Britislt lournal o! DerntatoloElpl 1998; 138: 456-460.
`
`Treatment of psoriasis with fumaric acid esters: results of a
`prospective multicentre study
`
`Summary
`
`I].MROWIETZ, E.CHI].ISTOPHERS, P.ALTMEYER+ AND THE PARTICIPANTS
`GERMAN MULTICENTIiE STUDYT
`Dcparilnent ol l)crnnLolo11y, IJtli\tusiLll ol Kicl, Schittcttltthnstr 7, 2410 5 Kiel, Gcrnaty
`+DepnrLmanL oJ Dcrntntololly, lilrlirUrivcrsily Bocluntt, Boclrunt, Gcnnnny
`
`IN THE
`
`Accepted lor publication .] 7 October 1997
`
`Systemic treatment of psoriasis with fumaric acid esters (FAE) has been found effective by empirical
`means. In recent years clinical studies have con{irmed the antipsoriatic activity of a de{ined mixture
`of different FAE. llhe aim of the present. prospective multicentre study was to investigate further the
`efficacy and sal'ety of FAIJ therapy in a large number of patients with severe psoriasis vulgaris. From
`101 patients included in the study 70 completed the treatment period of 4 months. Discontinuation
`was due to adverse events in seven, lack of efficacy in two, and other reasons, such as non-attendance
`for scheduled visits, in 22 patients, Ilvaluation ofoverall efiicacy showed a decrease in psoriasis area
`and severity index of 80% after 4 months ofFAE therapy. Laboratory investigations revealed a slight
`overall decrease of lymphocytes during the treatment period which was more than 50% below
`baseline in 10 patients. During weehs 4 and 8 mean eosinophil counts were above the normal range.
`At the end of FAE therapy elevated eosinophil counts had returned to normal values. None of the
`patients showed changes in renal function parameters throughout the study. Adverse events were
`reported in 69'Yo of the patients mainly consisting of gastrointestinal complaints (5 6%) and flushing
`(31%). In five patients gastrointestinal complaints and in two patients flushing led to withdrawai
`from the study. Taken together the results of this multicentre study showed iu a large number of
`patients that systemic FH.E treatment is effective in severe psoriasis vulgaris. Transient eosinophilia
`seems to be a characteristic feature of'l-AE therapy, while lymphocytopenia is usually mild. Adverse
`effects are dose-related and consist mainly of gastrointestinal complaints and flushing.
`
`In the past, nearly all treatment modalities lbr psoriasis
`have been found by empirical means. Based on the
`assumption that psoriasis represents a disorder r,vith a
`defective citric acid metabolism, fumaric acid csters
`(FAB) were given to patients in order to replace an
`endogenous need for lumaric acid. The lirst results
`were published in 1959r and during the lbllowing
`years FAB were prescribed by a small group of physicians
`in Germany, Switzerland and the Netherlands lbllowing
`these assumptions. An antipsoriatic action of F}\E was
`seen in previous studies which were conducted iu order
`to explore the therapeutic potential of FAE.2 t These
`investigations confirmed the efficacy oi FAE in psoriasis
`and characterized possible adverse evcnts.
`This report descr:ibes the results o[ a prospective
`multicentre study conducted in 12 dermatology centres
`
`i Participating centres are listed in t.hc acl<notvledgurents.
`Correspondence: Ulrich Mrowietz. E-mail: utnrorvielz@riertnatolo-
`gy.uni-kiel.dc
`
`in Germany, The aim of this study was to investigate
`I'urther the efficacy of FAE treatment in psoriasis in a
`large number of patients with special emphasis on an
`individually based dosage of oral F}\8. Furthermore, the
`study attempted to elucidate the rate and nature ol'
`adverse events more closely with particular emphasis on
`changes in blood values and on kidney function.
`
`Patients and methods
`
`I?atient selactiorr
`A total of 101 male (n: 68) and female patients
`(n:33) from 21to 69years of age (mean: 43'4years)
`was admitted to the study alter obtaining written con-
`sent. Patients with severe psoriasis of different clinical
`types (e.g. psoriasis vulgaris, guttate psoriasis, exanthe-
`matic psoriasis) were included in the study. The psoriasis
`area and severity index (PASI) at entry was at least 12.
`
`456
`
`O 1998 British Association ofDcrnatologists
`
`Sawai (IPR2019-00789), Ex. 1028, p. 001
`
`

