An Introduction to Arava (Leflunomide)

Dr David L Scott, Department of Rheumatology, GKT School of Medicine, Dulwich Hospital
Original article: 16/01/2003
Reviewed: 01/03/2010
Next review due: 01/03/2013

Background

Leflunomide is the only new standard disease-modifying anti-rheumatic drug to be introduced in the last two decades. When it was first produced it was unique in being designed and tested with this goal in mind. It is both effective and safe for a large number of patients.

Disease modifying drugs are used to treat inflammatory arthritis by decreasing joint inflammation. They act slowly – over weeks and months – and used to be called “slow-acting” drugs. However, disease modifying sounds more impressive than slow acting, and therefore the terminology has changed. Reducing joint inflammation also results in improved function and better quality of life. In the long-term it also decreases the progression of joint damage.

Leflunomide is a prodrug. This means it must be changed by patients' own metabolisms into the active drug. This conversion occurs in the stomach and blood soon after the leflunomide is taken.

The effect of leflunomide is due to “switching off” the lymphocytes that are on the point of attacking joints. These lymphocytes are one of the key cells causing inflammation in arthritis.

Long-term effect

Leflunomide has a long half-life. This means that the time taken for its active metabolite to reduce in effect by half is relatively long. This means that once leflunomide has entered the body it remains active for some time. Overall the active metabolite stays in the blood for about 2 weeks. There are benefits and disadvantages from this long half-life. Missing a single dose of leflunomide will not matter very much and as it has a long half-life its effect is stable. However, if patients experience side-effects it can take a long time to remove it from the system.

There are several ways of starting leflunomide. It can be given with a “loading” dose. This means that patients have a high dose for a few days to build the drug up to maximal strength as soon as possible. Alternatively, it can be started slowly at low dose and allowed to gradually build up effect. The trade off is between a rapid onset of action and the least possible side-effects.

Improvements in clinical trials

Leflunomide improves rheumatoid arthritis from around 4-6 weeks and continues to improve up to 4-6 months after starting treatment. It decreases the number of active joints, improves pain, and leads to better overall assessments of disease activity.

Six large clinical trials have established that leflunomide is effective. Four of these trials were original research studies. Two of them were follow up studies of the original research. These trials lasted up for up to 2 years. They involved 206 to 999 patients.

The conventional way to measure improvement is to assess the number of patients who improve by 20% or more on a range of measures of disease activity. Between 50% and 60% of patients improve by this amount when given leflunomide for 6 and 12 months. Without treatment less than 30% would improve in this way. These improvements are similar to those seen with other disease modifying drugs like methotrexate and sulfasalazine.

The number of patients who improve by 50% or 70% or enter remission also increases with leflunomide, though only a minority of patients will show such impressive benefits.

Effects on function, quality of life and erosive damage

Like all disease modifying drugs, leflunomide reduces disability, improves quality of life and reduces erosive damage of joints. These effects persist for 2 years or longer. The effects of leflunomide are comparable to those of methotrexate and sulfasalazine.

Combining with other disease modifying drugs

Leflunomide can be given in combination with other disease modifying drugs. There is limited data about combining leflunomide with most disease modifying drugs. The combination of leflunomide with methotrexate is more controversial. Some experts consider this increases the risk of serious side-effects, particularly liver toxicity. Others think it is safe and effective. Leflunomide can be combined with biologics in place of methotrexate.

Side-effects

Like all drugs used to treat arthritis, leflunomide causes a range of side-effects. Common problems are diarrhoea, nausea and reversible hair loss called alopecia. These are usually “nuisance problems” as opposed to major concerns. However, they can be unpleasant and demoralising and patients sometimes stop treatment because of them.

Rashes, often due to allergic reactions, are commonplace with leflunomide. Leflunomide tends to cause somewhat worse rashes than other disease modifying drugs, and treatment sometimes needs to be stopped due to rashes.

Some patients develop high blood pressure whilst taking leflunomide. It is therefore important to have your blood pressure checked before starting leflunomide and to have it checked from time to time whilst on treatment.

There is an increased risk of chest problems and infections with leflunomide. This is similar to the risks with other disease modifying drugs.

Leflunomide can damage the liver. Special care is needed in patients who drink alcohol or have a history of liver disease. There is debate about the risk of serious liver toxicity with leflunomide but caution is wise. Leflunomide can also reduce the number of white cells in the blood.

Patients who take leflunomide should be monitored for side-effects. This usually involves regular blood checks for blood and liver toxicity.

When patients have severe side-effects with leflunomide they may need to have the drug “washed out” from their body. This is because it is usually cleared slowly on account of its long half life. This involves taking either cholestyramine or activated charcoal for up to 11 days.

Pregnancy

Leflunomide should not be used during pregnancy and women who may become pregnant should not take leflunomide. This is because leflunomide has the potential to damage the unborn child.

As leflunomide can enter breast milk it should also not be taken during breastfeeding.

If a patient receiving leflunomide becomes pregnant the drug should be stopped and washed out immediately.

Other uses for leflunomide

There is no special reason to restrict leflunomide use to the treatment of rheumatoid arthritis. It can be beneficial in treating other auto-immune conditions.

There is good evidence that leflunomide can help people with psoriatic arthritis, and it is approved for treating this condition. It has also been used in other types of seronegative arthritis. It has been given to patients with Felty’s syndrome, which is an unusual complication of rheumatoid arthritis.

There is less evidence about its value in other disorders. It may be helpful in systemic lupus erythematosus.

Conclusions

There is a large and impressive body of evidence which shows that leflunomide is an effective and safe drug for use in patients with rheumatoid arthritis. Common adverse events with leflunomide, including diarrhoea, high blood pressure, weight loss and raised liver function tests, do not seem to result in major clinical problems. Despite these positive findings the use of leflunomide has remained relatively restricted. The reason for this is uncertain, and probably reflects custom and practice rather that evidence-based medicine.

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