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Fumaric acid esters (FAE)

Fumaric acid esters are marketed in Germany and constitute a mixture of dimethylfumarate  and calcium,  magnesium, and zinc salts of monoethyl hydrogen fumarate.   As such it has to be imported and used on a named patient basis in the UK, which renders this a more expensive therapy than ciclosporine or methotrexate. It is presented as 2 strengths initial and high strength which are gradually increased within the patients¡¯ tolerance according to the schedule summarised in the table. Dimethylfumarate (DMF), the main ingredient of the marketed mixture, is the active compound and is now demonstrated as efficacious in a phase III multicentre trial. Although not yet commercially available this single compound has fewer side effects and will be more readily licensed as a single entity drug.

Fumarates are thought to work by shifting a Th1-type cytokine response to a Th2-type pattern whereby IL-10 inhibits Th1 cytokines IL-2 , IL-12 and IFN gamma and by inhibiting translocation of nuclear factor kappa B (NF-kB).  

Patients tolerating the therapy can expect a 75% reduction in PASI in 4 months. However, all studies of the mixture of esters have a high dropout rate due to gastrointestinal complaints diarrhoea, stomach cramps and tenesmus that occur in up to 60% of patients and flushing in 30% of patients, which is worse at the onset of therapy. Headaches may be associated with sudden flushing. The frequency of flushing is greatest at the onset of therapy and decreases with prolonged treatment time. Both adverse events lead to drug withdrawal in about 7% of patients

Laboratory monitoring is required monthly particularly for lymphopenia (less than 20% of white cells) in 75% of patients is usually mild and plateaus. Transient eosinophilia is observed in 14-25% and lymphocytopenia was observed in 76%. Liver enzymes are frequently raised (25% of patients) and reverse on stopping therapy, raised cholesterol (17%), increase in triglycerides (8%), raised serum potassium (15%) and increase in serum creatinine (4%) and although proteinuria (11%) may occur there is no evidence of significant nephrotoxicity as seen with ciclosporin. There are no reports of severe long-term toxicity or development of cancer or a higher susceptibility for bacterial infections, thus making FAE a safe regimen, compared to other agents

Number of tablets of fumaric acid esters to be taken for treatment of psoriasis

A, low strength; B, high strength  

A reduction in FAE dose is required in the following situations: decrease in leucocyte count to below 3.0 ¡Á 10⁹/L; decrease in lymphocytes to below 0.5 ¡Á 10⁹/L; persistent eosinophilia ¡Ý 25%; rise in serum creatinine 30% above baseline; development of proteinuria. If the abnormal parameter improves, treatment with FAEs can be continued at a reduced dose. In case of a persistent abnormality or a further deterioration, FAEs must be withdrawn.

 References

J.J. Hoefnagel, H.B. Thio, R. Willemze, J.N. Bouwes Bavinck Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. British Journal of Dermatology Volume 149, Issue 2, Page 363-369, Aug 2003

Mrowietz, Christophers, Altmeyer For The German Fumaric Acid Ester Consensus Conference Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. British Journal of Dermatology Volume 141, Issue 3, Page 424-429, Sep 1999

This information forms part of the current BAD guidance document for the general management of psoriasis.  Other section in the document comprise: