Therapeutics Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis

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1 British Journal of Dermatology 23; 149: Therapeutics Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis J.J.HOEFNAGEL, H.B.THIO,* R.WILLEMZE AND J.N.BOUWES BAVINCK Department of Dermatology, B1-Q, Leiden University Medical Center, PO Box 96, 23 RC Leiden, the Netherlands *Department of Dermatology, Erasmus Medical Center, Rotterdam, the Netherlands Accepted for publication 23 January 23 Summary Background Therapy with fumaric acid esters (FAE) has been shown to be safe and effective in patients with severe psoriasis in several clinical studies with limited follow-up periods. In view of the chronic character of psoriasis, long-term safety aspects are of major importance in determining the suitability of a drug during prolonged periods of treatment. Objectives To investigate adverse events of therapy with systemic FAE with follow-up periods of up to 14 years, in order to determine safety aspects of their long-term use in patients with severe psoriasis. Methods Current and or past therapeutic use of FAE was reviewed in 66 patients with severe psoriasis. Results Forty-one of 66 patients had received FAE for at least 1 year, and 12 of these 41 patients had received FAE for between 1 and 14 years. Adverse events were reported in 73% of the patients. These were usually mild and mainly consisting of flushing (55%), diarrhoea (42%), nausea (14%), tiredness (14%) and stomach complaints (12%). A relative lymphocytopenia was observed in 76% of patients during therapy with FAE, resulting in a permanent discontinuation of therapy with FAE in four patients. A transient eosinophilia and moderate liver enzyme elevations were observed in 14% and 25% of patients, respectively. Conclusions The present study indicates that FAE can be considered as a safe long-term treatment in patients with severe psoriasis. Key words: fumaric acid esters, long-term safety, psoriasis In 1959 the German chemist Schweckendiek (who suffered from psoriasis himself) first reported the beneficial effects of systemic therapy with fumaric acid esters (FAE) in severe psoriasis. 1 The general practitioner Schäfer further developed this therapy and propagated its clinical use. 2 Since then FAE have been used on a small scale in the systemic treatment of severe psoriasis in Germany, Switzerland and the Netherlands. The first clinical studies compared the therapeutic effect of different FAE and showed the superior effect of a combination of dimethylfumarate and monoethylfumarate over dimethylfumarate Correspondence: J.N.Bouwes Bavinck. J.N.Bouwes_Bavinck@lumc.nl alone. 3,4 The commercial mixture of dimethylfumarate and monoethylfumarate, Fumaderm Ò, is generally used for the treatment of psoriasis and is available in two tablet formulations differing in strength and proportion of compounds. The components of a highstrength tablet are 12 mg dimethylfumarate, 87 mg monoethylfumarate Ca salt, 5 mg monoethylfumarate Mg salt and 3 mg monoethylfumarate Zn salt. A lowstrength tablet consists of 3 mg dimethylfumarate, 67 mg monoethylfumarate Ca salt, 5 mg monoethylfumarate Mg salt and 3 mg monoethylfumarate Zn salt. 5 Results obtained from several clinical trials showed the clinical efficacy and safety of FAE during 4 months of treatment in severe psoriasis vulgaris. 4 6 In a Ó 23 British Association of Dermatologists 363

2 364 J.J.HOEFNAGEL et al. randomized, double-blind, placebo-controlled clinical trial Altmeyer et al. showed improvement of psoriasis lesions in 7% of patients after 4 months of treatment. 5 In addition, a prospective multicentre study revealed a mean reduction in Psoriasis Area and Severity Index of 8% after 4 months. 6 In view of the chronic nature of psoriasis, long-term clinical efficacy and adverse events profile are of major importance in determining the suitability of a drug in the treatment of this skin disease. The studies of Kolbach and Nieboer 7 and Thio et al. 8 showed that FAE were also effective after a prolonged period of treatment of 2 and 3 years, respectively. Studies with longer follow-up times are lacking. Therapy with FAE has also been used in patients with psoriatic arthritis, but did not prove to be effective for this indication. 