GLASGOW, SCOTLAND — A proprietary formulation of fumaric acid esters has proved, during decades of use in Germany, to be a useful option for some patients with severe, recalcitrant psoriasis.
Although the therapy is less than perfect—with gastrointestinal side effects, slow onset of effect, and a 10% incidence of lymphocytopenia—it can be very effective in some patients, Catherine Smith, M.D., said at the annual meeting of the British Association of Dermatologists.
Since 2002, Dr. Smith and her colleagues at the St. John's Institute of Dermatology, London, have enrolled 62 patients with severe psoriasis that did not respond to standard therapies into an open study of Fumaderm, the German formulation of fumaric acid esters.
For this group of patients, treatment duration ranged from 4 weeks to 3 years, and 24 patients discontinued treatment, generally because of lack of efficacy. Although results at 16 weeks' follow-up for the remaining patients have been mixed, with 38% showing no improvement or worsening, a small subset (8%) had substantial improvement. “Importantly, these patients with very severe disease had a greater than 50% improvement compared to baseline,” Dr. Smith said.
It generally takes 4–6 weeks before clinical effects are seen, and many patients have difficulty tolerating the drug. Gastrointestinal side effects, most commonly diarrhea, are seen in more than two-thirds. The reason for these gastrointestinal disturbances is not clear but may be related to the current formulation, which is a mixture of several different fumaric acid esters and is licensed only in Germany, Dr. Smith said. A new microtablet formulation that consists solely of dimethyl fumarate has now been through phase II studies and is expected to be licensed in the United Kingdom, she said. This formulation, currently known as BG-12, is said to be associated with fewer adverse effects.
The other most common side effect of fumarates is flushing or redness, described by some patients as tingling or skin pain. Lymphocytopenia is also fairly common but resolves on cessation of treatment. Eosinophilia is seen in 50% of patients between weeks 4 and 8 of treatment, but this has not been associated with any clinical allergic responses.
Case reports of renal failure were published during the early 1980s, but these incidents were in patients on very high dosages of the drug, and no subsequent cases have been reported, Dr. Smith said.
No notable long-term toxicities have been seen. Unlike with other systemic therapies for psoriasis, there has been no association with malignancy, she said.
While Fumaderm is more costly than some older therapies, its price tag is half that of infliximab.
Fumaric acid esters were first used in 1959 by German chemist Walter Schweckendiek, who undertook an “n of one” study on himself because his severe psoriasis had not responded to the available therapies. At the time, it was thought that psoriasis resulted from a defect in metabolism. He postulated that because fumaric acid is involved in the tricarboxylic acid cycle and is therefore fundamental to cellular respiration, exogenous administration of the drug would be beneficial. He reported that his skin began to improve within 12 hours and cleared completely in 10 days (Med. Monatschr. 1959;13:103–4).
“As a consequence, use of fumaric acid esters mushroomed in Germany, and today accounts for 66% of prescriptions for severe psoriasis in that country,” Dr. Smith said.