`

`FUMAITIC ACID ESTERS FOR PSOITIASIS 457
`
`Tablc l. Dosage schcdule oI fumaric acid esters (fAIi) Ibr the treatme nt
`ol psoriasis.'I'u'o lormulations o[ Lablets diilcring in amount and
`composition ol F'AE are available
`
`30
`
`25
`
`20
`a
`Weck Morning Noon Evening EAE lormulation S , U
`10
`
`Dosage"
`
`1
`
`1 II 2
`
`II 1 1l 1 2 2 2
`
`I 2 3 4 5 6 7 t
`
`i 9
`
`5 0
`
`0 1 2 3 4 5 6 7 B 910111213141516
`Treatment Time (weeks)
`ligurc 1. Iillicacy ol fumaric acid estcr treatment in psoriasis as
`determined by psoriasis area and severity index (PASI) Irom baseline
`(week 0) until the end ol thc stucly at week 1 6. Mean and SD, n = 78.
`
`duration of FAE treatment was l6weeks with control
`visits at O, 2, 4, 6, B, 12 and 16 weel<s.
`
`Investigtrtions for asscssfleni oJ elJtcaql, saJetLJ and
`tolerabilitpy
`
`Patients were classified according to the PASI. Pruritus,
`joint pain and nail involvement were assessed using a
`five-point score from 0 to 4, in which 0 means complete
`absence and 4 means most severe involvement. Patients
`were asked lbr :rdverse events at each visit. At the
`baseline visit and al. the end of study, complete skin
`and physical examinations wele perlbrmed in order to
`detect any changes relatecl to FAE therapy. The following
`laboratory values were determined at each visit: serum
`creatinine, blood urea and nitrogen (BUN), serum
`glutamic oxaloacetic transaminase, serum glutamic
`pyruvic transaminase, 1-glutamyl transpeptidase, uric
`acid, lactate dehydrogenase, alkaline phosphatase,
`choline esterase, bilirubin, serum cholesterol and tri-
`glycerides, electrolytes, urine chemistry, as well as com-
`plete haematological values including differential
`count. Blood pressurc ar-rd body weight were also deter-
`mined at each visit.
`
`Results
`A total ol 70 patients completed the study. Thirty-one
`patients discontinued the study at various time intervals
`because of' adverse events (gastrointestinal complaints,
`n: 5; flush, r?: 1; incre.rsing pruritus, n: 1), lack of
`inh rorc^]1c fn
`clfir'aerz t/n - ))
`)) enrl nn--.^-^li.-^-
`-
`(n: 20).
`
`low strength
`low strength
`low strength
`high strength
`high strength
`high strength
`high strength
`high strenglh
`high strength
`
`l _
`
`l III 2 2
`
`" Number oI tablets.
`
`Patients with erythrodermic psoriasis were excluded
`from the study.
`Patients receiving systemic antipsoriatic treatment
`within the Iast 4 weeks, or specific topical therapies
`including UV radiation within l week belbre FAE treat-
`ment were excluded, Furthermore, patients concomi-
`tantly treated with nephrotoxic compounds, as well as
`patients with known hypertension, impaired liver or
`kidney function, a history of malignancy, leucocytope-
`nia (<4000/pL) or lymphocytopenia (<800/pL) did
`not erter the study,
`During the study salicylic acid-containing (<2%) or
`urea-corltaining (<10%) ointments were allowed fot
`topical treatment.
`
`Studpl design
`
`The study was carried out as an open multicentre study
`in 12 dermatology centres in Germany (see acknowl-
`edgments). Patients were tre ated with EAE in tablet form
`using two lormulations differing in strength (low
`strength tablets: 30 mg dimethylfumarate, 67 mg mono-
`ethyllumarate Ca salt, 5 mg monoethylfumarate Mg salt,
`3 mg monoethyllumarate Zn salt; high strength tablets:
`120 mg dimethyllumarate, 87mg monoethyll'umarate
`Ca salt, 5 mg monoethylfumarate Mg salt, 3 mg mono,
`ethylfumarate Zn salt), supplied as Fumaderm@ initial
`and Fumaderm@ by Fumedica GmbH, Herne, Gernrany.
`Dosage of FAII was perlbrmed accor:ding to a schedule
`displayed in Table 1. The FAE dose was individually
`adiusted up to a maximum dose ol six high sl.rength
`tablets corresponding to an overall dose ol'1'2 g/day. The
`
`O 19 9 8 llritish Association ol Dermatologists , British lotnml oJ Dernatolollpl, 1 3 8, 4 5 6-4 60
`
`Sawai (IPR2019-00789), Ex. 1028, p. 002
`
`

