Therapy
`
`Antipsoriatic effect of fumaric acid derivatives
`
`R esults of a multicenter double-blind study in I 00 patients
`
`Peter J. Altmeyer, MD, a Ulrich Matthes, MD, a Frank Pawlak, MD,a Klaus Hoffmann, MD,a
`Peter J. Frosch, MD,b Peter Ruppert, MD,b Sawko W. Wassilew, MD,c Thomas Horn, MD,c
`Hans W. Kreysel, MD,d Gerhard Lutz, MD,d Joachim Barth, MD,e Ilona Rietzschel, MD,e
`and Rajendra K. Joshi, PhDr Bochum, Dortmund, Krefeld, Bonn, and Dresden, Germany;
`and Zurich, Switzerland
`
`Background: Psoriasis vulgaris may benefit from treatment with fumaric acid and/or its de(cid:173)
`rivatives; however, because different preparations have been used, results have been contra(cid:173)
`dictory and difficult to interpret.
`Objective: The purpose of this clinical trial was to evaluate the therapeutic value of fumaric
`acid derivatives.
`Methods: A randomized double-blind study was carried out in patients with psoriasis, com(cid:173)
`paring a well-characterized formulation of fumaric acid derivatives with placebo.
`Results: The results indicated statistically significant superiority of the fumaric acid deriv(cid:173)
`atives over placebo. Adverse events (flush, gastrointestinal disturbances) were initially rela(cid:173)
`tively frequent, but decreased thereafter.
`Conclusion: Fumaric acid derivatives were found to be effective and safe in the treatment of
`psoriasis.
`(JAM ACAD DERMATOL 1994;30:977-81.)
`
`The use of"fumaric acid" as antipsoriatic therapy
`has been controversial for more than 30 years. 1 In(cid:173)
`sufficient knowledge of the pharmacologic and tox(cid:173)
`icologic properties of this highly potent material re(cid:173)
`sulted in widespread abuse. Uncontrolled ingestion
`and overdose from combined topical and systemic
`therapy led to considerable nephrotoxic side effects
`in some patients and negative publicity. 2-4
`A distinction must be made between fumaric
`acid, which has no effect on psoriasis, and its esters,
`which may possess antipsoriatic activity. In the past
`primarily the monoethyl and dimethyl esters of fu(cid:173)
`maric acid, or a mixture of the two, were used. In
`contrast to pure fumaric acid these esters can be ab(cid:173)
`sorbed by the body and are thus systemically active.
`
`From the Dermatological Clinic, University of Bochum•; Municipal
`Hospital, Dortmundb; Municipal Hospital, Krefeld"; Dermatological
`Clinic, University of BoMd; Dermatological Clinic Medical Acad(cid:173)
`emy "Carl Gustav Carus," Dresden"; and the Department of Phar(cid:173)
`macy, Federal Institute of Technology, Ziirich.r
`Reprint requests: Peter J. Altmeyer, MD, Professor, Director of the
`Dermatological Clinic, University of Bochum, Gudrunstr. 56,
`D-44791 Bochum, Germany.
`Copyright@ 1994 by the American Academy of Dermatology, Inc.
`0190-9622/94$3.00 + 0 16/1/52297
`
`The pharmacologic effects of the fumaric acid esters
`are still largely unknown. A few older publications
`reported effects in lymphocyte cultures. 5• 6 In phy(cid:173)
`tohernagglutinin-stimulatedhumanlymphocytesfu(cid:173)
`marie acid monoethyl ester inhibited the incorpora(cid:173)
`tion of thymidine and uridine into nucleic acids and
`of alanine and leucine into proteins.5 In 1985 van
`Dijk7 reported the use of fumaric acid derivates in
`32 patients. Efficacy was good in most patients; ad(cid:173)
`verse events involved mainly the gastrointestinal
`tract. In 1987 Bayard et al.8 evaluated 11 patients
`who received a combination of fumaric acid deriv(cid:173)
`atives for 3 months. Good results were noted in more
`than half of these patients. In 1989 Nieboer et al.9
`described 136 patients who had been treated in var(cid:173)
`iously designed studies and confirmed the efficacy of
`the fumaric acid derivatives. In the first placebo(cid:173)
`controlled, double-blind study of fumaric acid de(cid:173)
`rivatives Nugteren-Huying et al. 10 confirmed the
`positive results of earlier studies.
`To reexamine the clinical efficacy and side effects
`of fumaric acid derivatives, a large, randomized,
`double-blind, placebo-controlled study was con(cid:173)
`ducted.
