Getting Established on DMARD Therapy

Dr Raashid Luqmani DM FRCP FRCP(E), Consultant Rheumatologist/Senior Lecturer
Rheumatology Department, Nuffield Orthopaedic Centre, Oxford
Original article: 02/06/2006
Reviewed: 23/12/2008
Next review due: 23/12/2010

Once a patient is diagnosed as having rheumatoid arthritis, it can come as quite a shock for many people and be very bewildering. Many people have heard of arthritis but few of them understand what it means to have rheumatoid arthritis. There are lots of opinions about what treatment should be offered and the internet provides a wealth of information. However much of it is misleading and not based on sound scientific principles. Rumours about the potential hazards or benefits of individual treatments can be quite frightening and may have an undue influence on decisions to start or not start certain treatments.

It’s very important to understand that rheumatoid arthritis is a destructive process which, if left unchecked, will cause irreversible damage to joints in the majority of patients. It is also important to understand that this disease does not have a clear cause and this is true for many diseases that are termed ‘chronic’.

As soon as the diagnosis of arthritis is made, it is likely that DMARD therapy will be discussed. ‘DMARD’ stands for Disease Modifying Anti-Rheumatic Drugs. There is a range of drugs in this group and they have an effect on the underlying disease process. They are all capable of damping down the immune system to a greater or lesser extent. We don’t fully understand the way in which they work; many DMARD therapies were originally used for other diseases and were adapted for use in rheumatology because they were found to be effective for the treatment of rheumatoid arthritis.

In the last 15 years there has been considerable development of drug therapies which have been designed specifically for use in rheumatoid arthritis. However, we must regard all members of this group of DMARDs as being potentially useful for an individual patient, either alone or increasingly in combination. It would be a great shame to miss out on a drug which might be very helpful for a patient just because it’s old and, equally, some of the very new drugs may offer potential benefit for patients and just because they are very new doesn’t necessarily mean they are untested. All drugs go through rigorous testing before they are available for routine patient care.

The table below lists the available DMARD therapies and contains a brief description of each one.

