Macular Exanthema Due to Fumaric Acid Esters

Case Report

A 68-year-old white woman was admitted to the hospital for treatment of lichen planus that had been persisting for 10 years. She also presented with scarred alopecia, nail dystrophy, and mild infiltrates on both wrists. The oral mucosa was not affected. The papular infiltrates could be partially reduced by steroid creams. Previous systemic treatments included dapsone and chloroquine. These treatments had to be discontinued secondary to methemoglobinemia induced by dapsone and keratopathy with partial color blindness following the treatment with chloroquine.

To modulate the dominant Th1-immune response in lichen planus, therapy with dimethylfumarate 30 mg/d was begun. The patient tolerated the therapy very well during the first 4 days. On day 5, she developed a macular exanthema on her legs 7 hours after she had taken the last tablet, with resolution of the exanthema 7 hours later. Suspecting a flushing reaction with prolonged duration, we decided to continue the therapy. After the next dose, she noticed a macular exanthema on her chest and arms, subsequently spreading to her legs. She also reported pruritus. These symptoms resolved approximately 10 hours later, and the therapy was continued. Again, about 7 hours after drug intake, the exanthema reappeared. As the woman continued therapy for 3 more days, the reaction intensified (Figure 1). No changes of laboratory values, especially no increase in the number of eosinophils, were noted while the exanthema persisted. After the rash had been present for >24 hours, FAE therapy was stopped. The exanthema resolved after 3 days without treatment.

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Figure 1.

Macular exanthema occurring on the neck, trunk, and arms of the patient 7 hours after ingestion of the FAE.

At this point, we suspected that the skin reaction was caused by a mechanism other than flushing. We assumed that FAE may have induced an unusual allergic exanthema. Therefore, we started an allergy workup 2 weeks after clearing of skin lesions. Scratch testing resulted in an intense redness in the patient's test site at the forearm within 15 minutes. A similar reaction was seen in 3 healthy persons tested in parallel as controls. In all 4 persons, scratch testing with histamine was positive and testing with sodium chloride solution was negative. Another oral rechallenge with dimethylfumarate 30 mg produced a macular exanthema 7 hours after the woman had taken the compound, with rash resolution 1 day after a single dose of prednisolone 50 mg and topical betamethasone 0.1% cream.

Discussion

According to the Naranjo ¹⁵ causality assessment, the exanthema that appeared after dimethylfumarate was begun was probably elicited by FAE. The patient had to take valsartan because of arterial hypertension, but this drug was readministered after the exanthema resolved without any adverse effects.

The clinical picture of the adverse reaction is distinct from the well-known flushing often seen with FAE therapy. Flushing usually coincides with the resorption of the compound in the gut and occurs 4–6 hours after administration of the medication. It is accompanied by heat sensations and occasional redness of the face that persists for seconds or sometimes up to 30 minutes. In some cases, itching occurs 4–6 hours after ingestion of the drug. The mechanism of the flushing has not yet been fully elucidated. It is suspected that FAE may cause mast-cell degranulation and release of inflammatory mediators that can induce itching and flushing. ¹⁶ Alternatively, a nonimmunologically mediated contact urticaria has been suggested. ¹⁷ The flushing symptoms can be relieved by acetylsalicylic acid 1000 mg/d. ¹⁸

In our patient, the first signs of exanthema occurred 7 hours after administration of the drug, similar to the common flushing reaction. However, in contrast to the flushing, the macular exanthema persisted for up to 7 hours. A drug-induced rash can be elicited either by allergic mechanisms mediated by immunoglobulin E and specific T lymphocytes or by nonallergic hypersensitivity, pseudoallergy. The latter can be classified as a form of hypersensitivity, where a foreign substance exerts a direct effect on the immune system, resulting in clinical symptoms indistinguishable from allergic disease. ¹⁹ Furthermore, direct interaction of the drug or its metabolites with cells and components of the skin environment can induce adverse reactions.

In our case, the exanthema resembled a type IV reaction. This form of the immunologic response is also called delayed-type hypersensitivity and is mediated by activated T lymphocytes and other effector cells, mainly activated macrophages. It is characterized by a delayed onset of the reaction that can start days after the administration of the drug or antigen.

The scratch skin testing with FAE in our patient and the 3 control individuals resulted in an erythematous reaction at the test site in all 4 persons. This finding correlates with the literature, since De Haan et al. ²⁰ demonstrated the irritating and sensitizing properties of topically applied FAE. FAE and both of their derivatives, dimethylfumarate and monoethylfumarate, have been shown to be moderate contact sensitizers. In contrast to monoethylfumarate, dimethylfumarate can also induce contact-urticarial reactions. ²¹

Summary

We add the description of a prolonged adverse skin reaction to the known spectrum of adverse effects in FAE treatment. It will be important to distinguish the typical flushing reaction from other cutaneous adverse drug reactions resembling flushing because the first allows continuing of the treatment, whereas the latter indicates cessation of FAE therapy.