Fumaric acid esters: an alternative systemic treatment for psoriasis

M. Ameen and R. Russell-JonesSkin Tumour Unit, St. John’s Institute of Dermatology, London, UK

Summary We report the successful clearance of severe chronic plaque psoriasis following treat-ment with fumaric acid esters (FAE) in two patients who had failed previous systemictherapy. FAE is gaining increasing acceptance for the treatment of psoriasis in countriessuch as Germany and the Netherlands, but at present remains unlicensed in Britain.

Introduction

The chronic nature of psoriasis and its impact on thesocial life and psyche of a patient justifies the need for along-term oral therapy which lacks serious side-effectsand whose efficacy is present after prolonged use. Thefollowing case reports illustrate the important role thatfumaric acid esters (FAE) have played in the treatment ofchronic plaque psoriasis.

Case reports

Case 1

A 58-year-old man with a past medical history of insulindependent diabetes, ischaemic heart disease and hyper-tension, was first diagnosed with psoriasis in 1970. Thiswas widespread – it covered most areas of his body. Healso developed psoriatic arthropathy of the rheumatoidtype affecting several of his joints.

For his psoriasis, the patient has received numeroustopical treatments in conjunction with phototherapy.However dithranol caused burning and tar caused irrita-tion, and he did not respond to PUVA treatment.

Systemic therapy has included courses of methotrex-ate from 1982, which have partially controlled both hispsoriasis and psoriatic arthropathy. He has receivedcourses of etretinate on three occasions, but each time

it has caused marked elevations in his triglycerides upto16 mmol/L (normal range, 0.4–1.9 mmol/L). He hasreceived hydroxyurea twice, but on one occasion thiscaused a decrease in his haemoglobin, and on another hedeveloped a leucocytoclastic vasculitis, a rare althoughwell-recognized complication of treatment with hydro-xyurea. He has also undergone a trial of azathioprineand later mycophenolate mofetil, but showed noresponse to either. Cyclosporin was also tried followinga satisfactory renal EDTA clearance, but this was dis-continued following an increase in both his blood pres-sure and creatinine to 30% above baseline.

Methotrexate had been the only effective treatment,but produced nausea and on two occasions causedelevated liver function test (LFT) results. In July 1998he had 60% skin involvement with thick plaque psoriasis(Fig. 1), and was commenced on FAE (Fumaderm;Fumedica, Germany). He began at a dose of 60 mg o.d.,increasing to a maximum daily total of 360 mg after4 weeks. After 3 months of treatment, he achieved totalclearance (Fig. 2). His dose was therefore reduced to120 mg daily and at follow-up 4 months later his skinhas remained clear. He also notes an improvement in hisnail onychodystrophy, but his arthropathy is unaffected.He has experienced side-effects of abdominal cramps anddiarrhoea, which he has tolerated well. His blood testsshowed an eosinophilia of 2.6 × 109/L (normal range,0–0.4 × 109/L) during the second month of treatment,and he developed a mild lymphopenia of 0.6 × 109/L(normal range, 1.0–4.0 × 109/L) from the third month oftreatment. In 28 years of therapy, during which he hasrequired yearly hospital admissions, FAE has been theonly treatment to have cleared his psoriasis.

Clinical dermatology • Concise report

q 1999 Blackwell Science Ltd • Clinical and Experimental Dermatology, 24, 361–364 361

Correspondence: M. Ameen St John’s Institute of Dermatology, St Thomas’Hospital, London, SE1 7EH, UK.

Accepted for publication 31 March 1999

Case 2

A 45-year-old Asian man with a past medical history ofchildhood polio, chronic duodenal ulcers and alcoholicliver disease, has suffered from severe and chronic plaquepsoriasis for more than 20 years. He has failed to clear onall previous therapy. Topical treatments have includedshort contact dithranol, crude coal tar, topical calcipo-triol and steroids. He has received phototherapy withPUVA and UVB. Because of abnormal LFT, with anelevated alkaline phosphatase of 494 IU/L (normalrange, 38–126 IU/L) and g-glutamyl transferase of196 IU/L (normal range, 10–60 IU/L), he has neverbeen treated with methotrexate. Otherwise systemictreatments have included cyclosporin (but this was dis-continued following a fall in the glomerular filtrationrate to 50% of baseline value) and hydroxyurea (whichresulted in a fall in his haemoglobin). He has toleratedtreatment with acitretin but his psoriasis has shown littleresponse to this. In the last year he has had severaladmissions because of flare-ups of his psoriasis with both