Table 1

DMARD	TYPICAL DOSES	COMMENT
Methotrexate	Varies between 7.5-25 mg/week	This drug has been available for over 30 years and was originally established for use in cancer treatment and is still used for that purpose. However at very small doses it can be very effective for the treatment of rheumatoid arthritis and childhood forms of arthritis. It is probably the most effective drug for rheumatoid arthritis we currently have and is typically first or second choice DMARD treatment. It acts by suppressing the immune system and can slow down the progress of arthritis as well as making significant improvements in general wellbeing by reducing the inflammation.
Sulfasalazine	Between 1.5 and  3 grams per day (40mg/kg/day)	Sulfasalazine has been available since the 1940s and it is a combination drug containing an anti-inflammatory compound and an antibiotic. It is unclear how it works but it clearly does work for a large number of patients with arthritis. It is also used for the treatment of inflammation of the bowel. Like methotrexate it can damp down the immune system and ongoing monitoring is required for both these drugs.
Leflunomide	10-20 mg/day	Leflunomide is a relatively new agent introduced specifically for treating rheumatoid arthritis within the last 10 years. It has a particular effect on the lymphocytes which are the main cells involved in the arthritis process. It is likely to regulate the immune system by damping down the overactive lymphocytes but like other drugs it does have other side effects and therefore monitoring of blood count and liver function is necessary. Leflunomide may also cause high blood pressure and occasionally cause diarrhoea.
Azathioprine	Typically 2-2.5mg/kg/day	Azathioprine is a cytotoxic drug which is very widely used for damping down the immune system. It slows down the rate at which cells divide and the aim is to slow down the rate of cell division amongst the inflammatory cells. Typical side effects would include sickness and diarrhoea. It can lower the white cell count and platelet count, making you more prone to bruising, bleeding and infection.
Penicillamine	500-1000mg/day	Penicillamine is a very old drug for treatment of rheumatoid arthritis. Its mechanism of action is uncertain: it seems to damp down the immune system in a non-specific way. It must be taken as a single dose away from food because otherwise it binds food and does not get absorbed into your body and therefore won’t do you any good. It can have a number of side effects including sickness and diarrhoea, it can also cause skin rashes. Blood testing is necessary with blood count, and urine testing in case it has caused a small leak of protein through the kidney.
Injectable Gold	50mg/week- 50mg/month	Injectable Gold has been around since about the 1920s and was originally introduced as a way of treating what was thought to be an infectious cause of arthritis. Since then it has been shown that gold is not a good anti-infection drug and that arthritis is not caused by infection. Nevertheless the drug does seem to have some value when given over a long period of time by repeated injection. Like other non-specific DMARDs it damps down the immune system and seems to calm down arthritis. It has a number of side effects similar to penicillamine: it can cause skin rashes, nausea and diarrhoea. Blood testing is necessary to look for any reduction in the cell count and a urine check is required to look for any evidence of a protein leak through the kidney.
Hydroxy-chloroquine	6.5mg/kg/day, typically 200-400 mg/day	Hydroxychloroquine is a treatment for malaria but has been shown to damp down the immune system in a non-specific way. It is used widely for the treatment of lupus (SLE) but is also an established drug for the treatment of mild rheumatoid arthritis. The main side effect is of accumulation of the drug in the back of the eye if too much is given over too long a period of time. This can cause an interference with night-time vision and should be discussed carefully with your doctor before starting the treatment. If you have had a previous problem with your eyesight it may be best to see an eye specialist prior to starting treatment. No blood tests are required whilst receiving hydroxychloroquine.
Ciclosporin	2.5-4mg/kg/day in 2 divided doses	Ciclosporin is an established treatment to suppress the immune system in patients who are about to undergo kidney or heart transplant. Its effects on the immune system have been used for the treatment of patients with rheumatoid arthritis and it does seem to have an influence on the activity of the arthritis. Common side effects include a rise in blood pressure, increased hairiness, increased swelling of the gums and increased tendency to infection. There is also a risk of kidney disease on the drug including high blood pressure and interference with kidney function. The drug has to be monitored carefully, checking blood pressure and checking bloods regularly.
Etanercept	Typically 50mg/week,   either as a single injection (subcutaneous)    or as 2 injections on separate days  of 25mg each	Etanercept is one of the newer anti-TNF treatments. It is a receptor protein which binds to TNF (tumour necrosis factor) which is one of the most important inflammatory chemicals produced in patients with arthritis. TNF is important for normal health and it is not a good idea to block all TNF in the body, otherwise patients are at risk of infection. Etanercept is usually well tolerated, sometimes patients can experience a local reaction at the injection site of skin redness and soreness. This can be avoided in most instances by varying the site of the injection on each occasion over a cycle of 4-5 weeks (eg inject the outer side of the left thigh on the first week, the inner side of the left thigh on the second week etc). Most patients can give themselves their injections. No routine monitoring is required whilst on this drug but all patients should be attending hospital regularly for review.
Infliximab	Typically 3 mg/kg intravenous  infusion every 8 weeks	Infliximab was the first anti-TNF treatment to be established in rheumatoid arthritis. It has to be given by hospital doctors and nurses to ensure safety precautions are adhered to. It is used very widely for rheumatoid arthritis and directly blocks TNF by binding the normal TNF receptors instead of TNF. Too much reduction of TNF activity is harmful and may lead to susceptibility to infection, particularly tuberculosis. No specific blood tests are required but all patients should be under regular hospital review. Initial doses of infliximab are given more frequently to establish good control of the disease (the first 3 doses are all given within an 8 week period).
Adalimumab	Typically 40 mg every 2 weeks given by subcutaneous injection	Adalimumab is the newest of the anti-TNF drugs. It blocks the effects of TNF and like other anti-TNF drugs it has the potential to cause infection by suppressing too much TNF. All patients who are on this treatment must be under regular review by the hospital.
Rituximab	1g on 2 occasions 14 days apart,   then repeat after at least 6 months if effective	Rituximab is a treatment designed to attack B-cells, which are an important part of the immune system involved in rheumatoid arthritis. Rituximab is currently offered to patients who fail to improve with anti TNF therapy. It has a 50% chance of being extremely effective, and appears to be relatively safe.

How do I know which drug to use?

Your rheumatology specialist will give you advice on the drugs and will probably concentrate on methotrexate or sulfasalazine as the main first line agents. That is because there is most experience with these drugs and they have been shown to be the most effective of the list available to you. Your rheumatologist will explain both the advantages and the disadvantages and normally provide written advice which summarises this information. Specific information leaflets are available on these drugs from the Arthritis Research Campaign website http://www.arc.org.uk. Although much of the information you will be getting details the possible side effects of the drug, please remember that the main reason for being recommended these treatments is that you have arthritis and that it is a cause of significant pain and may cause disability and damage to your joints in the long term. It is sometimes difficult to remember the balance of good against bad when looking at the long list of potential side effects. Please remember that the disease itself has its own ‘side effects’ and unfortunately they are usually much more unpleasant than any of the drug therapies which may be used to try and damp down the disease.

Usually more than one drug will be recommended at the start of your treatment in the hope that two drugs together will achieve a more effective damping down of the disease. Most studies show that combination DMARD therapy is superior to single DMARD therapy. Despite the concern that many patients would naturally have that using two drugs is going to cause more side effects, in fact there is good evidence that this is not the case. This is probably due to the fact that you only need to use relatively low doses of each individual drug. However, should those drugs fail to achieve all that they should achieve, it is common practice to add yet another drug to help the first drugs to work better. Combinations of virtually all of the drugs in the list shown in Table 1 have been used successfully together and have shown to be helpful for many patients with arthritis.

When you first start taking a DMARD, it is important to remember that it can take up to 12 weeks before you start feeling any improvement from taking the drug. This is because these drugs take some time to get into the body and be absorbed in sufficient quantities to start affecting the joints. The doctor will advise you to continue taking the drug even though you don’t feel it is doing anything for you and you may even be starting to feel some side effects. It is important to remember this because in the long term if you stay on the drug then you are more likely to benefit than if you stop early on. However, if after 3 months, you really don’t feel any improvement from taking the drug it is likely that your doctor will want to either increase the dose, add in another drug or change to another DMARD.

How do DMARDs work?

Many of the older DMARDs were found to be effective in arthritis by trial and error. The theoretical reasons why some drugs might work, such as gold and penicillamine, are probably not the reasons why they actually work. More recent DMARDs, such as leflunomide, were specifically designed to be effective in rheumatoid arthritis by targeting the lymphocytes. Lymphocytes are an important set of cells which are responsible for regulating parts of the immune system. However, in rheumatoid arthritis lymphocyte activity is excessive and is very important in the mechanism of the arthritis. Other DMARDs have an effect on a number of different parts of the immune system and generally reduce the productivity of the cells so that less inflammatory chemicals are being produced. Good examples of these types of drugs are methotrexate, ciclosporin and azathioprine and these have more predictable mechanisms of action. Nevertheless all of the above drugs have been found to be effective in a number of patients with rheumatoid arthritis, regardless of their actual mechanism of action. More specific targeting of the mechanisms of arthritis is increasingly possible. The anti-TNF therapies provide an opportunity to suppress one specific chemical which is of great importance in many patients with rheumatoid arthritis. The targeting of specific cells such as the B cell which makes rheumatoid factor may also provide a further improvement in the battle against rheumatoid arthritis. However these are relatively new compounds and their use has to be carefully regulated to ensure that they are both safe and effective in the long term.

It’s increasingly common for newspapers and magazines to take an interest in arthritis. Stories which suggest that there are major breakthroughs in treatment have to be tempered by the reality that it may not be the correct choice for you. Furthermore, if your condition is responding well to current treatment, there is no evidence to justify changing to the new treatment. It is very unlikely that your rheumatologist would be unaware of developments in treating rheumatoid arthritis. Quite often, what is heralded as “new” in newspapers has been known about for many months, or may refer to new experimental evidence which often takes a few years to reach clinical practice. Patients sometimes feel the need to bring the latest information to their rheumatologist to keep them up to date. This is unnecessary, and may take up valuable time in the consultation which could otherwise be used to help your condition.

How do I know if a DMARD is working?

Remember that all DMARDs take some time to work and you won’t notice a difference for the first three months. It is really important to be patient during this time and your doctor may recommend other measures to provide symptom relief whilst waiting for the DMARD to become effective. There is no special blood test to tell you that the DMARD is working. In general there should be an improvement in the inflammation measures (particularly the CRP). However the best way of knowing if a DMARD is working is whether you feel better. You should be feeling less tired, with less stiffness, especially in the morning and you should notice a reduction in the swelling and tenderness of your joints.

If some of your joints have sustained damage as a result of prolonged arthritis it may not be possible to improve them using a DMARD. If, for example, many of your joints have improved but one has not then that one joint may be treated in a different way from the other joints. For example it might benefit from a local steroid injection or physical help or pain relief. Don’t feel that the DMARD is failing if it just fails to improve one joint whilst managing to improve other joints: that would be regarded as a success for the DMARD. Remember that DMARDs are designed to attack inflammation, they are not painkillers and it is therefore important that you should also be taking painkillers whilst you have pain. Lots of people need to take a DMARD and a painkiller separately and you and your rheumatologist will be able to decide that between yourselves when you are reviewed at clinic. There are some formal ways of measuring response to a DMARD and they will be used for all patients that are being treated with anti-TNF therapy; increasingly we are using the same methods for patients who are being treated with other DMARD therapy. A variety of response measures are available and they all consist of a composite measure including a tender joint count, swollen joint count, a blood test such as an ESR or a CRP and other measures of disease state (such as a visual analogue scale which is assessed by you, describing how you feel on a horizontal 10 cm line varying from very poor health to very good health, by putting a cross through the line nearest your current state).

What happens if a DMARD doesn’t work?

Unfortunately for a minority of patients a DMARD does not work: either it causes side effects which result in your having to stop the drug or it just doesn’t have enough of an effect to improve your arthritis. In these circumstances your rheumatologist will usually recommend either stopping that drug and changing to another one or increasing the dose of that drug, if there has been a partial response, or adding in another drug to help the first DMARD be more effective. Occasionally the side effects which the DMARD is causing may be treated by using another medication for that side effect, for example if the problem is nausea and sickness then it may be possible to successfully continue taking a drug with an anti-sickness pill to help you. This may sound rather complicated to have to take one pill in order to prevent side effects of another pill but in fact it’s very common practice. The reason for wanting to keep you going on the DMARD is the effect that it will ultimately have for protecting your joints from long-term harm and that’s a very important goal to bear in mind. Unfortunately no single drug achieves this goal without help in most cases and therefore you have to be prepared to accept the need for a number of different medicines to keep you in better health.

What happens next?

After the consultation about DMARDs you will have some time to make up your mind as to whether you do want to try this type of treatment and which of the types of treatment you would like to try. Your rheumatologist will often give you advice on what they think might be best for you and in general that is based on very sound experience of your specific condition and your specific circumstances. In most situations it is very easy to make the decision and to go to your GP to get a prescription to start the treatment. If there is doubt then it might be possible to go home and talk through your doubts with your family or friends or with your GP and quite often there is a rheumatology helpline, staffed usually by the rheumatology nurse specialist whom you can call upon for further advice about what to do next. Please bear in mind though that the decision to start a DMARD is a decision to try and prevent long-term harm done to your body by the disease. A lot of people do get worried about the long-term effects of drug treatments but this has to be balanced against the much more severe consequences of having uncontrolled rheumatoid arthritis in the vast majority of patients.

Why do I need blood tests for ongoing monitoring?