`
`977
`
`MYLAN PHARMS. INC. EXHIBIT 1030 PAGE 1
`
`

`

`978 Altmeyer et a/.
`
`Journal of the American Academy of Dermatology
`June 1994
`
`Table I. Remission indexes based on the PAST
`score
`
`Complete remission
`Good improvement
`Moderate improvement
`Slight improvement
`No change
`Deterioration
`
`.Remission index
`
`>95%
`70%-95%
`30%-69%
`<30%
`0%
`<0%
`
`PATIENTS AND METHODS
`
`One hundred patients of both sexes were admitted to
`the study (women of cbild-beari ng age only after exclu(cid:173)
`sion of pregnancy). The patients 18 to 70 years of age
`(drug group: mean 41.1 years [range 21 to 69 years];
`placebo group: mean 39.0 years [range 19 to 67 years])
`had psoriasis (chronic plaque type, exanthema tic guttate
`type, pustular type, psoriatic erythroderma) for at least 2
`years and were no longer or only insufficiently responsive
`to external therapy. Only patients in whom more than
`10% of the body surface was affected were included.
`Topical antipsoriatic drugs had to be withdrawn at least
`2 weeks before entering the study. O ther concomitant
`treatment not affecting psoriasis was to be kept constant
`whenever possible and was monitored particularly with
`respect to possible interactions. Topical preparations such
`as ointments and bath oils were allowed.
`The exclusion criteria were impaired kidney or liver
`function, cardiac disease, pregnancy (contraception was
`required during therapy), gastrointestinal disorders, or
`hematologic disorders.
`All patients were treated with either placebo or drug in
`tablet form according to a uniform randomization sched(cid:173)
`ule. The drug consisted of a mixture of dimethylfumaratc
`and monoethylhydrogenfumarates. It was available in
`two different enteric-coated formulations: low-strength
`tablets containing l 05 mg of ester mixture (30 mg dim(cid:173)
`ethylfumaratej75 mg monoethylhydrogenfumarate as
`calcium, magnesium, zinc salts) and as "forte" tablets
`containing 2 15 mg of ester mixture ( 120 mg dimethylfu(cid:173)
`marate/95 mg monoethylhydrogenfumarate as calcium,
`magnesium, zinc salts}.
`T he patients were treated with ascending doses as fol(cid:173)
`lows: In the first week 105 mg of the ester mixture or pla(cid:173)
`cebo daily, in the second week 210 mg per day. After the
`second week the "forte" form was given and the dose in(cid:173)
`creased by 215 mg per day (week 3) up to a maximum
`dose of I 290 mg (week I 6) ester mixture per day. Patients
`receiving placebo were given the corresponding numbers
`of tablets.
`The following laboratory studies were performed on
`dayO (TO) and after 2 (Tl), 4 (T2), 6 (T3), 8 (T4), !2
`
`(T5), and 16 (T6) weeks: hemoglobin; erythrocyte, leu(cid:173)
`kocyte, and diiferential counts; platelet count; levels of
`bilirubin, creatinine, urea, uric acid, glucose, alkaline
`phosphatase, transaminases, gamma-GT, cholesterol,
`triglycerides, calcium, sodium, and potassium; as well as
`urinalysis. Creatinine clearance was detennined at TO
`and after 16 weeks.
`The status of the disease was measured by determin(cid:173)
`ing the Psoriasis Area and Severity Index (PASI). The
`PASI values (P) were then used for calculation of are(cid:173)
`mission index (RI) giving the percentage improvement in
`the psoriasis at the time TI (TI = T 1-T6) compared with
`the starting time. The following formula was used:
`
`RI (~) = PASITO-PASITI
`PASITO
`X lOO
`0
`
`The calculated remission values were used as a basis for
`the classification listed in Table I. The clinical findings
`were evaluated al times TO (initial examination) and
`Tl-T6 (after 2, 4, 6, 8, 12,and 16 weeks). In addition, the
`pruritus, arthralgia, and nail deformities were assessed on
`the basis of a clinical score from 0 to 4 (O = none to
`4 = very severe). At each visit both the physician and the
`patient were asked to assess the outcome of therapy and
`any side effects. At the end of the study a global evalua(cid:173)
`tion of the outcome of treatment was made as weU as a
`comparison with the results of previous treatments.
`The following statistical tests were used: Wilcoxon(cid:173)
`Mann-Whitney U test, Mantei-Haenszel test, and chi(cid:173)
`square test for two or more factors. The laboratory results
`were examined for transitions with the t test and fre(cid:173)
`quency tables. In addition to the initial statistical meth(cid:173)
`ods the t test for unequal variances (Welch approxima(cid:173)
`tion) was used when the conditions for the t test were not
`fulfilled (significant F test, L¥ == 0.005). In general the sig(cid:173)
`nificance level was ex = 0.05.