6,9 At the time of Schweckendiek, FAE was prescribed to patients in order to replace a suspected endogenous deficiency of fumaric acid, a metabolite of the citric acid cycle. Then therapy with FAE was based on the hypothesis that a disturbed citric acid cycle is an important pathogenetic factor in psoriasis. The current theory of the mode of action of FAE in psoriasis is based on their immunomodulating properties and their inhibitory effect on keratinocyte proliferation and activation FAE induce a T-helper (Th) 2-like cytokine secretion pattern in T cells, shifting the enhanced Th1-mediated immune response underlying the psoriatic tissue reaction towards a Th2-mediated reaction. 1,11 At the onset of therapy with FAE the dosage should be gradually increased to a maximum of six highstrength tablets per day, mainly to avoid serious renal impairment. 17 If clearance or good improvement of the psoriasis lesions is achieved, the dosage should be individually reduced to a maintenance dose depending on the therapeutic effect and adverse events. The most frequently noted adverse events associated with therapy with FAE are flushing, diarrhoea and a relative lymphocytopenia. 18 Leucocyte differential counts, liver function tests, serum creatinine and urinalysis should be frequently monitored during therapy with FAE. 18 The aim of the present study was to assess adverse events after a prolonged period of treatment with FAE: up to 14 years of follow-up. In this report the therapeutic experience with systemic therapy with FAE in 66 patients with psoriasis was investigated with particular emphasis on the long-term changes of laboratory parameters. Patients and methods Patient selection In total, 35 patients diagnosed with psoriasis in the Department of Dermatology of the Leiden University Medical Center between 1 January 198 and 1 March 21 were retraced from the hospital registration system. As we were especially interested in long-term treatment with FAE a subset was selected, comprising all 235 psoriasis patients who visited the outpatient clinic for the first time before 1 January 1994 and whose last visit was after 1 January 2. A manual search of the 235 medical charts revealed 54 patients with current or past therapeutic use of FAE. Additionally, 12 patients were included who were known to be currently treated with FAE, but whose first visit to the out-patient clinic was after 1 January The final study population consisted of 66 patients. Methods Information about age at disease onset, type of psoriasis, dosage and treatment duration, reasons for (temporary) discontinuation, adverse events, patient satisfaction and the use of other antipsoriatic systemic therapies was collected from the medical charts and by questionnaire. The following laboratory parameters were monitored monthly during the first 6 months of treatment and thereafter at 3-monthly intervals: total leucocyte count, relative percentages of lymphocytes and eosinophils, serum creatinine, serum alanine aminotransferase (ALAT) and serum c-glutamyltransferase (c-gt). The data on laboratory parameters were statistically analysed using paired sample t-tests. The laboratory values after treatment durations of 1 year and 12 years were compared with the values at the start of therapy, and the 12-year values were compared with the 1-year values. Results Basic characteristics of the study population The study population consisted of 41 (62%) men and 25 (38%) women. The mean ± SD age of the patients at time of the questionnaire was 52 ± 14Æ7 years (range 25 82). The mean age at psoriasis onset was 23 years in men and 24 years in women. Of the 66 patients, 62 (94%) had psoriasis vulgaris, three (5%) had guttate psoriasis and one had arthropathic psori-

3 SAFETY OF FAE IN PSORIASIS 365 asis. Twenty-three (35%) of 66 patients had previously used other systemic antipsoriatic treatments such as methotrexate (n ¼ 8), acitretin (n ¼ 18) and ciclosporin (n ¼ 6). Four patients had used two and two patients had used three of these drugs before starting therapy with FAE. The questionnaires were completed by 48 of 66 patients (response rate ¼ 73%). Dosage, treatment duration and reasons for (temporary) discontinuation All 66 patients were treated with individually differing doses of FAE. At the onset of therapy with FAE the dose was gradually built up to a maximum of six highstrength tablets in 27 (41%) of 66 patients. The mean maintenance dosage was between three and four highstrength tablets per day. The treatment duration in the patients studied is shown in Figure 1. Forty-one of 66 patients had used FAE for at least 1 year and 12 patients of these 41 had number of patients months 6-12 months 1-2 yrs 2-5 yrs 5-1 yrs 1-14 yrs treatment duration Figure 1. Duration of therapy with fumaric acid esters in 66 patients. mts, months; year, years used the therapy for a period of between 1 and 14 