dEALTH SCIENCES UBRAt Y
`University of Wisconsin
`$~' _
`of :~n'" ~ inrlAn Dr. !'v'hrli~0"" Wis 53706
`
`Sawai (IPR 2019-00789), Ex. 1031, p. 001
`
`

`

`r-(cid:173)
`I
`
`JOURNAL of the
`AmeRICaN ACaDemy OF
`DerMaTOLOGY
`
`Copyright © 1989 by the American Academy oj Dermatology. Inc.
`
`CONTENTS April 1989
`
`CONTINUING MEDICAL EDUCATION
`
`Biology of sweat glands and their disorders. I.
`Normal sweat gland function
`K. Sato, W. H. Kang, K. Saga, and
`K. T. SatD Iowa City, Iowa
`
`CME examination
`
`Answers to CME examination (Identification
`No. 889-103), March 1989 issue of the
`JOURNAL OF THE AMERICAN ACADEMY OF
`DERMATOLOGY
`
`CLINICAL AND LABORATORY STUDIES
`
`Penile melanosis
`Jean Revuz, MD, and Thierry Clerici, MD
`Cretei/, France
`
`Lymphomatoid granulomatosis: Two cases with
`skin involvement
`Charles Camisa, MD Cleveland, Ohio
`
`In vivo binding site of pemphigus vulgaris
`antibodies and their fate during acantholysis
`Keiji Iwatsuki, MD,
`Masahiro Takigawa, MD,
`Shunsuke Imaizumi, MD,
`and Mizuho Yamada, MD
`H amamatsu, Japan
`
`Cutaneous diseases preceding diagnoses of
`lymphoreticuiar malignancies
`Marvin H. Klapman, MD
`Los Angeles, California
`
`537
`
`564
`
`566
`
`567
`
`571
`
`578
`
`583
`
`Continued on page 7 A
`
`5A
`
`"
`
`Editor
`Richard L. Dobson, MD
`Associate Editor
`Bruce H. Thiers, MD
`Editorial Office
`Department of Dermatology
`Medical University of South Carolina
`171 Ashley Ave.
`Charleston, SC 29425-2215
`803-792-5858
`
`Assistant Editors
`Philip C. Anderson, MD
`Columbia. Missouri
`Walter H . C. Burgdorf, MD
`Albuquerque. New Mexico
`Philip M. Catalano, MD
`Bradenton. Florida
`P. Haines Ely, MD
`Grass Valley. California
`Pearl E. Grimes, MD
`Culver City. California
`W . Clark Lambert, MD
`Newark. New Jersey
`Alfred T. Lane, MD
`Rochester. New York
`W. Mitchell Sams, Jr., MD
`Birmingham. Alabama
`Daniel N . Sauder, MD
`Hamilton. Ontario
`Maria L. Chanco Turner, MD
`Washington. D.C.
`Ronald G. Wheeland, MD
`Sacramento. California
`Founding Editor
`J. Graham Smith, Jr., MD
`Augusta. Georgia
`
`Vol. 20, No.4, April 1989, the Journal of the Ameri(cid:173)
`can Academy of Dermatology (ISSN 0190-9622) is
`published monthly
`by
`The C.V. Mosby
`Company, 11830 Westline Industrial Dr.. St. Louis,
`MO 63146-3318. Second class postage paid at St.
`Louis, MO, and additional mailing offices.
`Postmaster: Send address changes to The C.V. Mosby
`Company. 11830 Westline Industrial Dr., St. Louis,
`MO 63146-3318.
`Annual subscription rates: $65.00 for individuals,
`$120.00 for institutions.
`Printed in the U.S.A. Copyright @ 1989 by the
`American Academy of Dermatology, Inc .• P.O. Box
`3116: Evanston, IL 60204-31 16.
`
`April 1989
`
`Sawai (IPR 2019-00789), Ex. 1031, p. 002
`
`

