Dermatology Online Journal

Granuloma annulare disseminatum responding to fumaric acid esters
Uwe Wollina MD
Dermatology Online Journal 14 (12): 12

Department of Dermatology and Allergology, Hospital Dresden-Friedrichstadt, Academic Teaching Hospital of the Technical University of Dresden, Dresden, Germany. Wollina-uw@khdf.de

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Abstract

A 40-year-old man suffered from disseminated granuloma annulare not responding to topical steroids and PUVA-therapy. He was treated with fumaric acid esters and achieved a partial response within 3 weeks, a complete remission after 12 weeks. The literature on fumaric acid esters in granuloma annulare is reviewed.

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Case report

A 40-year-old man presented with a history of suddenly appearing and enlarging papules, disseminated over the body. A skin biopsy revealed typical granuloma annulare. Because he had numerous lesions in various stages the disease was classified as disseminated granuloma annulare. He was treated with topical corticosteroids and bath-PUVA for 3 months without response. Indeed, he observed new lesions on the trunk and arms (Fig. 1).

Figure 1
Figure 1. Typical lesion of granuloma annulare, newly developed despite bath-PUVA and topical steroids

The patient was healthy; there was no history of diabetes nor systemic medications. We decided to start oral treatment with fumaric acid ester (FAE), with Fumaderm initial® (Allmiral-Hermal, Reinbek, Germany). One tablet a day was initiated and this was increased to three per day within 3 weeks. Fumaderm initial® is composed of dimethylfumarate 30 mg, ethylhydrogenfumarate calcium salt 67 mg, magnesium salt 5 mg, and zinc salt 3 mg. After three weeks, because lesions showed partial clearance (Fig. 2), we changed to Fumaderm® tablets and increased the daily dosage from 1 to 2 tablets adding one tablet per week. Fumaderm® is composed of dimethylfumarate 120 mg, ethylhydrogenfumarate calcium salt 87 mg, magnesium salt 5 mg, and zinc salt 3 mg. Regular laboratory controls including complete blood count with differential and kidney function did not show any adverse reaction. The drug was well tolerated.

Figure 2a	Figure 2b
Figure 2a. Initial resolution of granuloma annulare lesions three weeks after initializing FAE therapy Figure 2b. Slightly hyperpigmented annular macular without palpable border after 12 weeks FAE therapy

Discussion

Granuloma annulare is a benign inflammatory papular eruption. About 10 percent of all patients suffer from the disseminated type, as did our patient. Current treatment modalities are based on case series and consensus since randomized controlled studies are missing. In disseminated granuloma annulare, ofte systemic treatment is necessary and agents such as dapsone, antimalarial drugs, isotretinoin, or PUVA-irradiation have been used successfully [1].

Fumaric acid esters have been used for disseminated granuloma annulare since 2001 when Schulze-Dirks and Plewig treated a 64-year-old woman with long standing disease. After 6 weeks they achieved an almost complete clearance [2]. Since then case reports and small series have been published (Table 1).

We achieved a rapid partial response in our patient who had not responded to either PUVA and/or topical corticosteroids. After 12 weeks the clearance was almost complete.

Fumaric acid esters show immunomodulatory activity and affect lymphocytes, dendritic cells, and endothelial cells. In vitro, they inhibit cytokine-induced E-selectin and VCAM-1 and ICAM-1 expression [3]; down-regulate CD62E expression on dermal microvessels [4]; and prevent the nuclear entry of NF-kappa B [5]. These effects are thought to contribute to granuloma resolution in vivo [6].

Adverse effects have been observed in more than 50 percent of reported cases, but are generally mild, transient, and dose-dependent. Nausea, diarrhea, flushing, leukopenia, lymphopenia, eosinophila, and elevation of liver enzyme function tests are the most common. Additional treatment is rarely necessary; most often a dose reduction will be enough. Monthly laboratory monitoring has been recommended during the first half-year of treatment, but later laboratory controls every two months are enough [6].

Fumaric acid esters are a second-line treatment option in granuloma annulare disseminatum. A response may be seen as early as 6 weeks after initiating this treatment but some patients may need a longer period of FAE-therapy. Clinical and laboratory monitoring is necessary.

References

1. Cyr PR. Diagnosis and management of granuloma annulare. Am Fam Physician 2006;74:1729-34. [PubMed]

2. Schulze-Dirks A, Petzoldt D. Granuloma annulare disseminatum: successful therapy with fumaric acid. Hautarzt 2001;52:228-30. [PubMed]

3. Vandermeeren M, Janssens S, Borgers M, Geysen J. Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VACAM-1, and ICAM-1 expression in human endothelial cells. Biochem Biophys Res Commun 1997;234:19-23. [PubMed]

4. Loewe R, Pillinger M, de Martin R, Mrowietz U, Gröger M, Holnthoner W, Wolff K, Wiegrebe W, Jirovsky D, Petzelbauer P. Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-kappa B-dependent manner. J Invest Dermatol 2001;117:1363-8. [PubMed]

5. Loewe R, Holnthoner W, Gröger M, Pillinger M, Gruber F, Mechtcheriakova D, Hofer E, Wolff K, Petzelbauer P. Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells. J Immunol 2002;168:4781-7. [PubMed]

6. Breuer K, Gutzmer R, Völker B, Kapp A, Werfel T. Therapy of non-infectious granulomatous skin diseases with fumaric acid esters. Br J Dermatol 2005;152:1290-5. [PubMed]

7. Kreuter A, Gambichler T, Altmeyer P, Brockmeyer NH. Treatment of disseminated granuloma annulare with fumaric acid esters. BMC Dermatol 2002;2:5. [PubMed]

8. Eberlein-König B, Mempel M, Stahlecker J, Forer I, Ring J, Abeck D. Disseminated granuloma annulare - treatment with fumaric acid esters. Dermatology 2005;210:223-6. [PubMed]

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