years. In 38 patients therapy with FAE was permanently discontinued for various reasons as outlined in Table 1. An exacerbation of psoriasis during therapy, after initial improvement, was the most frequently reported reason for discontinuation, after a median period of 18 months of therapy with FAE (Table 1). In five patients therapy with FAE was permanently discontinued because of a combination of factors. In 19 patients one or sometimes two or three periods of interruption occurred because of various reasons as shown in Table 1. Subjective adverse events Subjective adverse events reported in 48 (73%) of 66 patients are shown in Figure 2. The majority of adverse events occurred within the first 6 months of treatment. Flushing usually decreased in frequency during the course of treatment and gastrointestinal side-effects generally disappeared after prolonged and uninterrupted use. In nine of these 48 patients the subjective adverse events were the reason for discontinuation of treatment, which occurred between 4 and 32 weeks (mean 14) after the start of therapy with FAE. Laboratory parameters Leucocytes. Leucocytopenia was defined as < 4Æ 1 9 leucocytes L )1. In 17 (27%) of 63 patients leucocytopenia developed during therapy with a mean ± SD Table 1. Reasons for permanent discontinuation of therapy with fumaric acid esters in 38 patients and for temporary discontinuation in 19 patients in the total study population of 66 patients a Permanent discontinuation Treatment duration (months), median (range) Temporary discontinuation Related to clinical efficacy Clinical improvement of disease 4 (11%) 35 (5 9) 3 (16%) Lack of efficacy 9 (24%) 6 (1 22) 3 (16%) Exacerbation during therapy, 12 (32%) 18 (3 112) after initial improvement Related to adverse events Subjective adverse events 9 (24%) 3 (1 8) 6 (32%) Relative lymphocytopenia 4 (11%) 72 (6 93) 2 (11%) Elevated liver enzymes 2 (5%) 3 (1 4) 1 (5%) Elevated serum creatinine 1 (5%) Other reasons Replacement by methotrexate 1 (4%) 1 (5%) therapy Pregnancy 1 (4%) Chemotherapy 1 (5%) Insurance refunding problems 1 (4%) 2 (11%) Not clear 2 (11%) a Discontinuation may be for more than one reason.

4 366 J.J.HOEFNAGEL et al. percentage of patients 6% 5% 4% 3% 2% 1% % 55% flushing 42% 14% 12% 14% 2% 5% 2% diarrhoea nausea stomach complaints tiredness dizziness itching fever Figure 2. Subjective adverse effects during treatment with fumaric acid esters. value in these 17 patients of 3Æ4 ±Æ leucocytes L )1 and a minimum value of 2Æ4 1 9 L )1 in one patient. In 14 (82%) of these 17 patients a relative lymphocytopenia, defined as < 2% of the total leucocyte count, was observed. The course of the median leucocyte count during a period of 12 years of treatment did not show any marked alterations (data not shown). Lymphocytes. The percentages of patients with a relative lymphocytopenia (< 2% of the total leucocyte count) in relation to the duration of therapy with FAE are depicted in Figure 3. In 22 (35%) of 63 patients a relative lymphocytopenia existed at the start of therapy with FAE, possibly reflecting previous use of immunosuppressive therapy. Of the 41 patients without a relative lymphocytopenia at the start of therapy, 31 (76%) developed a relative lymphocytopenia after onset of therapy with FAE. A total of 18 patients developed a relative lymphocytopenia of 1% or less. Therapy with FAE was permanently discontinued in four of these patients, temporarily discontinued in one patient, and in five patients the dosage was reduced. In eight patients no action was taken, after which lymphocyte counts increased spontaneously to > 1%. Concomitant leucocytopenia was present in only four of these 18 patients. The median percentage of lymphocytes in the 41 patients who were followed for more than 1 year showed a significant decrease of 5Æ5% (95% confidence interval 2Æ5 8Æ6, P ¼ Æ1) after a period of treatment of 1 year compared with the start of the treatment (Fig. 4A). Thereafter, up to 12 years of treatment, the values did not show any further decrease (Fig. 4B). Statistical testing confirmed that the percentage of lymphocytes after 12 years of treatment was not significantly lower than after 1 year of treatment. 2-4% lymphocytes < 2% lymphocytes </= 1% lymphocytes 1% n = 63 n = 63 n = 51 n = 44 n = 41 n = 26 n = 18 n = 14 9% 8% 7% patients (%) 6% 5% 4% 3% 2% 1% % start therapy 3 months 6 months 9 months 1 year 3 years 6 years 1 years treatment duration Figure 3. Number of patients (%) with a relative lymphocytopenia in relation to duration of therapy with fumaric acid esters. mts, months; year, years.