`

`Volume 20
`Number 4
`April 1989
`
`Annular erythema with primary Sjogren's syndrome
`
`associated wi.th autoimmune disorders in their inothers.
`Dermatologica 1977;154:1 15-27.
`18. Miyagawa S, Kitamura W, Yoshioka J, et al. Placental
`transfer of anticytoplasmic antibodies in annular erythe(cid:173)
`ma of newborns. Arch Dermatol 1981;117:569-72.
`
`19. Usuda T, izawa Y, Yasue T, et al. Four cas~ of Sjogren
`syndrome having erythematous cutaneous manifestations.
`Jpn J Dermatol 1982;92:489-501.
`20. Cohen PR, Kurzrock R. Sweet's syndrome and malignan(cid:173)
`cy. Am J Med 1987;82:1220-6.
`
`Systemic therapy with fumaric acid derivates: New
`possibilities in the treatment of psoriasis
`c. Nieboer,a D. de HOOp,b A. C. van Loenen,c P. N. 1. Langendijk,C and E. van Dijka
`Amsterdam and Ede-Benneko'm, The Nethert"ands
`
`For the past two decadeS fumari~ acid (FA) therapy has become an increasingly popular
`treatment ill Western Europe for psoriasis. FA tlierapy originally was developed by
`Schweckendiek and subsequently standardized by Schafer. Schafer's fumaric acid
`compound therapy (FACT) consists of the oral intake of dimethylfumaric acid ester
`(DMFAE) and several salts of monoethylfumarlc acid ester (MEFAE) in combination
`with topical fumaric acid therapy (1% to 3% MEFAE in an ointment or FA in bathing
`oils) and a diet. Schafer claiined excellent results in a large number of patients.
`Preliminary studies by German dermatologists, however, revealed contradictory therapeu(cid:173)
`tic results and serious side effects, and FA treatment was soon abandoned by
`dermatologists. To assess the value of FA therapy we conducted an open pilot study of 36
`patients in which FACT therapy appeared to be rather effective. Thereafter, several
`controlled studies with MEF AE sodium in two different dosages versus placebo, and
`DMFAE versus placebo, were done. The results indicated that MEFAE sodium in
`dosages up to 240 mg daily was ineffective, whereas daily dosages of 720 mg resulted in a
`significant decrease in scaling and itching but did not affect extension of the eruption.
`DMFAE, 240 mg daily, produced a sigllificant amelioration and prevented extension.
`Side effects of FA treatment were nausea, diarrhea, general malaise, and severe
`stomachache. Mild disturbances of liver and kidney function during treatment were
`observed with the 720 mg dosage of MEFAE and with the 240 mg dosage of DMFAE.
`Moreover, a relative lymphopenia with a selective decrease of suppressor T lymphocytes
`occurred in about 50% of the patients treated with DMFAE. Although oral therapy with
`FA derivatives has to be considered experimental, it may be a new possibility in the
`systemic treatment of psoriasis. (J AM ACAD DERMATOL 1989;20:601-8.)
`
`HISTORY AND SUMMARY OF THE
`LITERATURE
`
`A new therapy, called the fumaric acid (FA)
`therapy, has become popular in the past 20 years in
`
`From the Departments of Dermatology,' and Clinical Pharmacy,'
`Free University Hospital, Amsterdam, and Stichting Ziekenhuis(cid:173)
`voorzieningen Gelclerse Vallei, Ede-Bennekom. b
`Accepted for publication May 24, 1988.
`Reprint requests: C. Nieboer, PhD, Department of Dermatology, Free
`University Hospital, Postbus 7057, 1007 MB Amsterdam, The
`Netherlands.
`
`Western Europe among thousands of patients with
`psoriasis. This therapy was initiated by Schwecken(cid:173)
`diek, a: biochemist who himself had psoriasis. I In
`further publications he introduced monoethylfu(cid:173)
`maric ester (MEF AE) and dimethylfumaric ester
`(DMFAE) because FA was poorly absorbed by the
`gastrointestinal tract. 2 This therapy was standard(cid:173)
`ized by Schafer, a Germari general practitioner,
`who added a strict diet in which patients were told
`to avoid several species, nuts, etheric oils, and
`wine. 3 A clinic specializing in this therapy was
`founded in Leysin, Switzerland.
`
`601
`
`Sawai (IPR 2019-00789), Ex. 1031, p. 003
`
`

`

`602 Nieboer et al.
`
`Previously reported results
`With this regimen, called fumaric acid com(cid:173)
`pound therapy (FACT), Schafer4 claimed a con(cid:173)
`siderable improvement in 70% of his 900 patients,
`with 20% total remission. Approximately 15%
`showed a moderate improvement, and 15% did not
`respond. In addition, a considerable unprovement
`of psoriatic arthritis was noted in many patients. In
`The Netherlands, Kunst5 saw similar results in 62
`patients. Both Schweckendiek6 and Schafer sup(cid:173)
`port the systemic therapy with topical application
`of 1% t6 3% FA and/or MEFAE in bathing oils
`aI1d ointments.6 The FA therapy initially was
`rejected by dermatologists on the grounds of con(cid:173)
`tradictory results 7 and of nephrotoxic and hepato(cid:173)
`toxic side effects,s.9 but the need for more reliable
`information was pointed out. 10 Recently a 50%
`success was described in an open long-term study in
`13 patients. I I Up to now double-blind studies have
`not been performed.
`
`Pharmacology and treatment
`The systemic prescription consisted initially of
`several mixtures of FA, DMFAE, and salts of
`MEFAE: calcium (Ca), ferrous (Fe), potassium
`(K), zinc (Zn), magnesium (Mg), cupric (Cu),
`manganese (Mn), and lithium (Li). Later this was (cid:173)
`simplified into two prescriptions: (1) enteric-coated
`tablets containing 120 mg DMFAE and MEFAE
`(FAE-forte): 87 mg Ca, 5 mg Mg, and 3 mg Zn
`and (2) enteric-coated tablets with 30 mg DMFAE
`and MEFAE (FAE-mitis): 56 mg Ca, 5 mg Mg,
`and 3 mg Zn. Usually medication was started with
`one F AE-mitis tablet a day. This dosage was
`increased weekly or monthly to a maximum dose of
`six F AE~forte tablets. When remission took place,
`the dosage was gradually reduced to a maintenance
`dose, usually one to three F AE-forte tablets a day.
`The pharmacologic and pharmacokinetic proper(cid:173)
`ties of the FA esters are unknown. Schwecken(cid:173)
`diekl2 based his therapy on the hypothesis that
`psoriasis is characterized by a defective carbohy(cid:173)
`drate metabolism in which the fumaric acid cycle,
`is disturbed. FA was
`especially it oxidation,
`reaction. Schaferl)
`thought
`to stabilize
`this
`assumed a relative cellular FA deficiency in psori(cid:173)
`asis. Experimental evidence for these hypotheses
`was not produced, however. In vitro experiments
`showed that MEFAE exhibited DNA synthesis in
`phytohemagglutin-stimulated lymphocytes. 14. 15 FA
`appeared to cause a 50% to 80% inhibition of the
`
`Journal of the
`American Academy of
`Dermatology
`
`solid growth of Ehrlich tumor cells in mice.16 In
`contrast it had no deleterious effect on the mono(cid:173)
`layer development of mouse and chicken embryo
`cells but exhibited a protective effect against toxic
`agents such as mitomycin C and aflatoxin. 17 Phar(cid:173)
`macokinetic studies with 1 gm FA showed no
`change in the serum FA levels in men. IS No
`pharmacokinetic studies have been performed with
`DMFAE and MEFAE, which probably are
`absorbed more readily than FA because of their
`better lipophilic properties. 19
`
`Side effects and toxicity
`
`The occurrence of serious side effects is a
`controversial matter. In mice the LD50 of FA is
`0.266 mg/gm body weight,16 and the LD50 for
`MEFAE is 6.88 mg/gm body weight, whereas
`dosages of more than 0.086 mg/gm caused toxic
`reactions in the heart muscle and the renal tubuli. 15
`With a solution of the F AE-forte tablets a similar
`LD50 occurred in mice and rats. In female animals
`the LD50 was higher than in males. II In human
`beings side effects20
`included flushing, which
`appeared 10 to 15 minutes after intake and lasted
`for half an hour in more than 50% of patients, and
`gastric and esophageal pain, nausea, and vomiting
`in 5% to 10%. These effects have led many patients
`to stop FA therapy. The use of enteric-coated
`tablets diminished these complaints considerably.
`In an inquiry of 32 patients who were treated in
`Leysin, van Dijk20 noted general malaise (7/32),
`dizziness (3/32), and initial rise of body tempera(cid:173)
`ture. Proteinuria was noted in three of six patients
`with extensive psoriasis after topical application of
`3% MEF AE in ointment. S Other authors did not
`observe nephrotoxicity even after long-term sys(cid:173)
`temic use of FA derivatives. I I, 13 Rise of the serum
`guanosine triphosphate level was seen by Kunst in
`19 of 62 patients and a drop in the peripheral
`lymphocyte count in 31 patients,5 both of which
`disappeared after therapy was discontinued. Con(cid:173)
`tact of MEFAE and DMFAE with normal skin
`caused an itching maculopapular erythema around
`psoriatic lesions.4 A few hours after pharmacy
`technicians had been capsulating FA derivatives,
`an itching erythema on their faces and arms also
`was noted.21
`
`Present study
`There were several reasons for our group to investi(cid:173)
`gate FA therapy despite lack of knowledge of its
`
`Sawai (IPR 2019-00789), Ex. 1031, p. 004
`
`