All DMARD therapies are capable of harm as well as good and it is important to know whether they are causing harm. Routine blood tests can usually predict the harm and avoid any harm because the blood tests are checked regularly and, should the tests start showing changes that are indicative of abnormalities, the drug can be stopped before any actual harm occurs. For some medicines such as methotrexate, a typical blood test required is a blood count to measure your white cell count level and your platelet count level. These levels should stay above the lower limit of normal indicating that you have enough white cells and platelets to respectively fight against infection and fight against bleeding excessively from minor cuts and bruises since these are the cells involved in these processes. In addition, all patients receiving methotrexate need to have regular checks of their liver function because methotrexate is known to cause a transient and reversible change in your liver enzyme levels. Whilst this might sound alarming, in fact it is very common for methotrexate to do this and so long as the enzyme levels remain within 2-3 times the upper limit of normal there is no cause for concern. If patients are being treated with methotrexate, liver function tests have to be checked at least every 2 weeks for the first couple of months and then every month thereafter. If the tests start to rise above the 2-3 times the top level then it is important for methotrexate to be stopped and for you or your GP to contact a rheumatology team for further advice. The advice may often surprise you because we may indicate that you have to temporarily stop methotrexate but then restart it once your blood tests return to normal again. In addition you may get advice to stop one of your other medications which you have been taking for a long time and which has never caused you problems before. Typically this is the anti-inflammatory drug which you may have been taking before you started the DMARD. This is because combinations of drugs (such as methotrexate and anti-inflammatory drugs) may occasionally cause more problems than individual drugs on their own. This does not mean that you cannot take an anti-inflammatory drug along with methotrexate but should you do so there may be a theoretical problem with your liver function tests, and I think you need to keep an open mind about which drug is doing you the most good compared to what might be doing you some harm. Sometimes it is better to stop taking an anti-inflammatory drug which might be providing short-term relief in order that you can gain long-term relief and benefit from methotrexate.

Why are steroids being suggested?

Very often when you first start taking a DMARD therapy you know that you are going to have to wait 3 months before any improvement occurs. Studies have shown that if you are also treated with a steroid such as prednisolone or methylprednisolone given over a short period of time, ie within that 3 month period, you can improve very rapidly and not suffer any long-term harm from the steroid treatment. Steroids can be given by injection into individual joints where they can achieve significant improvement for up to 3 months at a time, alternatively steroids can be given by injection into muscle and have effects all over the body. It is very common for a rheumatologist to recommend steroid treatment at the beginning of starting DMARD therapy. Steroids can have long-term side effects if given for a prolonged period of time but the plan in most instances is for a short course of steroid, and we would certainly strongly recommend that you follow this advice.

What about my other tablets?

In most instances your other tablets will be reviewed when it comes to starting DMARD therapy and you will be given specific advice if there are any particular precautions to take when starting a DMARD. This is to prevent your having any complications from combining different types of medicines together. On the whole most other medications do not interfere with DMARDs and nor do DMARDs interfere with most other medications but it is always wise to check. In terms of continuing your other medication for helping your arthritis, because of the delayed effect of DMARDs when they first start, it is usually recommended that you continue your pain relief and anti-inflammatory medicines at least for the first 3 months of starting a DMARD, but after that time it may be possible to either reduce or even stop some of your pain medicines and your anti-inflammatory medicines if the DMARD is working very well for you. This is something you should discuss with your rheumatology team.

Conclusion

In conclusion, the introduction of DMARD therapy in the management of rheumatoid arthritis has made a huge difference to improving patients’ lives. You may feel tempted to try delaying the start of these drugs that you might regard as serious and harmful until you feel you really need them. The evidence is quite the reverse in that the earlier you start these treatments the less harm you will come to in the long term because your disease will have been controlled before it has a chance to do you long-term harm. However, you have to remember that all drugs are potentially capable of harm and therefore you have to take appropriate precautions, watching out for side effects and having regular blood tests to monitor your health. The rheumatology team, your GP and you form the basis of your care network to ensure that your disease is minimised so that you can lead as active and pain-free a life as possible.

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