5 SAFETY OF FAE IN PSORIASIS 367 A % lymphocytes B % lymphocytes n = 63 n = Eosinophils. The percentage of eosinophils rose above the laboratory normal values (upper limit is 7% of the total leucocyte count) during therapy with FAE in nine (14%) of 63 patients. Relative eosinophilia was observed within 1 year of treatment in eight patients and after 4 years of treatment in one patient. An eosinophil count of 34% was observed in one patient. The eosinophilia was transient in all cases and no interventions were needed. Liver enzymes. Elevated liver enzymes (upper limits of ALAT and c-gt are, respectively, 45 U L )1 and treatment duration (months) treatment duration (years) Figure 4. Box plots of the median percentage of lymphocytes relative to the total leucocyte count during (A) 36 months and (B) 12 years of treatment with fumaric acid esters. The columns represent the values between the 25th and 75th percentiles with the median shown as a horizontal bar. The lower and upper limits of the vertical bars indicate the fifth and 95th percentiles. Outliers are shown as circles U L )1 ) were another relatively frequent abnormal laboratory finding in 16 (25%) of 63 patients. In 14 of these 16 patients an isolated elevation of c-gt was observed. The liver enzyme elevations resolved spontaneously or normalized after reduction of the dosage in all except three patients. In two patients elevated liver enzymes were the reason to withdraw therapy with FAE permanently and in one patient to withdraw therapy temporarily. Reintroduction of therapy with FAE induced no relapse of elevated liver enzymes in this patient. Creatinine. Elevated serum creatinine levels were reported during therapy with FAE in one of 63 patients (published previously by Dubiel and Happle ). Four years later therapy with FAE was reintroduced in this patient and serum creatinine has remained within the normal range during the following 11 years that she has been receiving therapy with FAE. Discussion Results of the present study show that therapy with FAE can be used for many years without important adverse events in patients with severe psoriasis. Thirtyfive per cent of the patients had previously used other systemic antipsoriatic therapies, illustrating the severity of disease in this group. The possibility of prolonged use of therapy with FAE is a clear advantage in view of the chronic nature of psoriasis, as reflected by a mean duration of disease of almost 3 years in these 66 patients. Subjective adverse events were reported in 73% of the patients, which is in agreement with previous studies. 5,6 Adverse events were generally mild and well tolerated and mainly consisted of flushing, gastrointestinal complaints and tiredness. Nevertheless, because adverse events were not systematically monitored and were based on reports in the medical charts and questionnaires only, the real percentage of subjective adverse events is probably higher. The majority of subjective adverse events occurred within the first 6 months of treatment and thereafter decreased in severity or resolved spontaneously. 8 The most frequently occurring change in laboratory parameters was a relative lymphocytopenia of < 2%, observed in 76% of the patients. Thio et al. observed a relative lymphocytopenia in 67% of their study population. 8 In their study Kolbach and Nieboer reported a level of 85% in 3 patients. 7 Relative lymphocytopenia did not always result in leucocytopenia. The

6 368 J.J.HOEFNAGEL et al. pre-existing lymphocytopenia in more than one-third of the study population could possibly be explained by the previous use of other systemic immunosuppressive antipsoriatic therapies. Furthermore, lymphocytopenia could be an intrinsic characteristic of psoriasis, but studies on this subject are lacking. A statistically significant decrease in the percentage of lymphocytes occurred during the first year of treatment, but this trend did not progress with advancing years of treatment. Relative lymphocytopenia did not appear to have important implications for the general health status of the patients. Frequent monitoring of lymphocytes, however, remains important and in our opinion the dosage of FAE should be reduced if the relative percentage of lymphocytes decreases to 1% or less. According to recent guidelines, the dose should also be reduced if lymphocytes fall below an absolute value of Æ5 1 9 L )1. 17 Transient eosinophilia was a less frequent laboratory finding in our study (14%). Similar results were found in other studies. 6,8 Relative eosinophilia could be explained by induction of a Th2 secretion pattern. 