`

`Volume 20
`Number 4
`April 1989
`
`Systemic therapy with fumaric acid derivatives 603
`
`pharmacologic and toxicologic properties. The first was
`strong pressure from the Dutch Federation of Psoriasis
`Associations, and the second was based on the results of
`two "protocolled" inquiries done by van Dijk; his first
`protocol was published in 1985.20 Both appeared to
`confirm the results reported by Schafer. Third, we
`observed that a distinct deterioration occurred in eight
`former Leysin patients after withdrawal of MEFAE
`from the FACT therapy. 22 Finally, an increasing num(cid:173)
`ber of patients with psoriasis were being treated with a
`possibly potent and perhaps dangerous therapy without
`sufficient medical supervision.
`This report comprises one open study of the FACT
`therapy, three controlled studies with MEFAE and
`DMFAE, one dose-finding comparative study with
`MEFAE, and one long-term open study with DMFAE.
`To the best of our knowledge this is the first report of
`controlled studies with FA esters in the treatment of
`psoriasis.
`
`PATIENTS
`
`Only patients older than 18 years of age with stable
`nummular and plaque psoriasis with at least 10%
`involvement of the body surface were included. Exclud(cid:173)
`ed were patients with erythrodermic psoriasis and
`generalized pustular psoriasis. FA treatment was started
`after previous therapy had been discontinued at least 2
`weeks. The studies were performed under a protocol
`approved by the Hospital's Ethical Committee.
`
`MATERIALS AND METHODS
`
`Patients were advised to take the FA medication in
`two daily divided dosages after meals. Topical treatment
`consisted of the application of bland creams or oint(cid:173)
`ments. Mild topical corticosteroids were allowed only on
`the face and the hands.
`Patients were seen at 4-week intervals. At each visit
`evaluation was done according to a psoriasis severity
`score based on extension of the eruption, scaling,
`redness, thickness of the lesions, and itching. In this
`system zero (0) represents the absence of signs or
`symptoms. The extension of the eruption was scored
`from 0 to 5, depending on the percentage of the body
`surface involved (1, 1 % to 10%; 2, 10% to 20%; 3, 21 %
`to 35%; 4, 36% to 50%; and 5, >50%). Zero to 3 was
`scored for the scaling (1, mild; 2, moderate; 3, heavy),
`redness (1 , rose; 2, red; 3, purple-red), thickness (1,
`slight induration; 2, moderate induration; 3, induration
`and elevation), and itching (1, slight; 2, moderate; 3,
`severe). The minimal score was 0, the maximal 17.
`After the final visit the effect of the treatment was
`estimated according to the final score and expressed as a
`percentage of the initial score. Statistical analysis was
`carried out with the chi-square test. Laboratory tests
`performed monthly included urinalysis; WBC count
`
`with differential; determination of hemoglobin, serum
`creatinine, blood urea nitrogen (BUN), transaminase,
`and alkaline phosphatase levels; and prothrombin and
`glucose times. At each visit the presence of following
`side effects were noted: fiushings, nausea, stomachache,
`dizziness, and headache.
`In the 12 patients in whom lymphopenia developed,
`the percentage of T and B cells and the thyroid serum
`ratio were determined.
`Study I: an open study with FACT therapy. This
`study included 36 patients, 15 women and 21 men, of
`whom 34 were evaluable. The average observation time
`was 9.7 months (1 to 32 months). Previous treatments
`had been unsatisfactory according to the patients.
`Medication started with one enteric-coated FAE-forte
`tablet a day the first week, two the next, and three
`during the third week. Depending on the results the
`dosage was increased to a maximum of six tablets a day.
`The average maintenance dosage was three to four
`tablets a day. In case of serious gastrointestinal com(cid:173)
`plaints FAE-mitis tablets were given during the first few
`weeks. All patients received a printed diet list.
`Study II: controlled study with MEF AE sodium
`(Na). In a double-blind study 240 mg MEFAE-Na was
`compared with placebo in 38 patients (22 women and 16
`men). Treatment started with one capsule of 60 mg
`MEFAE-Na or placebo a day for a week. The dosage
`was increased in 3 weeks to a maximum of 240 mg. The
`observation time was 4 months, from September until
`January.
`Study III: controlled study with DMFAE. In a
`double-blind study 240 mg DMFAE was compared
`with a placebo in 42 patients, 19 women and 23 men.
`The treatment schedule was similar to that in study II.
`The medication consisted of capsules filled with 60 mg
`enteric-coated granulate of DMFAE or with placebo
`granulate to a maximum dosage of up to four capsules a
`day. The observation time was 4 months, from October
`until February.
`Study IV: comparative study of 720 mg MEFAE(cid:173)
`Na compared with 240 mg MEFAE-Na. This dose(cid:173)
`finding study was performed because the daily 240 mg
`dosage of MEF AE was ineffective. It was performed in
`20 patients, 12 women and 8 men: 10 had been treated
`with 240 mg MEF AE and 10 with placebo in the
`previous 4 months. The first group was given 720 mg
`daily, the latter 240 mg. The observation time was 3
`months, from January until April.
`Study V: open continuation study with DMFAE.
`This open study comprised 56 patients. Thirteen of them
`had not responded
`to MEFAE-Na therapy, and
`DMFAE therapy was begun in September. After study
`III was finished in January a group of 30 patients, 20
`from the placebo group and 10 from the DMFAE
`group, entered the continuation study. The remaining 26
`
`Sawai (IPR 2019-00789), Ex. 1031, p. 005
`
`