`

`45U II.MI1OWIBTZ et al
`
`A25
`
`2.O
`
`a-
`
`l
`
`!
`
`\
`
`-l
`
`!
`
`0 1 2 3 4 5 6 7 I 910111213141516
`
`Joint Pain
`
`r-
`
`-t
`
`-l
`
`l----f
`
`--------+-----
`
`{
`
`0 1 2 3 4 5 6 7 I 910111213141516
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`q)
`
`oo
`U)
`
`ef
`
`,
`U)
`
`B 25
`z
`
`oooaefu
`
`)
`
`1.5
`
`1.0
`
`05
`
`0.0
`
`Pruritus
`
`and five (tt'/n) high strength tablets per day. The dect'ease
`in the mean PASI of all patients treated with l'AE for
`16 weeks is shown in Figure 1. From a mean PASI at
`baseline ol 20'04 therc was an 80% reduction down to
`a mean PASI of 4'03 at weel< I 5.
`
`Prm'ittts, joint pnin and nail invohtentent
`illhe rnean symptom score Ibr pruritus decreased from
`a baseline value o[ 2 04 to O'27 after 16 weeks of FAE
`therapy (Fig. 2A). For the symptom of joint pain, a
`slight reduction was seen during FAE treatment from a
`mean symptom score of 1.91 at baseline to 1'05 at
`week 16 (Fig. 2B). Nail involvement showed a slight
`improvement from a baseline mean score of 1'97 to a
`mean score ot I'22 at week 16 of FAE therapy
`(Fig. 2C).
`
`Lab o r ttt o r 11 iru e s ti g ati o ns
`No significant decrease in total leucocyte count was
`seen in the psoriasis patients treated with EAE. When
`leucocyte subtypes were analysed by differential count a
`slight decrease in the mean percentage of lymphocytes
`was noted. However, all values were within the range o[
`laboratory normal values. Only in onc patient (patieut
`66) did the total leucocyte number decrease by mor:e
`than 5 0% of baseline values alter 1 6 weeks of IIAIJ therapy
`(baseline: 9..5x103/pL; week 16: 3 9x103/pL). In a
`total of 10 patients the relative number o[ lymphocytes
`as determined by differential count decreased below
`507o of baseline values. In oue patient (patient t31)
`lynrphocytes comprised 29'lo ol white cells in the differ-
`ential count at baseline and 4% after 16 weeks o[ FAE
`treatment.
`The mean percentage of eosinophils increased above
`the laboratory normal values from week 4 to week 8 but
`was within the normal range at the end of EAE treat-
`ment at week 16. In nine patients eosinophil counts
`exceeded 20%, and in five patients eosinophil counts
`were be tween 10 and 20'k. 'lhe maximum eosinophilia
`ol 45'k was seerl at week 6 in one patient (patient 81)
`who had no eosinophils in the differential count at
`baseline. At the end of I]AE therapy the eosinophil
`count was decreased to 5% in this patient. All other
`Iaboratory parameters investigated during this study
`including serum creatinine and BUN did not show any
`signilicant changes. 'l'here was no change in blood
`pressure be{bre and at the end of the study.
`
`Nail lnwlvement
`
`-'a*
`
`a
`
`c2
`
`2
`
`>--<--
`
`_+--+-
`
`c)
`
`ooaI
`
`EfU
`
`)
`
`0.5
`
`0
`
`o 12 3 4 5 6 7 B 9'10111213141516
`Treatment Time (weeks)
`
`Figurc 2. Change in the mean symptom scores lor pruritus (-i\,
`o; n:79), joint pain (8, l; n:3.3), and nail involvernent (C, I
`n:75) in psoriasis patients where these symptoms were preseltt at
`the baseline examination during futnaric acid ester therapy lor
`I 6 wechs.
`
`Dosage and fficacy
`At the end of the study, 33 patients (46%) received the
`maximum dose of six high strength tablets per day. In
`eight patients this dose was given until week 10 and
`subsequently reduced due to treatment response. In 4{J
`patients the individual FAE dose was between one (69lo)
`
`@ 1998 British Association ol l)errlatologists, Britislt lounnl olDtrnntolollpl, 138, 456-460
`
`Sawai (IPR2019-00789), Ex. 1028, p. 003
`
`