erythroderma and pustulation. Recently he has devel-oped a severe arthropathy of his right sacroiliac joint andright knee, but because of his abnormal LFTs he wasconsidered unsuitable for any second-line immunosup-pressive treatments.

In November 1998, when he had 80% coverage ofplaque psoriasis (Fig. 3), he was commenced on FAE(Fumaderm) which was gradually increased to 120 mgb.d. Together with topical treatment with emollients anda moderately potent steroid, his skin has cleared com-pletely for the first time in over 20 years, and he hasremained in remission at follow-up 10 weeks later (Fig.4). He has experienced mild adverse effects of abdominalcramps and diarrhoea but these have improved withtreatment; so far his blood parameters have remainedstable.

Discussion

Treatment with FAE was first initiated in 1959 bySchweckendiek, a German biochemist who based his

Fumaric acid ester treatment of psoriasis • M. Ameen and R. Russell-Jones

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Figure 1 Case 1. Plaque psoriasis prior to treatment.

Figure 2 Case 1. Total clearance after three months of therapywith FAE.

Figure 3 Case 2. Extensive psoriasis prior to treatment.

Figure 4 Case 2. Four months after commencement of FAE.

treatment on the assumption that psoriasis is a disorderof defective citric acid metabolism.1 This therapy waslater standardized by Schafer, a German general practi-tioner, who developed fumaric acid compound therapy,consisting of dimethylfumarate together with salts ofmonoethylfumarate. With this he found considerableimprovement in 70% of his 900 patients with 20%remaining in total remission.2

Evidence of the high clinical efficacy of FAE treatmenthas been reported in several double-blind placebo-con-trolled studies.3–7 The results of the most recent study byMrowietz et al. are in accordance with previous studies,and showed a reduction in the psoriasis area and severityindex score of 80% during a 16-week period with adverseeffects in 69% of patients.7 Adverse effects consist mainlyof gastrointestinal complaints of gastric and oesophagealpain, and diarrhoea. Patients also frequently reportedflushing, fatigue and nausea and occasionally these ledto a cessation of treatment. It has been shown that theseare better tolerated if FAE treatment is commenced at avery low dose and gradually increased, and that whenremission takes place, the dose is reduced to amaintenance dose.5,6 In addition, the gastrointestinalside-effects usually disappear with prolonged and unin-terrupted use.8 Blood tests may show a rise in LFTparameters after prolonged use, which normalize afterthe discontinuation of treatment.3,4 A mild lymphopeniahas been reported in almost all studies using FAE.Kolbach et al. found it in 85% of their patients, evenafter long-term treatment,9 and reports that it did notseem to affect the health of patients who did not suffer ahigher rate of viral and bacterial infections; it alsoresolves following cessation of treatment.3,5 A transienteosinophilia commonly occurs from weeks 4–8, and thisis found to resolve spontaneously during the course oftreatment.5,7 The occurrence of serious, though reversiblerenal side-effects that have been sporadically reportedwere probably as a result of uncontrolled ingestion andoverdose from combined topical and systemic FAE therapy,and have not been reported in the controlled trials.10,11

The effects of treatment with FAE are usually apparentafter approximately 4 weeks.3,6 In addition, somepatients with psoriatic arthropathy noticed an improve-ment in their joint pain,3,6 and in some there was animprovement in their onychodystrophy.6 FAE have alsobeen shown to produce good clinical results in erythro-dermic and pustular psoriasis,6 and several studies havealso concluded that they are effective and suitable for thelong-term management of psoriasis.8,12

Until recently, there has been little knowledge aboutthe mode of action of FAE in the treatment of psoriasis.Several studies have now shown that FAE selectively

upregulate several cytokines, thereby enhancing theTh2 response,13–15 and they also inhibit the inductionof several adhesion molecules implicated in the patho-genesis of psoriasis.16

In conclusion, FAE represent an important immuno-suppressive tool in the treatment of recalcitrant plaquepsoriasis. Adverse effects are dose-dependent anddecrease in frequency during the course of treatment.They are generally well tolerated by patients, and if theyare closely monitored there appear to be few serious toxicsequelae.