`

`604 Nieboer et al.
`
`Journal of the
`American Academy of
`Dermatology
`
`Table I. Results of fumaric acid derivatives in psoriasis with the use of different treatment schedules
`(studies I-V)
`
`Study
`
`I: Open FACT studyt
`II: Double-blind study
`MEFAE-Na (240 mg)
`Placebo
`III: Double-blind study
`DMFAE (240 mg)
`Placebo
`IV: Comparative study
`MEFAE-Na (720 mg)
`MEFAE Na (240 mg)
`V: Open long-term study
`DMFAE (240 mg)
`
`n
`
`36
`
`19
`19
`
`22
`20
`
`10
`10
`
`56
`
`<25
`
`Improvement (%)*
`I
`I
`25-50
`
`>50
`
`Deteriorated:j:
`
`Discontinued
`
`4(11%)
`
`6(17%)
`
`23(64%)
`
`0(0%)
`
`3(8%)
`
`9
`8
`
`4
`12
`
`3
`6
`
`6
`5
`
`6
`1
`
`4
`1
`
`1
`2
`
`6
`0
`
`3
`3
`
`3
`4
`
`0
`5
`
`0
`0
`
`1
`1
`
`6
`2
`
`0
`0
`
`14(25%)
`
`12(22%)
`
`19(33%)
`
`0(0%)
`
`Early§
`11(20%)
`
`Latell
`4(7%)
`
`*Measured according to a psoriasis severity score (see text).
`tFAE-forte and a dietary regimen (see text).
`:j:Final score> 125% of the initial score.
`§Discontinuation because of gastrointestinal complaints.
`IIDiscontinuation because of deteriorated laboratory values.
`
`patients were admitted as new patients between Septem(cid:173)
`ber and February. All patients were treated with
`capsules filled with 60 mg enteric-coated granulate of
`DMFAE. Dosages ranged from 60 to 240 mg a day.
`The observation times ranged from 4 to 9 months.
`Study VI: controlled study with topical MEF AE. In
`this double-blind left/right trial, six patients, three
`women and three men, with symmetric lesions on the
`limbs were treated with 3% MEFAE-Na in white
`petrolatum versus white petrolatum alone. The observa(cid:173)
`tion time was 3 weeks.
`Parallel with this study, the skin toxicity of MEFAE
`was investigated in 12 healthy control subjects, seven
`women and five men. Different concentrations of
`MEFAE-Na (i.e., 0.3%, 1%,3%) in white petrolatum
`were applied at night on the same spots of the volar side
`of the right forearm for 5 days. Reactions were noted
`after the first, the third, and the fifth nights.
`
`THERAPEUTIC RESULTS
`
`The results of studies I to V are summarized in
`Table 1.
`
`Study I: FACT treatment
`
`Of the 36 patients 23 showed an improvement of
`more than 50% and 16 more than 90%. Decreased
`itching and scaling usually began at the end of the
`first month of treatment. In the next month
`induration of thickness decreased gradually and
`lesions started to disappear. In the months thereaf(cid:173)
`ter improvement continued. Lesions of the legs and
`
`scalp were the last to improve, and nails showed
`little tendency to improve. Of 26 patients who did
`not observe the diet strictly, 25 did not notice any
`. negative influence on the psoriasis. Arthritis com(cid:173)
`plaints diminished or disappeared in 7 of 10
`patients with psoriatic arthritis. Two patients with(cid:173)
`drew from the therapy without reason, and one
`stopped because of serious gastrointestinal com(cid:173)
`plaints.
`
`Study II: double-blind study with 240 mg
`MEFAE-Na versus placebo
`
`There was no difference between the numbers of
`improved, unimproved, or deteriorated cases in
`both groups. The average final score was the same
`in both groups, and so were the average final scores
`of each factor. Only the itching score showed a
`greater drop in the MEF AE-N a group than in the
`placebo group.
`
`Study III: double-blind study with a 240 mg
`DMF AE versus placebo.
`
`In this study there was a significant difference
`(p < 0.01) between the results of the DMFAE
`group versus the placebo group regarding the
`numbers of moderately and greatly improved cases.
`Improvement started usually within 6 weeks. The
`average final total score in the DMF AE group
`dropped to 60% versus a rise to 105% in the
`placebo group. This difference between both
`
`Sawai (IPR 2019-00789), Ex. 1031, p. 006
`
`

