Leflunomide

Author: Prof. Dr. med. Peter Altmeyer

Last updated on: 29.10.2020

Definition
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Drug from the group of immunosuppressive drugs; used as a basic therapeutic agent (disease modifying antirheumatic drug, DMARD) in the treatment of rheumatoid arthritis and psoriasis arthropathica (psoriatic arthritis).

Pharmacodynamics (Effect)
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The active metabolite inhibits, among other things, dihydroorotate dehydrogenase, a key enzyme in pyrimidine synthesis and thus nucleic acid biosynthesis. Pyrimidine is a nucleotide that plays a role in cell division. It is produced in the body in two different ways:

In the so-called "salvage pathway" metabolism
Through the "de novo synthesis".

Pyrimidine is mainly synthesized on the alternate metabolism. However, some cells, including activated lymphocytes, prefer to use de novo synthesis. Leflunomid prevents the de novo synthesis of pyrimidine and thus blocks the proliferation of activated lymphocytes. Over time, not enough activated lymphocytes are available to maintain chronic inflammatory processes. This interrupts the disease process at a crucial point. Leflunomide and its active metabolites are excreted via stool and urine.

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Indication
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Approved for the treatment of rheumatoid arthritis (Europe and USA).
Approved for the treatment of psoriatic arthropathica (psoriatic arthritis) (Europe).
Results of clinical studies suggest that Leflunomide may also be used in Wegener's disease and systemic lupus erythematosus under certain circumstances.
Own observations show good efficacy of Leflunomide in patients with seronegative spondarthritis. However, there are no large, systematic studies available that go beyond the observation of individual cases.

Limited indication
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Psoriasis vulgaris ( off-label use); however, there is little clinical data available on this.

Pregnancy/nursing period
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Cave! Leflunomide must not be prescribed during pregnancy (teratogenic effect on fetuses) and lactation (passes into breast milk).

Remember! Women of child-bearing age must use reliable contraception protection during treatment with Leflunomid and for a waiting period of about 2 years after discontinuation!

Remember! Men should also use reliable contraception during treatment with Leflunomid to avoid any risk to the fetus.

Dosage and method of use
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Saturation of the level: Initial 100 mg/day p.o. for 3 days. From day 4: once/day 20 mg p.o. In case of side effects, reduce the dose to 10 mg/day (although in these cases the effectiveness is also reduced).

Undesirable effects
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Integument: Erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, rarely allergies. Often effluvium at the beginning of the therapy. Overall, dermatological side effects are described in about 2% of patients.
Extracutaneous: increase in blood pressure (RR?controls!). Blood count changes (lymphopenia); rarely nephrogenic and hepatogenic NW. Reversible reductions in sperm count and sperm motility. Diarrhoea, constipation, nausea, also nausea.

Interactions
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Simultaneous treatment with other basic therapeutics (e.g. methotrexate, chloroquine etc.) should be carried out under strict conditions. The (highly effective) combination of leflunomide/methotrexate can increase the risk of serious liver damage (e.g. granulomatous hepatitis).

Contraindication
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patients < 18 years.
Men who do not practice safe contraception or whose partners do not practice safe contraception. Men with a desire to procreate.
Pregnancy, nursing.
Hypersensitivity to the active substance Leflunomide or another component of the drug, severe immune defects (e.g. HIV infection), significantly restricted bone marrow function or severe disorders of blood formation (e.g. severe anaemia).
Severe infections, impaired liver function, moderate to severe impairment of kidney function.

Preparations
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Arava film-coated tablets

Note(s)
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Remember! Clinical effect occurs on average after 14 days.

Literature
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Cuchacovich M et al (2002) Leflunomide decreases joint erosions and induces reparative changes in a patient with psoriatic arthritis. Ann Rheum Dis 61: 942-943
Jakob A et al (2005) Skin ulceration after leflunomide treatment in two patients with rheumatoid arthritis. J Dtsch Dermatol Ges 4: 324-327
Pipitone N et al (2003) Current concepts and new developments in the treatment of psoriatic arthritis. Rheumatology (Oxford) 42: 1138-1148
Reich K et al (2002) Treatment of severe psoriasis and psoriatic arthritis with leflunomide. Br J Dermatol 146: 335-336
Wozel G, Pfeiffer C (2002) Leflunomide--a new drug for pharmacological immunomodulation. dermatologist 53: 309-315