Arava / Leflunomide                             by drdoc on-line

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DNA physiology

Action and dosing


Special warnings

The genetic makeup of humans and animals, consist of DNA, within the nucleus of a cell. From this comes the code that is interpreted and then converted into protein production and building of cells and tissues.

Leflunomide, like Methotrexate is one of several types of therapies that interfere with cell turnover. Methotrexate interferes with an enzyme called dihydrofolate reductase, whilst leflunomide interferes with an enzyme called dihydroorotate dehydrogenase. This results in inhibition of synthesis of Pyrimidines - key components of DNA.

The DNA molecules constitute the foundation of genes. It consists of chains of four Nucleic acid bases, known as Purines, (Guanosine and Adenosine), and Pyrimidines, (Cytosine and Thymidine), The molecule, a double helix structure unwinds and  is "transcribed" to form an exact copy of the gene - messenger RNA, which is then "translated" to sequences of amino acids which unite to form proteins. The protein then undergoes post translational modification, with three dimensional changes induced by cross linking of molecules. Defects in the process results in disease. 

The abnormality of the gene sequence is called mutation. This can be due to single or multiple deletions or insertions of nucleotide bases, disrupting the normal coding sequence. Sometimes several segments of the DNA are moved to other areas, a process called translocation. Such mutations develop with successive division of the cells, and may be serious or non significant. Significance depends on the site of the change rather than simply the size of the change, as a mutation of even one nucleic acid in a critical place can produce serious consequences.

The faster cells divide, the greater the turnover of the genetic molecules, and the more susceptible they are to disruption. Some organs have a turnover of cells including the cells lining the bowel wall, the bone marrow - blood forming cells, the skin and hair cells and the germinal cells or the ovary and testis. Other organs have a very slow turnover, for example brain, and neurological cells and muscle and fat cells. Therefore the fast turnover cells are susceptible to damage in any interference with the nuclear division process.

Interference with cell division and turnover can be used therapeutically in several circumstances. The commonest example of therapeutic application is in treatment of malignancy. In malignancy, the cancer cells are dividing rapidly, and stopping or slowing of the turnover, results in shrinkage or suspension of tumor growth and proliferation. 

The next commonest therapeutic application is in therapy of inflammatory disease, where white cells are produced in a rapid response to inflammation or infection. 

The Rheumatic diseases are the most typical example of autoimmune inflammatory disease, where the body fights itself in an ongoing destructive manner causing disease. The interference with cell turnover is one way to reduce the inflammation at source and not merely as a symptomatic therapy.

If we reduce cell turnover, both good and bad effects are produced as the division of normal cell turnover may also be disrupted. Therefore we need to check that no damage is done to certain organs - especially bone marrow which makes our blood cells, gastrointestinal mucosa and germinal cells of the ovary and testis. Genetic abnormality can hence result with use of drugs that interfere with cell division when used during formation of sex cells and in pregnancy with development of the fetus in-utero.

Leflunomide has several actions as a result of its inhibition of Pyrimidine formation. In fact the drug is metabolized to it's active form -known as A77-1726. It is then extensively protein bound. Excretion of A77 1726 occurs approximately 43% in urine, 48% in feces. There is no food interaction.
It has a half life of 2 weeks, and hence remains in the body a long time after each administration. A starting loading dose of 100 mg daily for 3 days is needed to rapidly reach a steady drug level. Thereafter, a maintenance dose of 20 mg/day is used. If it is essential to remove drug rapidly from the body due to side effect, the elimination can be hastened by using cholestyramine or activated charcoal. 

The drug inhibits lymphocyte proliferation, and reduces chemicals called adhesion molecules which allow the immune cells to home in to the area of inflammation. As a result the immune process is slowed. The drug inhibits the clonal expansion of the activated lymphocyte population.

The drug is tested in multiple trials over the past 5 years and has been launched in the USA and European union. Caution regarding side effects especially the liver require monitoring by a specialist and this is detailed below. There is no doubt that there is a place for the drug in the management of Rheumatoid arthritis, and trials are well underway in the management of other arthritis groups especially spondyloarthropathy. Trials are also in progress as combination therapy with other disease modifying therapies.