`

`Volume 20
`Number 4
`April 1989
`
`Systemic therapy with fumaric acid derivatives 605
`
`Table II. Side effects of fumaric acid derivatives in psoriasis therapy
`
`1
`-t
`16
`1
`1
`
`Side effects
`
`Gastrointestinal (nausea, stomachache, diarrhea)
`Generalized malaise
`Flushing/tingling of face
`Headache
`Dizziness
`Papular rash
`Laboratory findings
`Proteinurea
`Elevation of serum levels
`Creatinine
`BUN
`Transaminase, prothrombin time,
`glucose time
`Alkaline phosphatase
`Leukocytopenia «3.5 X 109/L)
`Lymphopenia «20%)
`.
`«0.5 X 109/L)
`
`1(36)
`
`14
`2
`20
`
`3
`
`1
`
`10
`1
`1
`
`3
`
`2
`2
`2
`
`2
`
`V(56)
`
`29
`11
`11
`1
`1
`2
`
`4
`
`1
`1
`2
`
`2
`5
`25
`3
`
`16
`6
`6
`
`2
`
`1
`2
`14
`1
`
`*1, FACT treatment; II, 240 mg MEFAE-Na vs placebo (only MEFAE sodium responsible but DMFAE groups are mentioned). III, 240 mg
`DMFAE vs placebo (only MEFAE sodium reponsible but DMFAE groups are mentioned); IV, 720 mg MEFAE sodium vs 240 mg MEFAE
`sodium (only 720 mg group mentioned); V, 240 mg DMFAE continuation study.
`tNo abnormalities detected.
`
`groups included all factors. The extent of eruption
`showed a drop to 67% in the DMF AE group versus
`a rise to 123% in the placebo group. Two of three
`patients with psoriatic arthritis reported improve(cid:173)
`ment. Nail lesions, found in nine patients of the
`DMFAE group, improved in two cases. Six of 22
`DMFAE-treated patients had to stop therapy
`because of serious gastrointestinal complaints dur(cid:173)
`ing the first 2 weeks of the trial.
`
`Study V: comparative study 720 mg versus 240
`mg MEFAE-Na
`
`No difference was seen between the 720 mg
`versus the 240 mg regimen with regard to the
`number of improved patients. The average final
`scores of the total groups and the extent of the
`eruption, the redness and the thickness were the
`same, but significant differences (p < 0.05) were
`noted between the final scores of scaling and
`itching of both groups.
`
`Study V: open continuation study with 240 mg
`DMFAE
`In this study 22% of the cases showed moderate
`and 33% considerable improvement. This improve(cid:173)
`ment included all factors and was maintained in all
`except two patients who had a serious relapse
`despite therapy. In seven of nine patients with
`
`psoriatic arthritis there was an improvement of the
`involved joints. Nail abnormalities present in 15
`patients showed little or no tendency to disappear,
`except in three patients who were treated for more
`than 6 months. Eleven patients (20%) had to stop
`therapy because of serious gastrointestinal com(cid:173)
`plaints.
`
`Study VI: double-blind left/right study with
`3% MEFAE-Na in white petrolatum
`
`During the 3 weeks of observation no difference
`was found between the placebo- and the MEF AE(cid:173)
`Na-treated side.
`
`SIDE EFFECTS
`
`The incidence of the various side effects is
`summarized in Table II. Gastrointestinal com(cid:173)
`plaints and flushing with tingling of the face and
`upper part of the arms for about 30 minutes were
`the most frequent side effects in study I. Gastroin(cid:173)
`testinal symptoms were in nearly all cases gastric
`and/or esophageal pain, sometimes accompanied
`by nausea and vomiting. In one case these com(cid:173)
`plaints led to discontinuation of the therapy. Diar(cid:173)
`rhea occurred in three cases.
`From studies II to V it appeared that the
`gastrointestinal symptoms were caused mainly by
`DMFAE. The enteric-coated FAE-forte tablets in
`
`Sawai (IPR 2019-00789), Ex. 1031, p. 007
`
`