`
`RESULTS
`
`A predominance of male patients was found in
`both the drug group and the placebo group. The pa(cid:173)
`tients in the drug group had psoriasis for an average
`of 14.6 years (2 to 45 years) and those in the placebo
`group for an average of 15.6 years (2 to 51 years).
`The distribution of the different forms of psoriasis
`was homogeneous in the two groups. Evaluation of
`homogeneity showed no signiticant differences be(cid:173)
`tween the individual centers.
`In Fig. 1 the P ASl scores in the drug group are
`compared with those in the placebo group. The data
`indicate that there was a definite and continuous
`drop in the index in the drug group. Compared with
`a starting value of21.57 (TO) thePASI determined
`in the sixteenth week (T6) was 10.77. In contrast,
`the PAS! in the placebo group remained practically
`
`MYLAN PHARMS. INC. EXHIBIT 1030 PAGE 2
`
`

`

`Journal of the American Academy of Dermatology
`Volume 30, Number 6
`
`Altmeyer eta/. 979
`
`5
`
`0 ~--------------------------------------~
`Baseline
`week 2
`week4
`week6
`week 8
`week 12
`week 16
`J • Fumaric acid derivates • Placebo I
`Duration of treatment
`Fig. I. Influence on mean PAS! of fumaric acid derivatives and placebo during 16 weeks
`of treatment.
`
`patients (n)
`
`30 .-------------------------------------------,
`
`25
`
`20
`
`15
`
`10
`
`5
`
`RI<O
`RI=O
`Rl<30
`Rl=70-95 Rl=30-69
`Rl>95
`Fig. 2. Physicians' judgment of the therapeutic effect of fumaric acid derivatives (FAD) and
`placebo. RI, Remission index.
`
`constant during the en tire test period. The difference
`between the groups at T6 (week 16) is significant
`(p < 0.0001 ).
`At the end of the study physicians were requested
`to assess the effects of treatment as follows: complete
`remission, good improvement, moderate improve(cid:173)
`ment, slight improvement, no change, deterioration.
`A significant difference (p < 0.0001) in favor of the
`drug group was found (Fig. 2). In 71.3% of the
`drug-treated patients the degree of remission was
`described as complete, good, moderate, or slight. In
`addition, I. 8% showed no response and l 0.2% showed
`deterioration. In the placebo group 18% had an
`complete remission to slight improvement, whereas
`82% remained unchanged or deteriorated. Analysis
`of the individual data of the pati~nts with a positive
`
`response shows that the most marked treatment ef(cid:173)
`fects were found between the second and twelfth
`treatment weeks. In I 3 of 36 patients with a positive
`response the greatest tendency towards improve(cid:173)
`ment was between the second and fourth weeks; in
`five this occurred between the twelfth and sixteenth
`weeks.
`At the end of the study the clinical symptom ar(cid:173)
`thralgia had been alleviated in the drug group com(cid:173)
`pared with the placebo group (p < 0.002). No sta(cid:173)
`tistically significant differences were found with re·
`spect to "nail changes," although in individual
`patients (n = 15) marked improvement in onycho(cid:173)
`dystrophy was seen. There was a marked difference
`(p < 0.0001) between the two groups at the end of
`the study with respect to adverse reactions. In the
`
`MYLAN PHARMS. INC. EXHIBIT 1030 PAGE 3
`
`

`

`980 Altmeyer et al.
`
`Journal of the American Academy of Dermatology
`June 1994
`
`drug group adverse reactions occurred in 75.5% of
`the patients and in the placebo group in 16.0%.
`During the entire study period abdominal distur(cid:173)
`bances such as diarrhea were reported 27 times
`(placebo twice), stomachache or stomach cramps 35
`times (placebo twice). Flush was reported 21 times
`(placebo none), skin burning twice (placebo once),
`itching once (placebo none), and heat sensations
`three times (placebo none). These figures refer to the
`total number of side effects during the entire study,
`that is, a single symptom occurring several times in
`one patient was counted several times.
`There were no changes in hemoglobin or erythro(cid:173)
`cyte count during the 16 weeks. No differences were
`detectable either between groups or within groups.