`

`Adtterse events
`Adverse cvents were reported in 6{l patients (69%)
`treated with EA.E fbr psoriasis in this study. Most lie-
`quently gastrointestinal complaints were noted (56%
`of patients with adverse events). Gastrointestinal
`symptoms included diarrhoea, tcnesmus, meteorism,
`stomach pain, and increased fiequency of stools.
`Flushing was recognized by 31,/o of patients reporting
`adverse events. Syrnptoms cotlsisted of sudden redness
`of the skin as well as suclden heat attacks lasting
`between minutes and a few hours. In seven patients
`(7%) adverse events led to withdrawal from FAE
`treatment.
`
`Discussion
`
`The results of this study revealed that FAII treatment lbr
`psoriasis is an effective modality as demonstrated by a
`reduction in PASI ol' B0(l/o during a 16-weeh period.
`These results are in accordance with previous multi-
`centre studies reporting FAE treatment in psoriasis
`patients.a 6 Adverse events were seen in 69,/n ol'patients
`and these mainly consisted ol' gastrointestinal com-
`plaints including diarrhoea and stomach ache. Another
`adverse event specilic lbr FAII therapy consisted of
`flushing, occurring irregularly and lasting between
`minutes and hours.
`A special emphasis in this study was on the individual
`dose adjustment in order to achieve an optimal ther-
`apeutic response using the lowest close possible. I'he
`results show that 46% ol the patients required the
`maxirnum dose ol six high strength tablets per day. In
`I7'k ol these patients the dose could subsequently be
`reduced ruhile naintaining the therapeutic result. In 6,/o
`ol the patients a clinical response could be induced with
`only one high-strength tablet per day. Our data indicate
`that an ir.rdividually based dose adjustment should
`generally be performed according to the treatment
`response in order to optimize FAE ther:apy.
`Laboratory investigations revealed a slight decrease
`in leucocytes which was due to a decrease in the relative
`number of lyrnphocytes. 'I'his observation is known
`from previous short-term studies2'a and was recently
`reported in psoriasis patients treated with FAE on a
`long-term basis (up to 3 years).s ln an additional inves-
`tigation addressing this issue it was shown that B and T
`lymphocytes were equally r:cduced in number with
`CD8-positive cells being slightly more decreased in
`nurnber as compared with CD4-positivc cells,T
`In contrzrst to other systenic antipsoriatic rerneclies,
`
`FUX4ARIC ACID ESTERS FOR PSORIASIS 459
`
`therapy with F,A.E shows several aspects which appear
`unique lbr this regimen. FAE are given in increasing
`doses and these have to be balanced with the appear-
`ance of side-efl'ects, especially gastrointestinal com-
`plaints, Apparently, irritation of the gastrointestinal
`system caused by the rather large doses of difl'erent
`FAE derivatives determines the amount of drug being
`ei'fective. Such a regimen demands carefu] monitoring
`by the physician and the provision of detailed informa-
`tion to the patient. The mechanism of action of FAI in
`psoriasis is poorly understood. Earlier worl< demon-
`strated antiproliferative activity of FAE for HaCaT
`keratinocytes in vitro.s It was also shown that the
`interleukin(IL)-1cr-induced expression of ICAM-1 on
`HaCaT cells was inhibited by dimethyllumarate.e
`Other investigations have shown that monoethyl
`I'umarate inhibited thymidine incorporation in human
`lymphocyte cultures, which points towards an anti-
`proliferative effect on these cells.ro Recently, De Jong
`and coworkersll demonstrated that monomethylf'uma-
`rate stimulated Th2 responses of human T cells in vitro.
`As psoriasis is regarded as a lfh.l -type inflammatory
`disorder, the shilt in the direction of a 'I'h2 pattem rrray
`lead to improvement ol'the disease.l2
`The diversity of Thl/Th2 responsiveness could well
`play a signilicant part especially undcr treatment con-
`ditions. Thus it has been shown that Thl-regulating
`compounds, for instance interferon-ry, may worsen
`psoriasis.
`In support of this concept is the (transient) blood
`eosinophilia as seen in this study and also noted before
`by others.2'a's As II-4 is able to stimulate eosinophil-
`activating cytokines, Ibr example eotaxin,r 3 this supports
`the concept of Th2 activation.
`In a recent study it could be demonstrated that
`dimethylfumarate, but not monoethylfumarate or
`l'umaric acid, inhibits cytokine-stimulated expression
`of'the adhesion molecules ICAM-.I , VCAM-:I and E-
`selectin in human umbilical vein endothelial cells as
`measured by ELISA and nRNA expression (Northem
`blotting).ra As adhesion to endothelial cells is a crucial
`step before the emigration ol'leucocytes into the tissue,
`this observation may be ol'major importance tbr the
`anti-inflammatory effect ol'FAE. From the results of
`these Iirst experimental studies, it may be suggested
`that dilferent FAE could exert dillerential effects with
`regard to target cells and cellular I'unctions investigated.
`Finally, it is worthwhile noting that nail involvement,
`pruritus, and as shown by this preliminary evetluation,
`also joint pain become ameliorated during IAE trcat-
`ment. These observations indicate FAE efi'ectiveness
`
`O 1998 BriLish Association ol Dermatologists, British lounnl ol Dcnnntolollt, 138, 456-460
`
`Sawai (IPR2019-00789), Ex. 1028, p. 004
`
`