`

`606 Nieboer et al.
`
`Journal of the
`American Academy of
`Dermatology
`
`Table III. Percentage of lymphocytes in WBCs and immunotyping of peripheral lymphocytes in 12
`patients with DMF AE-induced lymphopenia
`
`Lymphocytes
`
`Normal
`
`Percentage in peripheral blood
`15%-40%
`Before treatment
`15%-40%
`After treatment
`1.9 ± 0.6 X 109 jL
`Number after
`Ficoll isolation
`Pan T
`T helper
`T suppressor
`Th-Ts ratio
`B lymphocytes
`
`70 ± 10%
`48 ± 5%
`29 ± 5%
`1.7 ± 0.4%
`14 ± 5%
`
`Patient No.
`
`12
`
`20
`11
`0.8
`
`59
`45
`16
`2.8
`4
`
`25
`14
`0.6
`
`50
`43
`5
`8.6
`3
`
`23
`12
`0.6
`
`51
`42
`8
`5.2
`14
`
`21
`13
`1.1
`
`58
`34
`12
`2.8
`2
`
`16
`13
`0.6
`
`66
`54
`16
`3.4
`4
`
`27
`7
`0.8
`
`70
`55
`16
`3.4
`6
`
`22
`8
`0.7
`
`45
`45
`6
`7.5
`10
`
`24
`15
`1.3
`
`25
`12
`0.2
`
`25
`12
`0.5
`
`24
`11
`10
`11
`0.1 0.6
`
`71
`54
`41
`78
`42
`36
`56
`60
`15
`6
`15
`13
`3.7 6.0 2.8 4.6
`4
`9
`8
`11
`
`76
`50
`14
`3.7
`7
`
`study I caused less frequent and less serious
`stomach pain and nausea than the enteric-coated
`DMFAE in studies III and V. In those studies
`about 20% of the patients stopped therapy. On the
`other hand, the feelings of flushing and tingling
`were less intense and less frequent in the DMF AE
`groups than in the MEF AE-N a groups. In the
`latter about 90% of the patients had these sensa(cid:173)
`tions intermittently.
`Proteinurea occurred in 3 of 10 patients treated
`with 720 mg MEF AE-N a but was not noticed in
`patients treated with 240 mg MEF AE-N a. In two
`cases there was a rise in serum creatinine and
`BUN. These disturbances also were found in the
`DMF AE groups. Abnormal liver function test
`results were seen in the 720 mg MEF AE group
`and with long-term DMFAE therapy. Mter dis(cid:173)
`continuation of treatment normalization took place
`within 3 months. The changes in liver and kidney
`test results were not found in the FACT treatment
`of study 1. An important side effect of DMFAE
`was lymphopenia and leukopenia, which disap(cid:173)
`peared 6 months or more after discontinuation of
`the therapy. Lymphopenia was observed in about
`60% of the DMF AE-treated patients in studies III
`and V. In four the lymphocyte count dropped to
`0.5 X 109/L, requiring discontinuation of treat(cid:173)
`ment. Immunotyping in 12 cases of lymphopenia
`showed an elevated thyroid serum ratio in all cases,
`resulting from a decrease in T suppressor lympho(cid:173)
`cytes. In eight cases a decrease of the percentage of
`B lymphocytes was also seen. There was a signifi(cid:173)
`cant relation between a 50% or more improvement
`with DMF AE
`therapy
`and
`lymphopenia
`
`(p < 0.01). Lymphopenia, however, was not
`observed in study 1.
`Contact of MEF AE-N a with the normal skin of
`patients with psoriasis caused an itching and burn(cid:173)
`ing maculopapular eruption in all cases. A similar
`reaction was provoked in 10 of 12 volunteers after
`overnight application of 0.3%, 1 %, and 3%
`MEFAE-Na in white petrolatum on the volar skin
`of the right forearm. In all 10 volunteers the
`-reaction was present after one night of application.
`No clear differences between the particular per(cid:173)
`centages were noted.
`
`DISCUSSION
`
`The results of our studies seem to confirm the
`therapeutic properties of FA ester in psoriasis as
`reported by Schafer. The influence of the knowl(cid:173)
`edge of side effects on the reliability of double(cid:173)
`blind studies is a matter of discussion. 23 Inasmuch
`as no better method is available, we considered this
`study design the most suitable in spite of the high
`incidence of side effects that to some extent
`violated the double-blind rules. From both double(cid:173)
`blind studies (studies II and III) it appeared that
`DMFAE was more active and that MEFAE had a
`favorable effect only on scaling and the itching
`when dosages of 720 mg/day were given. The
`therapeutic results of the FACT treatment were
`obtained with an average dosage of three and one
`half F AE-forte tablets, in which a maximal dose of
`six tablets was allowed. In study I considerably
`higher doses of DMF AE were used (i.e., 360 to 720
`mg a day) than in the double-blind and open
`continuation studies with DMFAE alone. The
`
`Sawai (IPR 2019-00789), Ex. 1031, p. 008
`
`

