Methotrexate in Rheumatoid Arthritis

Robin Butler MD FRCP, Consultant Rheumatologist. Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry
Original article: 01/08/2006
Reviewed: 15/11/2011
Next review due: 15/11/2014

Background and mechanism of action

Methotrexate (MTX) was introduced in 1947. Because it slows down the growth of rapidly dividing cells it was used in high doses to treat people with leukaemia and other forms of cancer. In the early 1950s it was used in much lower doses to treat people with the skin condition psoriasis. Some people who had an inflammatory arthritis associated with their psoriasis noted that their joints improved as well as their skin, as did a few people with rheumatoid arthritis (RA) who were given MTX. However studies have indicated that significant numbers of people with psoriasis developed cirrhosis of the liver after long-term treatment. As a group these people had a very high alcohol intake which was probably a major contributory factor, although recent work suggests that people with psoriasis who receive MTX may be more vulnerable than others to liver damage. As a result of the liver problems MTX was used rarely by rheumatologists for some years.

Methotrexate began to be used increasingly in RA in the 1980s and clinical trials demonstrated its efficacy in the mid-1980s. Studies have shown that it is generally well-tolerated in comparison with other disease-modifying drugs (DMARDs) used to treat RA. There have been numerous studies of its use since then both used alone (monotherapy) and in combination with other DMARDs. In recent years it has become clear that the earlier in the course of RA that a DMARD is started the better the long-term outcome. MTX is now regarded as the “gold standard” against which conventional DMARDs and the newer 'biologic therapies' (drugs that target particular parts of the immune system) are measured, and it is generally agreed that it should be used early in the course of RA in most people with the condition. RA is a long-term condition and there are a finite number of drugs available. It can be helpful to try MTX again in people who have had an inadequate response the first time, especially if the initial dose was modest.

How does it work?

Methotrexate has numerous effects on processes in the body which could be relevant in RA and it is not possible to pin-point a single effect which explains its effectiveness. At the doses used in RA, i.e. generally between 7.5 and 20mg weekly, it does not have a significant anti-cancer or immunosuppressive effect, but it does modify the abnormal immune processes which cause RA.

It is clear that genetic factors influence both the response to MTX and the risk of side-effects. Although progress is being made in identifying these factors, there is at present no reliable way of predicting who will respond well, and who is at increased risk of side-effects.

How is it taken?

Methotrexate is usually given once weekly as an oral dose. Practice varies but it is usually started at around 7.5mg weekly and the dose is then increased as necessary by 2.5mg at a time over the next few months. Most people will respond to 7.5–20mg weekly but some may need 20-30mg weekly. Occasionally even higher doses are used. In general higher doses are more effective but also more likely to cause side-effects. MTX can be given as a weekly injection when people experience bad nausea with tablets, or if the response is inadequate when taken by mouth.

MTX depletes the body of folic acid and the frequency of side-effects can be reduced by taking supplements of folic acid. This can be taken as 5-10mg weekly or as two tablets of Pregaday daily (the preparation taken by pregnant women to prevent birth defects which can be purchased over-the-counter in pharmacies without a prescription). Taking higher doses may reduce the efficacy of MTX and most rheumatologists recommend taking the folic acid one or two days after the MTX, and in particular not taking it on the same day as the MTX.

Efficacy

Comparison with placebo

Several studies in the mid-1980s showed that MTX was more effective than placebo (dummy) treatment and led to the widespread use of MTX in the treatment of RA. The ACR (American College of Rheumatology) criteria, which is used to measure how active RA disease activity is has shown improvements overall with doses currently used. It has been shown that about 55% of RA patients will obtain an ACR50 response to MTX (i.e. will see a 50% improvement) and 35% an ACR70 response (i.e. a 70% improvement) respectively in scores of rheumatoid disease activity compared with pre-treatment values. Best results are obtained in early RA and with rapid escalation of the dose of MTX. 

Comparison with other DMARDs

MTX and leflunomide appear to be of similar efficacy and tolerability. MTX is probably a little more effective than sulfasalazine with comparable tolerability. Several studies have shown that injected gold and MTX are of similar efficacy, but people on gold are more likely to get side-effects, so it is not often used these days. MTX also appears to be similar in efficacy to cyclosporin, but the latter can cause hypertension and impaired kidney function so it is used much less frequently than ten years ago. MTX is both more effective and better tolerated than azathioprine, and the latter now has little place in the treatment of RA.

People tend to stop DMARDs either because the drug is not working, or because it is causing side-effects. Two large studies in the USA showed that people were more likely to remain on MTX long-term than conventional DMARDs including gold, penicillamine, hydroxychloroquine and azathioprine. The same is likely to apply to leflunomide.