`Leukocytes showed a mild decrease in week 8 in both
`the drug group and the placebo group but showed no
`further changes after this time. The between-group
`comparison showed no significant difference for
`week 16, w:hereas the within-group comparison
`showed a significant decrease in the drug group
`(p = 0.0163). Eosinophils showed a significant in(cid:173)
`crease in the drug group from 2.0% (TO) to 3.4%
`(T2) (p < 0.05). A further increase was observed at
`T4 ( 4. 7%) but was not significant. Eosinophilia of
`28% was found in one patient. Eosinophil counts re(cid:173)
`mained unchanged in the placebo group. In the drug
`group a nonsignificant reduction in lymphocyte
`counts was measured between TO and T6. In the
`placebo group the values remained unchanged. The
`values for platelets, bilirubin, urea, creatinine, glu(cid:173)
`cose, alkaline phosphatase, transaminases, gamma(cid:173)
`GT, cholesterol, triglycerides, and urinalysis did not
`change significantly in either group. There were no
`significant differences in creatinine clearance in ei(cid:173)
`ther group.
`Treatment was terminated prematurely in 19 pa(cid:173)
`tients (38.8%) in the drug group and 29 (58.0%) in
`the placebo group. These withdrawals had no neg(cid:173)
`ative influence on the value of the study because the
`"carry forward last value" method was applied. The
`19 patients in the drug group terminated treatment
`for the following reasons: four because of side
`effects, five because of deterioration; 10 gave several
`reasons (e.g., "no change, increase in the extent of
`the disease, and side-effects"). Gastrointestinal side
`effects were the main reasons for termination. By
`comparison most of the drop-outs in the placebo
`group were due to worsening (n = 22), one because
`of gastrointestinal disturbances and six because of
`general dissatisfaction with the outcome of treat(cid:173)
`ment.
`
`DISCUSSION
`
`The results of our multicenter, randomized, dou(cid:173)
`ble-blind clinical trial clearly confirm the antipsori(cid:173)
`atic efficacy of the fumarate mixture. It is indicated
`for treatment of extensive severe psoriasis that no
`longer responds to external therapy but not for sta(cid:173)
`ble chronic plaque psoriasis. 12 The clinical results
`were good in labile or pustular psoriasis.
`The main side effects of the fumarates are diar(cid:173)
`rhea, nausea, or other gastrointestinal complaints7-9
`· that limit the use of the preparation. Expected gas(cid:173)
`trointestinal problems were the reason we chose a
`slow increase in dosage in the first weeks of treat(cid:173)
`ment. Experience has shown that this leads to better
`tolerability. Flushing occurs Y2 to 2 hours after tak(cid:173)
`ing the fumaric acid esters and persist for up to Y2
`hour. They were described as tolerable by all pa(cid:173)
`tients and did not lead to discontinuation of treat(cid:173)
`ment in any of them. The reason for the flush is not
`known.
`The relatively late response of some patients to
`treatment should be noted. In 36.1% of responders,
`the maximal effect was between the second and
`fourth week. Five patients were distinct late re(cid:173)
`sponders with a maximal effect between the twelfth
`and sixteenth weeks. We suspect that fumarates
`show clinical effects only after a saturation phase of
`several weeks. A definite disadvantage of the study
`design was the composition of the drug itself. The
`administered preparation was composed of several
`fumaric acid esters and their salts so that conclusions
`from this study can be made only with respect to the
`overall mixture and not to an individual component.
`In addition, for gastrointestinal reasons the study
`protocol prescribed use of a low-strength form in the
`first 2 weeks of treatment that contained a different
`mixture ratio from that of the "forte" form.
`Some noteworthy individual findings were notre(cid:173)
`vealed by a purely statistical evaluation (e.g., the
`improvement in patients with severely mutilating
`onychodystrophy). Striking improvements were ob(cid:173)
`served from treatment with the fumaric acid esters.
`In some patients with psoriatic arthropathy (n = 7),
`the joint complaints did not respond despite notice(cid:173)
`able effects on the skin, whereas others showed im(cid:173)
`pressive clinical improvement in the joint pain.
`
`REFERENCES
`l. Schwcckendiek W. Heilungvon Psoriasis. Med Monat~chr
`1959;13:103-4.
`2. RoodnatJI, ChristiaansMHL, Nugteren-Huying WM, et
`
`MYLAN PHARMS. INC. EXHIBIT 1030 PAGE 4
`
`

`

`Journal of the American Academy of Dermatology
`Volume 30, Number 6
`
`Giandoni and Grabski
`
`a!. Akute Niereninsuffizienz bei der Behandlung der Pso(cid:173)
`riasis mit Fumarsaureester. Schweiz Med Wochenscbr
`1989;119:826-30.
`3. Dubiel W, Happle R. Behandlungsversuch mit Fumarsiiu(cid:173)
`remonoethylester bei Psoriasis vulgaris. Z Haut-Geschl Kr
`1972;13:545-50.