`

`Volume 20
`Number 4
`April 1989
`
`Systemic therapy with fumaric acid derivatives 607
`
`MEFAE doses in the FACT treatment ranged
`between 300 and 540 mg a day, that is, above the
`240 mg in the ineffective double-blind trial with
`MEF AE and below the 720 mg in the comparative
`dose-finding study. These higher doses might
`explain the better results of the FACT treatment in
`comparison with the open DMFAE treatment.
`Whether the addition of the salts of MEF AE to
`DMF AE has any additional or even potentiating
`effect will be a matter of investigation. The diet did
`not seem to influence the results. '
`The most serious subjective side effect was
`severe pain in the stomach and esophagus often
`combined with nausea and generalized malaise.
`This led to early discontinuation of therapy in 20%
`to 30% of the DMF AE-treated groups. Investiga(cid:173)
`tions revealed that more than 80% DMF AE of the
`enteric-coated granulated capsules were released
`within 30 minutes in acid medium, whereas the
`enteric-coated tablets used in the FACT treatment
`conformed to the U.S.P. standard.24 This standard
`requires no release
`in artificial gastric juice
`(pH = 1) for 2 hours and approximately complete
`release in artificial intestinal medium (pH = 6.8)
`within 45 minutes. A possible explanation of the
`adverse reactions to enteric-coated DMFAE gran(cid:173)
`ules is the comparatively rapid release in the
`stomach. Nevertheless, in the FACT treatment
`these complaints also occurred in about 40%. The
`flushing and tingling sensations in the face and
`upper portion of the arms were caused mainly by
`MEF AE salts. These also caused a toxic rash after
`contact with
`the skin. As aforementioned,
`DMFAE may have similar properties.
`Disturbances of liver _ and kidney functions were
`produced by MEFAE (720 mg) and DMFAE in
`20% and 8% of patients, respectively. They disap(cid:173)
`peared after therapy was discontinued. Surprising(cid:173)
`ly these side effects were not observed in FACT(cid:173)
`treated patients. Also, we were puzzled as to why
`the enteric-coated tablets caused almost no lym(cid:173)
`phopenia whereas this was seen in about 50% of the
`patients treated with DMF AE enteric-coated gran(cid:173)
`ulated capsules. Chemical analysis of this DMF AE
`did not reveal any impurities that might explain the
`lymphopenia. Another surprising finding was that
`the lymphopenia was caused mainly by a selective
`decrease of suppressor T cells. As has been suggest(cid:173)
`ed,25,26 this might point to a possible role of T
`lymphocytes in psoriasis. A more likely explana-
`
`tion, however, is that DMF AE acts as a cytostatic
`agent. According to pharmacokinetic principles of
`absorption rate in relation to blood levels, the peak
`blood levels obtained with enteric-coated granu(cid:173)
`lated capsules must be higher than those obtained.
`with the enteric-coated tablets. With relatively
`high peak blood levels DMFAE may be toxic to
`suppressor T celis, B cells, and to a lesser extent the
`bone marrow, as has been described for cyclophos(cid:173)
`phamide.27,28 With low blood levels DMFAE may
`exert its cytostatic effect only on dividing cells in
`the psoriatic lesions.
`
`REFERENCES
`1. Schweckendiek W. Heilung von Psoriasis vulgaris. Med
`Montatsschr 1959;13: 103-4.
`2. Schweckendiek W. Behandlung von Psoriasis mit lipoid(cid:173)
`loslichen Fumarsaureverbindungen. Medizin Heute
`1966;15:219-20.
`3. Schafer GN. Psoriasis mit Fumarsaure beherrschbar.
`Selecta 1982;17:1868-72.
`4. Schafer GN. Fumarsaure lindert die Schuppenfiechte.
`Selecta 1984;15:1260-1.
`5. Kunst L. Psoriasis behandeling. Ned Tijdschr Geneesk
`1985;7:16-24.
`6. Schweckendiek W. Fumarsaure und Psoriasis. Erfah(cid:173)
`rungsheilkunde 1981 ;30:613-21.
`7. Vonkennel J, Zingsheim M. 1st ein Heilung der Psoriasis
`iiber den Intermediarstoffwechsel moglich? Med Welt
`1961 ;12:1697-700.
`8. Dubiel W, Happle R. Behandlungsversuch mit Fumar(cid:173)
`sauremonoathylester bei Psoriasis vulgaris. Z Haut(cid:173)
`Geschlkr 1972;47:545-50.
`9. Raab W. Psoriasis-Behandlung mit Fumarsaure und
`Fumarsaureestern. Z Hautk