A 20-year study of 1240 people with RA in Kansas showed that the use of MTX was associated with a 50% reduction in the risk of death during follow-up whereas conventional DMARDs including sulphasalazine, gold, hydroxychloroquine and penicillamine had no such effect.

Use of MTX in combination with other DMARDs

Over the past 5-10 years the use of combinations of DMARDs has increased and it has become clear that some combinations can give better results than the component DMARDs used singly, without any increase in toxicity. MTX is a key component of the most effective combinations which include the triple combination of methotrexate, sulfasalazine (SSZ) and hydroxychloroquine (HCQ); MTX + SSZ; MTX + HCQ, and MTX + leflunomide (LEF). The use of such combinations can be particularly useful when it is not possible to use anti-TNFα drugs e.g. in people with recent cancer or chronic infection.

Some studies have shown very impressive results in early RA when combinations of MTX + SSZ + HCQ have been used with low-dose oral steroids, or MTX + SSZ plus high-dose steroid followed by gradual reduction in the steroid dose. High doses of steroids are not suitable for everyone e.g. those with diabetes or osteoporosis, but this is an exciting area for further study.

Effect on x-rays

Rheumatologists are keen to see that a drug slows down the rate of deterioration in joint damage seen on x-ray, as there is a close correlation between the degree of joint damage and both disability and the need for operations.

Several studies have shown that MTX is better at slowing x-ray deterioration than placebo, and also better than azathioprine, penicillamine and auranofin (gold injections). It has a similar effect to leflunomide, sulphasalazine and cyclosporine, but is less effective than anti-TNFα drugs.

Use of MTX in combination with anti-TNFα drugs

Anti-TNFα drugs are biologic therapies that neutralise the effect of TNFα, a pro-inflammatory agent which plays a major role in causing inflammation in RA. There are now five agents licensed in the UK for the treatment of RA: infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira), certolizumab pegol (Cimzia) and golimumab (Simponi). In many studies in people with an inadequate response to MTX who were given one of these TNF-α inhibitors, there was greater improvement in those given the biological agent with the MTX than in those continuing MTX alone.

The product licence for infliximab (Remicade) states that it should be given in conjunction with methotrexate. This is to reduce the risk of an immune response to one of the components of infliximab which is produced in mice. Clinical trials in people with early RA have shown that when MTX or etanercept were used as monotherapy or in combination, those given the combination did much better both in terms of clinical response and x-ray damage than those given either etanercept or MTX alone. The same has been shown for adalimumab. As with infliximab, standard current practice is therefore to give MTX with etanercept and adalimumab.

In the widely quoted BeSt study people with early RA were started on treatment with either:

Group 1: MTX, sulphasalazine and other DMARDs used sequentially as monotherapy
Group 2: MTX, sulphasalazine and other DMARDs
Group 3: MTX combined with sulfasalazine, hydroxychloroquine and steroids, initially in high dose or
Group 4: High-dose MTX plus infliximab

People in the two latter combination groups had a more rapid response to treatment, and they also had less joint damage seen on x-ray at two years. These studies suggest that the early use of TNF-α inhibitors plus MTX in RA could have significant long-term benefits in comparison with MTX alone but unfortunately this study has had limited impact on the treatment of early RA in the UK because NICE has not authorised the use of TNF-α inhibitors before conventional DMARDs including MTX have been shown to be inadequate.

Use with other biologic therapies

Rituximab (Mabthera), abatacept (Orencia) and tocilizumab are biological agents which target parts of the immune system other than TNFα.

Rituximab targets B cells and gives comparable results to TNF-α inhibitors when used with MTX. NICE has approved it for use in people with RA who have failed to respond to or are unable to take at least one anti-TNFα drug.

Abatacept inhibits T cells. It is usually given with MTX and can be effective even in people who have not responded to anti-TNFα drugs. NICE has approved it for use in people with RA who have failed to respond to or are unable to take at least one anti-TNFα drug and rituximab.

Tocilizumab is another biologic therapy that blocks the effects of the pro-inflammatory cytokine IL-6. NICE has approved it for use in people with RA who have failed to respond to or are unable to take at least one anti-TNFα drug and rituximab.

Frequently asked questions

What are the possible side-effects?

Up to 30% of people experience side-effects which limit the dose of MTX which they can take, and some of them stop treatment as a result. In others the symptoms are an inconvenience but the benefits from taking the drug make it worth continuing. Nausea, loss of appetite, sore mouth and diarrhoea are fairly common (up to 10%). The level of liver enzymes can be checked by a blood test and mildly increased levels are also fairly common (up to 20%). If this increase is more severe the drug will have to be stopped, or the dose reduced. Headaches (up to 10%) and some hair loss (about 3%) can also occur.