1 Elevated liver enzymes were found in 25% of the patients, but an association with therapy with FAE was doubtful in all cases. Elevations of liver enzymes were usually moderate and resolved spontaneously or after reduction of the dosage of FAE. Thio et al. 8 reported elevated liver enzymes in 4% of their patients, but in other studies no significantly changed liver function tests have been reported as a result of therapy with FAE. 5,6 There was one case of elevated serum creatinine during therapy with FAE found in our study. A relationship with therapy with FAE may be doubtful in this case, because reintroduction of therapy with FAE in this patient did not result in a relapse of this laboratory finding during the following 11 years. In the early days of therapy with FAE a few cases of acute renal failure were reported, some of which were thought to be caused by an initial overdose of FAE In subsequent clinical studies in which FAE were used according to a gradually increasing dosage regimen, no significant changes in serum creatinine were found. 5,6 Renal impairment therefore seems to be a rare, but severe adverse effect of therapy with FAE which is probably associated with an initial overdose of FAE. Frequent monitoring of serum creatinine and urinalysis remain important for early detection of renal problems. The chronic nature of psoriasis and its impact on the quality of life demand a long-term therapy that lacks serious adverse events and with efficacy persisting after prolonged use. Subjective adverse events of therapy with FAE are usually well tolerated and patients can be easily monitored for abnormal laboratory parameters. Regarding the benefit risk ratio, therapy with FAE is, in our opinion, suitable for prolonged use in severe psoriasis. In conclusion, therapy with FAE deserves acceptance as an effective antipsoriatic treatment which can be safely used for prolonged periods and should be more widely prescribed in the systemic treatment of severe psoriasis. Acknowledgments We thank all patients for participating in this study and Dr P.Eilers, Department of Medical Statistics, Leiden University Medical Center for statistical analysis. References 1 Schweckendieck W. Heilung von Psoriasis. Med Monatschr 1959; 13: Schäfer GN. Fumarsäure lindert die Schuppenflechte. Selecta 1984; : Nieboer C, de Hoop D, Langendijk PN et al. Fumaric acid therapy in psoriasis: a double-blind comparison between fumaric acid compound therapy and monotherapy with dimethylfumaric acid ester. Dermatologica 199; 181: Nugteren-Huying WM, van der Schroeff JG, Hermans J, Suurmond D. Fumaric acid therapy for psoriasis: a randomized placebo-controlled study. J Am Acad Dermatol 199; 22: Altmeyer PJ, Matthes U, Pawlak F et al. Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 1 patients. J Am Acad Dermatol 1994; 3: Mrowietz U, Christophers E, Altmeyer P. Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. Br J Dermatol 1998; 138: Kolbach DN, Nieboer C. Fumaric acid therapy in psoriasis. results and side-effects of 2 years of treatment. J Am Acad Dermatol 1992; 27: Thio HB, van der Schroeff JG, Nugteren-Huying WM, Vermeer BJ. Long-term systemic therapy with dimethylfumarate and monoethylfumarate (Fumaderm) in psoriasis. J Eur Acad Dermatol Venereol 1995; 4: Peeters AJ, Dijkmans BAC, van der Schroeff JG. Fumaric acid therapy for psoriatic arthritis. Br J Rheumatol 1992; 31: Ockenfels HM, Schultewolter T, Ockenfels G et al. The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokines and inhibits cytokines of the psoriatic cytokine network. Br J Dermatol 1998; 139: de Jong P, Bezemer AC, Zomerdijk TP et al. Selective stimulation of T helper 2 cytokine responses by the antipsoriasis agent monomethyl-fumarate. Eur J Immunol 1996; 26: Stoof TJ, Flier J, Sampat S et al. The antipsoriatic drug dimethylfumarate strongly suppresses chemokine human keratinocytes and peripheral blood mononuclear cells. Br J Dermatol 21; 144:

7 SAFETY OF FAE IN PSORIASIS Zhu K, Mrowietz U. Inhibition of dendritic cell differentiation by fumaric acid esters. J Invest Dermatol 21; 116: Thio HB, Zomerdijk TPL, Oudshoorn C et al. Fumaric acid derivatives evoke a transient increase of intracellular free calcium concentration and inhibit the proliferation of human keratinocytes. Br J Dermatol 1994; 131: Dubiel W, Happle R. Behandlungsversuch mit Fumarsäuremonoäthylester bei Psoriasis vulgaris. Z Haut Geschlechtskr 1972; 47: Roodnat JI, Christiaans MHL, Nugteren-Huying WM et al. Akute Niereninsuffizienz bei der Behandlung der Psoriasis mit Fumarsäure-Estern. Schweiz Med Wochenschr 1989; 119: Dalhoff K, Faerber P, Arnoldt H et al. Akutes Nierenversagen unter Psoriasistherapie mit Fumarsäurederivaten. Dtsch Med Wochenschr 199; 1: Mrowietz U, Christophers E, Altmeyer PJ. Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. Br J Dermatol 1999; 141:

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