Arava (leflunomide) is a cytotoxic, a so-called cell-killing medicine, marketed by Sanofi and approved by the U.S. Food and Drug Administration (FDA) for treating rheumatoid arthritis.

Leflunomide, the active ingredient of Arava, also is being researched as a steroid-sparing alternative for the treatment of sarcoidosis, especially for disease affecting the eyes or lungs. The corticosteroid medication prednisone and the cytotoxic agent methotrexate are the most common treatment options for sarcoidosis patients. The concern with those medications, however, is that many patients do not tolerate or respond to them well.

How Arava works

Arava inhibits an enzyme called dihydroorotate dehydrogenase (DHODH) that is involved in pyrimidine synthesis. Pyrimidines are building blocks of DNA, and of its chemically-related cousin RNA.

Sarcoid granulomas mainly consist of lymphocytes, a type of immune cell. These cells multiply at a high rate, so they depend heavily on de-novo pyrimidine synthesis. Other cell types can cover their pyrimidine need through a salvage pathway. Already used pyrimidines are broken down into intermediate precursor molecules, and then recycled to build new pyrimidines. For this reason, lymphocytes are the main cell types affected by Arava.

Arava in clinical trials

Leflunomide has not been tested in randomized clinical trials for the treatment of sarcoidosis, but a few small studies suggest that sarcoidosis patients may benefit from this medication.

One study retrospectively looked at 32 sarcoidosis patients, most commonly with pulmonary or ocular disease, who had received leflunomide. Twelve of 17 patients treated with leflunomide alone, and 13 of 15 patients treated with leflunomide plus methotrexate, showed a complete or partial response.

Another retrospective study looked at 76 patients with pulmonary and extra-pulmonary sarcoidosis who had received leflunomide treatment. Prior to treatment start, 76 percent of the patients had received corticosteroids by mouth, and 86 percent had received non-steroid immunosuppressive medication. The main reasons for starting leflunomide treatment were an insufficient response to prior therapy (in 79 percent of cases) and toxicity from previous therapy (in 17 percent of cases).

In patients with pulmonary sarcoidosis, the mean forced vital capacity (FVC) and the mean diffusing capacity for carbon monoxide (DLCO), both parameters of lung function, improved. In patients with extra-pulmonary sarcoidosis (mostly affecting the skin, eyes, and nasal sinuses), 51 percent had a complete response, and 32 percent had a partial response.

More information about Arava

The most common side effect of Arava is diarrhea. Further side effects include nausea, stomach pain, and hair loss, which are less common.

As a cytotoxic medication that suppresses the immune system, Arava increases susceptibility to infections.

Arava also is toxic to the liver. Elevated liver enzymes, a sign of inflamed or damaged liver, is a common side-effect. Patients with liver disease or hepatitis B or C infection should not be considered for Arava therapy.

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