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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 in Scandinavia 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 as a single agent and in combination with other anti-rheumatic drugs. 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 disease-modifying drugs (DMARDs) and new biological agents 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 is a finite number of drugs available, and 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.
Further reading:
Pincus & Sokka Should aggressive therapy for rheumatoid arthritis require early use of weekly low-dose methotrexate, as the first disease-modifying anti-rheumatic drug in most patients? Rheumatology 2006 45: 497-499
Kapral et al. Methotrexate in rheumatoid arthritis is frequently effective, even if re-employed after a previous failure. Arthritis Research & Therapy 2006, 8: R46
Tilling et al. Methotrexate and hepatic toxicity in rheumatoid arthritis and psoriatic arthritis. Clinical Drug Investigation 2006 26: 55-62
How does it work?
Methotrexate has numerous effects on biological processes 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 5 and 30mg weekly, it does not have a significant anti-cancer or immunosuppressive effect, but it does modify the abnormal immune processes which cause RA.
MTX inhibits the activity of an enzyme called dihydrofolate reductase which is involved in the production of folic acid. Folic acid is required for the efficient activity of various other important enzymes involved in the production of proteins, and these enzymes too are inhibited by MTX and its breakdown products. The production of DNA and RNA (the genetic material of cells) is reduced whereas there is increased production of adenosine which has anti-inflammatory properties. Overall there is reduced growth and development of cells and reduced protein synthesis. Rapidly dividing cells including those of the immune system are particularly susceptible to these effects of MTX, which is believed to explain its efficacy in RA. There are also effects on the production of cytokines (proteins which have pro- or anti-inflammatory effects in RA); on the breakdown of bone; on the activities of neutrophils and macrophages (cells involved in inflammation) and the production of rheumatoid factor. MTX increases the production of the cytokine IL-10 and reduces that of nitric oxide which is associated with a favourable change in the ratio of TH1/TH2 lymphocytes and in apoptosis.
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.
MTX is largely removed from the body by the kidney, so its use in people with significantly impaired kidney function is potentially hazardous.
Further reading:
Wessels et al. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology 2008 47: 249-255
Herman et al. Methotrexate selectively modulates TH1/TH2 balance in active rheumatoid arthritis patients. Clinical & Experimental Rheumatology 2008 26: 317-323
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.
Further reading
Whittle & Hughes Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review . Rheumatology 2004 43 : 267 - 271.
Prey S, Paul C Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review. British Journal of Dermatology 2008 Oct 20. [Epub ahead of print]
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. Overall with doses used currently about 55% of people will obtain an ACR50 response to MTX and 35% an ACR70 response i.e. 50% and 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 sulphasalazine 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. One recent study showed that if someone had a poor response to MTX, there was only a limited chance of them responding well to an alternative DMARD.
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, sulphasalazine (SSZ) and hydroxychloroquine (OHC); MTX + SSZ; MTX + OHC, and MTX + leflunomide. The use of such combinations can be particularly useful when it is not possible to use TNF-α inhibitors 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 + OHC 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.
Further reading
Van der Kooij et al. Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score. Annals of the Rheumatic Diseases 2008 66: 1356
Choi et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002 359: 1173-1177
Choy et al. A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology 2005 44 : 1414 – 1421
Makinen et al. Sustained remission and reduced radiographic progression with combination disease modifying antirheumatic drugs in early rheumatoid arthritis. Journal of Rheumatology 2007 34: 316-321
Verschureren et al. Daily practice effectiveness of a step-down treatment in comparison with a tight step-up for early rheumatoid arthritis. Rheumatology 2008 47: 59-64
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. It has a similar effect to leflunomide, sulphasalazine and cyclosporine, but is less effective than TNF-α inhibitors.
Further reading
Pincus et al. Evidence from clinical trials and long-term observational studies that disease-modifying anti-rheumatic drugs slow radiographic progression in rheumatoid arthritis: updating a 1983 review. Rheumatology 2002, 41:1346-1356
Use of MTX in combination with TNF-α inhibitors
TNF-α inhibitors are biological agents which neutralise the effect of TNF-α, a pro-inflammatory agent which plays a major role in causing inflammation in RA. There are currently three agents licensed in the UK for the treatment of RA: infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira). In many studies in people with an incomplete 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 single agents 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 MTX, sulphasalazine and other DMARDs either sequentially as single agents (Group 1) or in combination (Group 2); MTX combined with sulphasalazine, hydroxychloroquine and steroids, initially in high dose (Group 3); or high-dose MTX plus infliximab (Group 4). 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.
Further reading
van der Heijde et al. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 2006 54: 1063-1074
Emery et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET) Lancet 2008 372: 375-382
Breedveld et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006 54: 26-37
Weinblatt et al. Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis : ARMADA 4 year extended study. Ann Rheum Dis 2006 65: 753-759
Goekoop-Ruiterman et al. Clinical and Radiographic Outcomes of Four Different Treatment Strategies in Patients With Early Rheumatoid Arthritis (the BeSt Study): A Randomized, Controlled Trial. Arthritis & Rheumatism 2005 52: 3381-3390
Use with other biological agents
Rituximab (Mabthera), abatacept (Orencia) and tocilizumab are biological agents which have different modes of action to TNF-α inhibitors. Rituximab targets the CD20 molecule on 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 at least one TNF-α inhibitor.
Abatacept modulates the interaction of CD80 or CD86 with CD28: a costimulation signal required for full activation of T lymphocytes. It is usually given with MTX and can be effective even in people who have not responded to TNF-α inhibitors. Although it has a product licence for the treatment of RA in the UK NICE has unfortunately ruled against its use in the NHS and so it is rarely used here.
Tocilizumab is another biological agent which prevents the pro-inflammatory cytokine IL-6 from activating its receptor. It is likely to be licensed in the UK in the near future, although access to it is likely to be restricted until it has been evaluated by NICE.
Further reading
Emery et al. The Efficacy and safety of Rituximab in patients with active rheumatoid arthritis despite methotrexate treatment . Arthritis & Rheumatism 2006 54: 1390-1400
Kremer et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis. Annals of Internal Medicine 2006 144: 865-876
Smolen et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008 371: 987-997
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 pronounced 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.
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 above 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 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 women 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 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 NSAID as their joint stiffness is not relieved by ordinary pain-killers, 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?
People on MTX should have flu vaccine each year.
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
http://www.rheumatoid.org.uk/article.php?article_id=553
What tests are recommended for people on MTX?
The British Society for Rheumatology 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
http://rheumatology.oxfordjournals.org/cgi/data/kel216a/DC1/1
National Patient Safety Agency guidance on 'Improving Compliance with Oral Methotrexate'
http://www.npsa.nhs.uk/nrls/alerts-and-directives/alerts/oral-methotrexate/
ARC methotrexate drug information sheet
http://www.arc.org.uk/arthinfo/patpubs/6247/6247.asp
Original article: 01/08/2006
Reviewed: 01/12/2008
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