Volume 27 Number 5, Part 1 November 1992 Brief communications 769 1 I Fumaric acid therapy in psoriasis: Results and side effects of 2 years of treatment Dinanda N. Kolbach, MD, and Cornelis Nieboer, MD, PhD Amsterdam, the Netherlands Fumaric acid (FA) therapy for psoriasis consists of the daily oral intake of either dimethyl fumaric acid ester (DMFAE, monotherapy) or DMFAE taken with salts of monoethyl FA (MEFAE) (FAC, combination therapy). Information on background and details of this therapy have been given in a pre- vious report. 1 The efficacy of this treatment has been confirmed in several double-blind 4-month studies, l, 2 No significant differences could be found between DMFAE monotherapy and FAC therapy when equivalent dosages of DMFAE were taken. 3 In these reports several side effects were observed. In addition, serious kidney disturbances (acute tubular necrosis) have been reported. 4, s Only two controlled studies of long-term FA therapy have been pub- lished with limited numbers of patients, l, 6 This ar- ticle reports the long-term effects of DMFAE mono- therapy and FAC therapy. MATERIAL AND METHODS Patients. Patients (N = 196) older than 18 years of age with nummular and plaque-type psoriasis with at least 10% involvement of the body surface were included. Twenty-three had arthralgia, 15 in the DMFAE group and 8 in the FAC group. Patients with generalized pus- tular psoriasis were excluded. Other contraindications were pregnancy, history of stomach or intestinal disease, liver or kidney disorders, and cardiovascular complaints. Women of child-bearing age were treated only if ade- quate contraceptive measures were taken. The choice of therapy was determined by a patient's insurance; only some could recover the costs of FAC therapy. Medication. The DMFAE group (n = 129) was treated with capsules filled with 60 mg of semienteric coated granulate of DMFAE. In the first week the dosage was 60 rag/day. This was increased weekly by 60 nag to a maximum of 240 mg/day. The FAC group (n = 67) was treated with two types of enteric-coated (Fumaderm) tablets: (1) "Mite," containing 30 mg of DMFAE, 5 mg From the Department of Dermatology, Academic Hospital Free Uni- versity. Reprint rexlumts: Cornelis Nieboer, Department of Dermatology, Ac- ademic Hospital Free University, De Boelelaan 1117, 1081 HV Am- sterdam, the Netherlands. 16/54/37817 Mg-, 3 mg Zn-, and 56 mg Ca-MEFAE; or (2) "Forte," containing 120 mg of DMFAE, 5 mg Mg-, 3 mg Zn-, and 87 mg Ca-MEFAE. Medication started with one "Mite" tablet per day to be increased weekly to three tablets per day. In the fourth week medication was switched to one "Forte" tablet per day and this was increased weekly to a maximum of four tablets per day, in two divided doses after meals. Topical treatment consisted of the applica- tion of a bland cream or ointment or a mild topical cor- ticosteroid. Evaluation. Therapeutic evaluation was done in the periods 3 to 6 months, 6 to i 2 months, 12 to 18 months, and 18 to 24 months. The results were scored according to a simplified severity score as described previouslyJ Improvement of more than 75% was considered sufficient; less extensive improvement, deterioration, and exacerba- tion were caUed insufficient. Statistical analysis was done with the chi-square test. Side effects were noted. Labora- tory tests included urinalysis, white blood cell count with differential, as well as determination of hemoglobin, serum creatinine, blood urea nitrogen (BUN), and tran- saminase and alkaline phosphatase levels. RESULTS The percentage of patients that continued the therapy was significantly higher in the FAC group than in the DMFAE group after 6 months (Table I). After 24 months 55% continued the FAC medica- tion versus 16% of the DMFAE users. In Table II the therapeutic results after 3 months are shown. Sufficient results were obtained in approximately 50% of the FAC-treated patients during the entire study. In the DMFAE group the percentage of suf- ficient responders declined from 32 to 18 during the 24 months. These differences were statistically sig- nificant. The first signs of improvement were usually noted after 3 weeks. Disappearance of the lesions started in the following weeks. Improvement of nail dystrophy occurred in about half the patients after several months of therapy. A decrease in arthralgias was noted in 27% of the DMFAE-treate~ and in 50% of the FAC-treated patients. The most important reason to discontinue the therapy was an insufficient result in the DMFAE group (36%). Side effects were the most frequent