Assessment of improvement is measured in several ways:
Joint counts
Patient assessments
Physician assessments
Functional scores especially the SF36 and the HAQ health assessment questionnaire scoring systems.

The responders were assessed for the American College of Rheumatology Criteria for minimal 20% response - ACR 20, Minimal 50% response - ACR 50 and Minimal 70% response - ACR 70.

Xray assessments especially using sharp and Larsen scoring was also assessed.

Studies were performed in patients compared to placebo, methotrexate and sulphasalazine over 24-48 months

Results show no statistical difference in response between Methotrexate and Leflunomide. Both are vastly superior to placebo. Response starts at within 3 - 12 weeks.

All indices showed improvement - including patient and physician global assessments, and joint swelling scores as well as tender scores. ACR improvement criteria also were similar to methotrexate. A very notable finding however is the reduction in erosion scores and retardation of radiological progression

In addition, there is a reduction in inflammatory markers of inflammation - the ESR and the CRP. These are used by Rheumatologists as markers of disease activity.

Mechanism of Action of Leflunomide


Structure of Leflunomide





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Criteria for achieving an ACR 20/50/70% response

Include the following:

20/50/70% improvement in tender joint count
20/50/70% improvement in swollen joint count


20/50/70% improvement in 3 of the following 5 criteria:

Patient pain assessment
Patient global assessment
Physician global assessment
Patient self-assessed disability
Acute phase reactant  (ESR or CRP)

The joints should be meticulously examined and a total
 of swollen joints are assessed by the examiner

Measurements of Quality of life

Measurements of Quality of life


XRAY assessment

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The toxicity profile that is of most concern is that of bone marrow effect, with reduction in white cell count, the platelets and the haemoglobin. The second major concern is that of liver dysfunction. There are reports of liver failure, but these are rare, and the incidence must be taken in the context of the severity of the disease in terms of risk-benefit ratio. Rheumatoid arthritis is a SEVERE disease, and use of Leflunomide versus potential benefit must be weighed up by the consulting physician. Of clear importance therefore, is the requirement for the understanding of the Physician and patient for the potential risks. Monitoring of the blood count and liver function is VERY important. Therefore it is recommended that this is done, at baseline, and 2 weekly intervals for 2 months then monthly for 2 months then  2 monthly.

Pregnancy information

ARAVA / Leflunomide CANNOT be use in pregnancy and is potentially highly teratogenic - toxic to the fetus. Before using ensure that the patient is not pregnant and not planning on becoming pregnant. CONTRACEPTION is mandatory if of childbearing potential. If a couple decide to become pregnant there is a specific method of drug elimination including taking cholestyramine to eliminate the drug and to measure drug levels before pregnancy would become safely possible This applies to the male and the female patient.

Side Effects of Leflunomide LF versus Methotrexate MTX and Placebo PL 
Strand et al. 1999 Arch Intern Med 159:2542
Description Leflunomide % MTX % PL %
Diarrhea 27 9 13
Liver test elevations 15 3 11
Headache 12 7 13
Alopecia 10 1 6
Rash 11 6 4
Abdominal pain 4 5 5
Hypertension 4 3 1
New-onset hypertension 2 0 2
Mouth ulcer 5 5 8

Liver function intervention

If ALT / SGPT values repetitively > 2 x upper normal  dose reduction to 10 mg/day  / discontinuation

If ALT / SGPT values repetitively > 3 x upper normal


In Summary - Arava shows

Reduction in signs and symptoms of RA 
Effectiveness in early and late RA 
Demonstration of an early and sustained response 
Improvement in functional ability and quality of life
Slowing of radiographic disease progression 
Offer of additional efficacy in combination with methotrexate
A satisfactory safety profile when monitored correctly

CONTRACEPTION is mandatory

Monitoring of blood count and liver function tests are mandatory



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April 2002