References

1 Scheweckendiek W. Heilung von Psoriasis. Med Mon-tatschr 1959; 103–4.

2 Schafer GN. Fumarsaure lindert die Schuppenflechte.Selecta 1984; 15: 1260–1.

3 Nieboer C, de Hoop D, van Loenen AC et al. Systemictherapy with fumaric acid derivatives: New possibilities inthe treatment of psoriasis. J Am Acad Dermatol 1989; 20(4): 601–8.

4 Nugteren-Huying WM, van der Schroeff JG et al. Fumaricacid therapy for psoriasis: a randomised, double-blind,placebo-controlled study. J Am Acad Dermatol 1990; 2 (1):311–2.

5 Nieboer C, de Hoop D, Langendijk PNJ et al. Fumaric acidtherapy in psoriasis: a double-blind comparison betweenfumaric acid compound therapy and monotherapy withdimethylfumaric acid ester. Dermatologica 1990; 181:33–7.

6 Altmeyer PJ, Matthes U, Pawlak F et al. Antipsoriaticeffect of fumaric acid derivatives. Results of a multicenterdouble-blind study in 100 patients. J Am Acad Dermatol1994; 30: 977–81.

7 Mrowietz U, Christophers E, Altmeyer P et al. Treatmentof psoriasis with fumaric acid esters: results of a prospec-tive multicentre study. Br J Dermatol 1998; 138: 456–60.

8 Thio HB, van der Schroeff JG, Nugteren-Huying WM et al.Long-term systemic therapy with dimethylfumarate andmonoethylfumarate (Fumaderm) in psoriasis. J Eur AcadDermatol Venereol 1995; 4: 35–40.

9 Kolbach DN, Nieboer C. Fumaric acid therapy in psoria-sis: Results and side-effects of two years of treatment. JAm Acad Dermatol 1992; 27: 769–71.

10 Roodnat JI, Christiaans MH, Nugteren-Huying WM et al.Acute kidney insufficiency in the treatment of psoriasisusing fumaric esters. Schweiz Med Wochenscher 1989;119 (23): 826–30.

11 Stuhlinger W, Innerebner M, Aberer W. The nephrotoxiceffect of therapy with fumaric acid esters in psoriasis.Deutsch Med Wochenschr 1990; 115 (45): 1712–5.

12 Altmeyer P, Hartwig R, Matthes U. Efficacy and safetyprofile of fumaric acid esters in oral long-term therapy

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with severe treatment refractory psoriasis vulgaris.A study of 83 patients. Hautarzt 1996; 47 (3):190–6.

13 Ockenfels HM, Schultewolter T, Ockenfels G et al. Theantipsoriatic agent dimethylfumarate immunomodulatesT-cell cytokine secretion and inhibits cytokines of thepsoriatic cytokine network. Br J Dermatol 1998; 139:390–5.

14 De Jong P, Bezemer AC, Van Zomerdijk TPL et al.Selective stimulation of T helper 2 cytokine responses

by the anti-psoriasis agent monomethylfumarate. Eur JImmunol 1996; 26: 2067–74.

15 Asadullah K, Schmid H, Friedrich M et al. Influence ofmonomethylfumarate on monocytic cytokine formation –explanation for adverse and therapeutic effects in psoria-sis? Arch Dermatol Res 1997; 289: 623–30.

16 Vandermeeren M, Janssens S et al. Dimethylfumarate isan inhibitor of cytokine-induced E-selectin. VCAM-1 andICAM-1 expression in human endothelial cells. BiochemBiophys Res Commun 1997; 234: 19–23.

Fumaric acid ester treatment of psoriasis • M. Ameen and R. Russell-Jones

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