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`770 Brief communications Journal of the American Academy of Dermatology Table I. Data of patients treated with DMFAE (n = 129) and FAC therapy (n = 67) Period (too) DMFAE treatment* Treated (per period) Discontinued (per period) 3 129 (100%) 25 (t9%) 6 104 (81%) 36 (28%) 12 68 (53%) 23 (18%) 18 45 (35%) 15 (12%) 24 30 (23%) 9 (7%) FAC treatment]' Discontinued Treated Discontinued Discontinued (cumulative) (per period) (per period) (cumulative) 25 (19%) 67 (100%) 7 (11%) 7 (11%) 61 (47%) 60 (90%) 9 (13070) 16 (24%) 84 (65%) 51 (76%) 3 (4%) 19 (28070) 99 (77%) 48 (72%) 9 (!3%) 28 (42%) 108 (84%) 39 (58%) 2 (3%) 30 (44%) *Dimethylfumaric acid ester, 120 to 240 rag/day. ]'Fumaric acid combination (see text). Dosage of DMFAE: 240 to 480 rag/day. Table IL Results of treatment with DMFAE or FAC per observation period after 3 months DMFAE treatment FAC treatment Period (too) Results No. Sulficient* Insufficient'l" Results No. Sufficient Insufficient 3-6 104 41 (32%)~ 63 (49%) 60 32 (48%) 28 (42%) 6-12 68 41 (32%) 27 (21%) 51 31 (46%) 20 (30%) 12-18 45 34 (26%) 11 (9%) 48 34 (51~ 14 (21%) 18-24 30 23 (18%) 7 (5%) 39 31 (46%) 8 (13%) *Sufficient: Improvement more than 75%. ]'Insufficient: Exacerbation, no improvement, or improvement less than 75%. :[:Percentages of the entire patient population. reason to stop in the FAC group (i.e., in l 8%). For the DMFAE group this percentage was 26%, but this difference was not significant. In the first 6 months gastrointestinal complaints were the most frequent in both groups. Later general malaise and abnormal laboratory values became important. Mild deviations of liver and kidney functions were seen in three patients and one patient, respectively. They disappeared promptly after discontinuation. Leuko- cytopenia occurred in 4%. The most frequently oc- curring laboratory deviation was lymphopenia that started to appear after 3 months. After 24 months 86% of the DMFAE-treated and 81% of the FAC- treated patients were so affected. Discontinuation of the therapy led to normalization in most cases, but this required several months up to more than 6 months. Recurrence of psoriasis after discontinuation of therapy varied. In cases of complete or almost com- plete healing, recurrence, if any, occurred after more than 6 months. When the medication was stopped for other reasons, worsening was observed within 4 weeks. A rebound phenomenon was not seen. DISCUSSION FAC treatment was significantly superior to DMFAE. The amounts of DMFAE in the FAC therapy were twice that of the DMFAE monother- apy. Apparently a dosage of 480 mg of DMFAE per day is necessary to achieve a satisfactory improve- ment in approximately 50% of the patients. This is a slightly lower rate than has been described with long-term retinoid therapy] The mechanism of FA therapy is still unknown. There are strong indications that FA esters have an- tiproliferating properties, slt Immunologic modula- tion might be another possibility. Additional phar- macologic and pharmacokinetic studies are neces- sary. 12 Another aspect of FA therapy is side effects. Flushing occurs in 50% of patients but this is usually tolerable. Gastrointestinal complaints are the most important symptoms in the first months. With enteric coating these are less severe. Acute tubular necrosis was not seen in our series. This is probably due to the low initial dosage and the slow increase in dosage. 13 The most frequent side effect was lym- phopenia in 85% of patients still in treatment after