`4. Raab W. Treatment of psoriasis with fumaric acid and fu(cid:173)
`marates. Z Hautkr 1959;10:671-9.
`5. Petres J, KalkoffKW, Baron D, et al. Der Einfluss von Fu(cid:173)
`marsiiuremonoethylester auf die Nucleinsiiure und Pro(cid:173)
`teinsynthese PHA-stimulierter menschlicher Lym(cid:173)
`phozyten. Arch Derm Forsch 1975;251:295-300.
`6. Hagedorn M, Kalkoff KW, Kiefer G, et al. Fumarsiiure(cid:173)
`monoethylester: Wirkung auf DNA-Synthese und erste
`tierexperimentelle Befunde. Arch Derm Forsch 1975;
`254:67-73.
`7. van Dijk E. Fumaarzuurvoor de bebandelingvan patienten
`met psoriasis. Ned Tijdschr Geneesk 1985;129:485-6.
`
`8. Bayard W, Hunziker Th, Krebs A, et al. Perorale Lang(cid:173)
`zeitbehandlung der Psoriasis mit Fumarsaurederivaten.
`Hautarzt 1987;38:279-85.
`9. Nieboer C, de Hoop D, Van Loenen AC, et al. Systemic
`therapy with fumaric acid derivatives: new possibilities in
`the treatment of psoriasis. JAM ACAD DERMATOL 1989;
`20:601-8.
`10. Nugteren-Huying WM, van der Schroeff JG, Hermans J,
`et al. Fumaric acid therapy for psoriasis: a randomized,
`double-blind, placebo-controlled study. JAM ACAD DER(cid:173)
`MATOL 1990;22:311·2.
`11. Fredriksson T, Petterson U. Severe psoriasis: oral therapy
`with a new retinoid. Dermatologica 1978;157:238-44.
`12. Matthes U, Pawlak F, Altmeyer P. Oral therapy or severe
`psoriasis by derivatives of fumaric acid: an open long-term
`studyoveroneyear[Abstract].Presentedat the 18th World
`Congress of Dermatology, New York, June 12-18, 1992.
`1992:146A.
`
`Cutaneous candidiasis as a cause of delayed
`surgical wound healing
`Martin B. Giandoni, MD, and William J. Grabski, MD San Antonio, Texas
`
`Background: Reports in the literature of surgical wounds infected with Candida species are
`scant.
`Objective: We describe a subset of patients with cutaneous candidiasis whose only clinical
`finding was delayed wound healing.
`Methods: Surgical wounds managed with moist occlusive postoperative dressings were ob(cid:173)
`served for delayed healing.
`Results: Three patients are described who demonstrated delayed wound healing with failure
`to epithelialize. Fungal cultures from each patient revealed heavy growth of Candida. The
`problem resolved quickly with a modified wound care regimen and application of an anti yeast
`cream.
`Conclusion: Cutaneous candidiasis can be a cause of delayed wound healing, especially in
`surgical wounds treated with antibacterial ointments and occlusive dressings.
`(J AM ACAD DERMATOL 1994;30:981-4.)
`
`Cutaneous candidiasis associated with a surgical
`wound is probably more common than is generally
`recognized. 1• 2 Cutaneous candidiasis usually ap(cid:173)
`pears as a brightly erythematous eruption with su(cid:173)
`perficial erosions, crusting, and small pustules in
`both a central and satellite distribution. Occasion(cid:173)
`ally this appearance is associated with a surgical
`wound, but few reports in the literature describe this
`complication. We describe three illustrative pa-
`
`From the Dermatology Service, Brooke Army Medical Center.
`Presented at the national meeting of The American Society for Derma(cid:173)
`tologic Surgery, Charleston, S.C., March 18, 1993.
`Reprints not available.
`16/1/52479
`
`tients, although we have seen many more, with sur(cid:173)
`gical wounds that failed to heal completely after an
`extended period. We postulate that cutaneous can(cid:173)
`didiasis associated with a surgical wound that fails
`to reepithelialize is common. This phenomenon has
`been briefly noted previously,2 and we believe that it
`should be emphasized further. We discuss the spec(cid:173)
`trum of clinical presentation of this condition, the
`factors that favor cutaneous candidiasis in a surgi(cid:173)
`cal wound, and a simple regimen to treat the condi(cid:173)
`tion.
`
`CASE REPORTS
`Case 1. An 81-year-old woman had a large basal cell
`carcinoma excised from her left cheek. The defect re-
`981
`
`MYLAN PHARMS. INC. EXHIBIT 1030 PAGE 5
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`