`

`460 U,MROWIETZ el nl
`
`even lbr those complicating signs of psoriatic skin
`disease which are still dilficult to treat. Future studies
`will help to establish more firmly the therapeutic value
`of treatment of thosc aspects oi psoriasis and also will
`eventually sort out the more efl'ective compounds
`among the various delivatives of F-AE presently used.
`
`Acknowledgments
`
`List oJ ptnticipatitl.g centres
`Bochurn: R.Hartwig, llAltmeyer; Essen: H-M.Ockenfels,
`M.Goos; Freiburg: M.Augustin, E.Schdpf; Hannover:
`J.EIsner, M.Korner, A.I(app; I(iel: ll.Mrowietz, E.Christo-
`phers; I(oln: H-J.Schulze, l'.Iftieg; Leipzig: H.Neubauer,
`U.F.Haustein; Magdeburg: R.Sabel, H.Gollnicl<; Mainz:
`R.E.Schopl, I.I(nop; Mr-inchen I: M.Rcicl<en, M.l(oll-
`mann, G.Plewig;' Miinchen II: M.Thewes, R.Engst,
`J.Ring; Miinster: U.Amann, A.Piecl<enecker,'I'.A.Luger.
`
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`
`Sawai (IPR2019-00789), Ex. 1028, p. 005
`
`

`

`Sawai (IPR2019-00789), Ex. 1028, p. 006
`
`