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`Volume 27 Number 5, Part 1 November 1992 Brief communications 771 2 years in both series. This lymphopenia is caused by loss of suppressor T cells and B lymphocytes ~ and seriously restricts FA therapy. Unless this compli- cation can be eliminated, FA therapy should only be prescribed under weU-controUed conditions, with timely interruptions to normalize the lymphocyte count. REFERENCES I. Nieboer C, de Hoop D, van Loenen AC, et al. Systemic therapy with fumaric acid derivatives: new possibilities in the treatment of psoriasis. J AM ACAD DERMATOL 1989;20:601-8. 2. Nugteren-Huying WM, van der Schroeff JG, Hermans J, et aL Fumaric acid therapy for psoriasis: a randomized, double-blind, placebo-controlled study. J AM ACAD DER- MATOL 1990;22:31 1-2. 3. Nieboer C, de Hoop D, Langendijk PNJ, et al. Fumaric acid therapy in psoriasis: a double-blind comparison be- tween fumaric acid compound therapy and monotherapy with dimethyl fumaric ester. Dermatologica 1990;I 81:33-7. 4. Roodnat JI, Christiaans MH, Nugteren-Huying WM, et al. Akute Niereninsuffizienz bei der Behandlung der Pso- riasis mit Fumars/iure-Estern. Schweiz Meal Wochenschr 1989;119:826-30. 5. DalhoffK, FaerberP, SackK, etal.AkutesNierenversagen unter Psoriasistherapie mit Fumars~.urederivaten. Dtsch Med Wochenschr 1990;115:1014-7. 6. Bayard W, Hunziker Th, Krebs A, eta[. Perorale Lang- zeitbehandlung der Psoriasis mit Fumars//urederivaten. Hautarzt 1987;38:279-85. 7. Gollnick H, Orfanos CE. Clinical efficacy of retinoids: Eu- ropean experience. In: Roenigk HH Jr, Maibach HI. p 597-614. New York: Marcel Dekker, 1985. 8. Petres J, KalkoffKW, Baron D, etal. Der Einfluszvon Fu- mars~iuremono~ithylester auf die Nuekleins/iure und Pro- teinsynthese PHA-stinmlierter menschlicher Lympho- cyten. Arch Dermatol Forschung 1975;25:295-300. 9. van der Schroeff JG, Oudshoorn C, Nugteren-Huying WM, et al. Inhibitory effects of fumaric acid derivatives on cell proliferation and differentiation [Abstract]. J Invest Dermatol 1989;92:537A. 10. Kuroda K, Akao M, Kanisawa M, et al. Inhibitory effect of Capsula bursapastoris extract on growth of Ehrlieh solid tumor in mice. Cancer Res 1976;36:1900-3. 11. Sarheim BS. Psoriatic fibroblasts in cell culture. Contribu- tion to the mode of action of fumarates in psoriasis treat- ment. Thesis Diss ETH Nr. 9070, Ztirieh t990. 12. Baumann M. Pharmakokinetische Untersuchungen mit Fumars~iurederivaten in vitro und in vivo. Thesis Diss ETH Nr. 8848. Ziirich 1989. 13. Dijk van E. Fumars/iuretherapie,--Stand der Forschung und offene Fragen. PSO Magazin, Wissenschaftliches Beiheft 6, 1990. Ed. Stiftergesellschaft Deutseher Psoriasis Bund e.V., Hamburg. Traumatic folliculitis of the legs: A persistent case associated with use of a home epilating device Robert C. Wright, MD Denver, Colorado A 31-year-old woman had a prolonged case of folliculitis after using a home epilating device for hair removal from the legs. I have seen other cases of traumatic folliculitis, and there are several reports in the literature that have involved home epilating devices. 14 CASE REPORT A 31-year-old white woman had an eruption on her legs of 6 months' duration. The problem developed after she had been using an epilating device for approximately 1 year. The device produced a circular motion over hair- bearing areas. She treated half of one leg about every 3 weeks. Because of the eruption, she had discontinued the From the Department of Dermatology, University of Colorado School of Medicine. No reprints available. 16/54/38308 use of the epilating device 5 months earlier. Subsequent hair removal involved shaving with a safety or an electric razor. She denied plucking the hairs or use of a depilatory. For several months before the onset of the eruption and up until the time it began, she had been running a tread- mill in tights three times per week. Physical examination revealed numerous erythema- tous, follicular, crusted papules on the legs. A potassium hydroxide preparation and bacterial culture were nega- tive. Initial treatment with 2.5% hydrocortisone cream and 2% mupirocin ointment provided only slight improve- ment. Additional treatment with systemic and topical erythromycin, topical benzoyl peroxide, and 0.025% tri- amcinolone cream was ineffective. A skin biopsy speci- men showed a prominent ingrown hair in the reticular dermis with granulomatous inflammation (Fig. l). Sub- sequent treatment included UVB phototherapy with slow gradual improvement. She has now had the problem for more than 16 months after discontinuing use of the epi- luting device.
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