be easier to see on the palms of the hands or the soles of the feet), becoming suddenly very confused, drowsy or dizzy, or fainting and not being able to be woken can be a rare but serious allergic reaction to methotrexate, anaphylaxis, and is a 999 or A&E emergency too. For any of these, call 999 and do not drive yourself to A&E.

If none of those applies, get in touch with your rheumatology team, your GP or NHS 111 that same day for any of these:

• Breathlessness that is new, persistent or getting worse, a dry cough that will not clear, or new chest pain; in pregnancy, breathlessness that comes on suddenly, or when you lie down, or with dizziness, is for your midwife or maternity unit straight away, or, before a first midwife appointment, your GP surgery or early pregnancy unit, or NHS 111 when they are closed
• An infection that is not settling, a fever, or a sore throat that lingers
• Skin that becomes painful, hot and swollen, around a cut or anywhere else, or redness that spreads, since this can be cellulitis, an infection of the skin, whose redness may be harder to see on black or brown skin; with a fever or feeling unwell, short of the signs that follow, at A&E or through NHS 111; with a very high temperature or feeling hot, cold or shivery, a fast heartbeat or fast breathing, purple patches on the skin, which may be less obvious on black or brown skin, feeling dizzy or faint, confusion, or skin that is cold, clammy or pale, it is a 999 or A&E emergency, as are the signs of sepsis above
• Contact with anyone who has measles, chickenpox or shingles
• Unexplained bruising or bleeding
• Urine that has turned dark, or a yellow tint to the skin or eyes
• Swelling of the hands, ankles or feet, or a change in how often you pass urine, or passing none at all
• Mouth ulcers that are severe, or vomiting so bad that nothing stays down

A daily dose where a weekly one was meant is a reason to speak to the prescribing team, a pharmacist or NHS 111 promptly, and not to wait and see how you feel. A pregnancy that may already have begun while you are taking it goes to your rheumatology team at once, and the team decides about the next dose.

A hot, swollen joint with a fever or feeling unwell needs emergency assessment the same day, either at A&E or by calling NHS 111, not a routine appointment: an infected joint has to be ruled out at once, and that holds whether or not methotrexate is in the picture. A joint that turns hot and swollen suddenly, without a fever, still needs an answer the same day, from your rheumatology team, your GP or NHS 111, rather than being written off as a flare; our septic arthritis guide explains why. A joint that will take no weight at all, or that cannot be moved, is a 999 or A&E emergency, whether or not there is a fever.

Short of a 999 or A&E emergency, and of a hot, swollen joint or a skin infection with a fever or feeling unwell, which is for A&E or NHS 111 the same day, your GP or NHS 111 is the place to start with anything urgent. Flares of the arthritis itself are a different matter, covered in our guide to managing flares. If you cannot tell how urgent something is, asking is never a mistake.

Methotrexate has held its place for decades as the treatment newer ones are measured against, and for most people it settles into an uneventful weekly habit that keeps the arthritis quiet year after year. That rests on simple things: the weekly day kept, the folic acid taken as prescribed, the blood tests attended, and questions asked early rather than late. Reviews also test the treatment itself: examination, blood results and, where it helps, point-of-care ultrasound can show whether the joints are truly quiet, and the choice to carry on, adjust or add something is then made on evidence, not guesswork. Knowing how the medicine works, and how it is watched, is what lets you take it with confidence.

Is methotrexate chemotherapy?

The molecule is the same one that treats some cancers, at doses many times larger, and that is why the packet leaflet talks about cancer and why so many people ask the question. What rheumatology does with it is another thing altogether: one small weekly dose, whose purpose is to settle an overactive immune system, not to kill cells. At that dose it is neither given nor experienced as chemotherapy, whatever the word suggests.

When will I feel methotrexate working?

Slowly. Up to twelve weeks on the full dose can go by before any difference shows, and the full effect builds over several months. Until then, symptoms are sometimes held down by a steroid acting as a stopgap, which our guide to steroids in rheumatology describes. Give it the early weeks and months before concluding that it is not working, and reach that judgement with your team rather than alone.

Why do I take folic acid with it?

Folic acid is a vitamin. Prescribed alongside methotrexate, as it usually is, it cuts down side effects such as nausea and mouth ulcers, and it does so without getting in the way of the treatment. How and when you take it is your prescriber's call within the weekly routine, and that normally means not on your methotrexate day. Follow the prescription as written rather than adjusting it yourself, and ask your team if any part of the routine is unclear.

Can I still have a drink on methotrexate?

Usually yes, in moderation. The liver has to cope with both, so the limit is 14 units a week at most, taken across the week rather than in one evening; many people choose to drink less than that. Drinking heavily, or bingeing, is a different matter and is to be avoided. Tell your team honestly what you drink, since every monitoring blood test includes a check on the liver.

What if I want to get pregnant while taking methotrexate?

In pregnancy methotrexate is unsafe: it has to be stopped well ahead of trying to conceive, and a pregnancy-compatible treatment is arranged to replace it. The UK rheumatology guideline puts the minimum gap at one month before planned conception, many teams advise three months, and the timing that is right for you is a specialist decision. Stopping is not a decision to take alone; your rheumatology team plans the timing and the replacement with you. Anyone who suspects they are already pregnant on methotrexate should get in touch with their team without delay. The planning in more depth is in our guide to arthritis, autoimmune conditions and pregnancy.