Potentially more serious side-effects such as reduction in the numbers of white blood cells or platelets can also be detected by a blood test. These problems occur in up to 5% of people on MTX. Rarely the drug can induce pneumonitis: inflammation in the lungs (about 1%). People with pre-existing lung disease seem to be at increased risk of this problem. Pneumonitis causes shortness of breath and troublesome cough, and people who develop this should stop the drug and consult their doctor as a matter of urgency.

MTX is largely removed from the body by the kidney, so its use in people with significantly impaired kidney function is potentially hazardous. 

It is doubtful whether MTX increases the risk of serious infection in the doses typically used to treat people with RA.

Can you drink alcohol when on treatment with MTX?

As noted at the beginning of this article, there are concerns that MTX may increase the risk of cirrhosis, particularly in those who drink alcohol to excess. If the levels of liver enzymes are persistently raised MTX is usually stopped. Experience over the past fifteen years is generally re-assuring and there is no convincing evidence that the frequency of cirrhosis in people with RA treated with MTX is greater than in the population at large. However the risk is likely to be greater in people with other risk factors for cirrhosis such as heavy alcohol intake or infection with hepatitis B or C.

Because of the possibility of an increased risk of liver damage with MTX the safest policy is to avoid alcohol if you are on MTX. Many rheumatologists believe however that it is safe to have up to ten units of alcohol per week i.e. a total of ten glasses of wine or five pints of beer or lager. People on MTX would be very unwise to exceed the maximum limit recommended for the population at large i.e. 14 units for women and 21 for men per week.

Can methotrexate injure the unborn child?

Yes, although this is not inevitable and the magnitude of risk cannot be stated reliably. A child conceived by either a mother or a father who is taking MTX may be born with deformities. The risk is such that termination of pregnancy must be considered if a parent on MTX conceives a child. It is therefore vital that men or women on MTX ensure that they use effective contraception. If a man or woman on MTX decides they would like to have a child, it is recommended that they stop the MTX for a period of at least three months before they try to conceive, and some authorities recommend waiting six months.

Women can start taking MTX again once the child is born, but should not breast-feed while on the drug. It may be necessary therefore for a mother to choose whether breast-feeding or re-starting MTX is more important to her at that time.

Does MTX interact with other drugs?

The antibiotics trimethoprim and sulphamethoxazole (often combined as co-trimoxazole) also have anti-folate effects (ie they impair the function of folic acid) and should be avoided or used with great caution by people on MTX as there is a risk of severe bone marrow depression leading to serious infection or bleeding.

There is also increased risk of toxicity if MTX is taken with acitretin (a treatment for severe psoriasis); the epilepsy drug phenytoin, and with the anti-malarial pyrimethamine.

When MTX use became widespread there were concerns that non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin might increase the risk of side-effects when taken with MTX. However most people with RA cannot manage without regular NSAIDs as their joint stiffness is not relieved by ordinary painkillers, and further experience in tens of thousands of people with RA treated world-wide suggests that this is very rarely a problem with the doses of MTX used to treat RA.

Can people on MTX have immunisations?

It is generally recommended that people on MTX have the flu vaccine annually.

It is recommended that people on MTX do not receive live vaccines, and should not do so until three months after stopping MTX. Live vaccines include oral polio and typhoid vaccines, measles, mumps, rubella (MMR), varicella (chickenpox/shingles) and yellow fever. BCG immunisation should not be given either. The inactivated polio vaccine (IPV) and killed typhoid vaccine can be given and there is no problem with hepatitis A and B, tetanus, anthrax, cholera, plague or rabies.

This advice may affect your choice of holiday as some countries insist on evidence of immunisation against yellow fever before a person is allowed to enter their country.

Further reading

Immunisation for people with rheumatoid arthritis

What tests are recommended for people on MTX?

The British Society for Rheumatology (BSR) recommends that people starting MTX should have a full blood count, kidney and liver function tests and a chest x-ray before starting treatment. Blood count and liver function tests should be checked by blood test every two weeks until six weeks after the last dose increase. Thereafter tests should be done monthly until the disease and dose of methotrexate have been stable for one year when the frequency may be reduced in some cases.

Further reading

British Society for Rheumatology methotrexate monitoring guidelines

National Patient Safety Agency guidance on 'Improving Compliance with Oral Methotrexate'

Arthritis Research UK (ARUK) methotrexate drug information sheet


References available on request

If you would like to hear other people's experience of using Methotrexate, watch Christine, Jane and Megan's stories by clicking here.

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