REVIEW ARTICLE

Fumaric acid esters for psoriasis: a systematic review

D. Smith1

Received: 15 November 2015 / Accepted: 16 May 2016 / Published online: 7 June 2016

� Royal Academy of Medicine in Ireland 2016

Abstract

Background Psoriasis is a chronic skin disease associated

with increased morbidity and mortality. Effective and safe

long term treatment options are required tomanage the illness

successfully. A number of systemic agents are available,

however, each of them has potentially significant side effects.

Fumaric acid esters (FAE) are used first line in Germany for

the management of moderate to severe psoriasis, however,

their use in Ireland is on an unlicensed basis (Clinical and

Experimental Dermatology 37:786–801, 2012).

Objectives The purpose of this literature review is to

evaluate the efficacy and safety of FAEs in the manage-

ment of moderate to severe psoriasis in adult patients. The

reviewer intends to systematically review all available lit-

erature on the efficacy and/or safety of fumaric acid esters

in the management of moderate to severe psoriasis in adult

patients.

Methods A systematic review of the literature was per-

formed by one reviewer. The PubMed, TRIP, Embase,

and Cochrane Collaboration databases were systemati-

cally interrogated to include randomised controlled tri-

als, cohort studies and case studies evaluating the

efficacy and/or safety of FAEs in the management of

moderate to severe psoriasis in adult patients. Inclusion

criteria were studies which included adults over 18 years

of age, with a diagnosis of moderate to severe chronic

plaque psoriasis, who were treated with FAEs and no

other systemic anti-psoriatic agents concurrently.

Exclusion criteria were studies involving children, mild

psoriasis, studies which did not include patients with

chronic plaque psoriasis, the use of FAE for the man-

agement of illnesses other than psoriasis, and patients

treated with more than one systemic anti-psoriatic agent

concurrently.

Results In total 19 articles were selected for review

including 2 randomised placebo controlled trials, 1 non-

randomised comparative study, 7 retrospective cohort

studies, 2 prospective cohort studies and 7 case studies.

The findings suggest that FAEs are a safe and effective

treatment option for the management of moderate to

severe psoriasis in adult patients. Gastrointestinal side

effects may occur on treatment initiation and may be

minimised by slow dose titration. Lymphocytopenia and

eosinophilia are common, however, they are rarely of

significance and there is no high level of evidence avail-

able to suggest a resultant increased risk of infection or

malignancy. Rarely alterations of renal and hepatic

function may occur, however, these are largely reversible

on treatment withdrawal.

Conclusion In conclusion, the use of FAE in the man-

agement of moderate to severe psoriasis is a promising

treatment option, especially for those patients intolerant

of, or unresponsive to other agents. If blood parameters

are closely monitored during treatment as per the Euro-

pean Medicine Agencies guidelines (European Medicines

Agency, ‘Updated recommendations to minimise the risk

of the rare brain infection PML with Tecfidera’, http://

www.ema.europa.eu/docs/en_GB/document_library/Press_

release/2015/10/WC500196017.pdf, 2015) they may be

safely used in practice. The licensing of FAEs in Ireland for

the treatment of moderate to severe psoriasis would be

desirable, increasing available treatment options.

Keywords Fumaric acid esters � Fumaderm � Psoriasis

& D. Smith

smithd1@tcd.ie

1 Department of Dermatology, University Hospital Limerick,

Limerick, Ireland

123

Ir J Med Sci (2017) 186:161–177

DOI 10.1007/s11845-016-1470-2

Introduction

Psoriasis is a chronic skin condition with systemic mani-

festations, which presents in 2–3 % of the population

[20, 24]. The disease typically has an early onset, usually

between the ages of 20 and 30. It also has a chronic

relapsing nature [6, 18]. Recent epidemiological studies

have highlighted the association between moderate to

severe psoriasis and the metabolic syndrome and cardio-

vascular disease [26]. Psoriasis patients also have a higher

incidence of depressive illness and a decreased life

expectancy [6, 26]. Given the high morbidity and increased

mortality associated with moderate to severe psoriasis

effective, affordable and safe long term treatment options

are essential.

European guidelines (2009) have focused on the man-

agement of chronic plaque psoriasis which accounts for

more than 80 % of cases. This variant is defined by sharply

demarcated, erythematous and scaly plaques, typically on

extensor surfaces [18]. Tools for assessing severity include

the Psoriasis Area and Severity Index (PASI), with mod-

erate to severe disease being defined as a PASI of[10

[18]. In addition other measures such as the Physicians

Global Assessment of disease severity (PGA), body surface

area (BSA), or quality of life indices such as the Impact of

Psoriasis on health related quality of life (HRQoL) may be

used [18]. For moderate to severe disease phototherapy,

systemic agents and biologics may be used [18]. However,

many treatment modalities carry the risk of significant side

effects.

While phototherapy is a safe treatment option, there is a

risk of actinic damage, premature skin aging and potential

carcinogenic effects [18]. In addition, many patients over

time have disease which becomes refractory to ultraviolet

light.

Systemic antipsoriatic agents include methotrexate,

cyclosporin and fumaric acid esters. Methotrexate is an

effective treatment modality. Although it is potentially

hepatotoxic, the vast majority of patients do not suffer

hepatic damage from methotrexate as it is used in pso-

riasis. Methotrexate is also teratogenic, this necessitates

that patients use effective contraception during therapy

and for 6 months post-methotrexate. While cyclosporin

therapy is valuable acutely, long term use is not advo-

cated given the risk of cutaneous malignancies, lym-

phoma, raised blood pressure and nephrotoxicity [6].

Topical and oral retinoids may also be used; however,

these are contraindicated during pregnancy and concep-

tion and may cause hypertriglyceridemia [6]. As with

methotrexate, alcohol abuse with retinoids is also prob-

lematic as it is associated with an increased risk of

hepatic toxicity.

The biological therapies licensed for psoriasis consist of

monoclonal antibodies such as infliximab, adalimumab and

ustekinumab. Biologicals or monoclonal antibodies are

highly effective; however, they may pose an increased risk

of immunosuppression, and are an expensive treatment

modality [6, 18]. There is a theoretical risk of increased

haematological malignancies; however, there is no research

evidence that biological agents used for psoriasis cause an

increased risk of lymphoma and/or haematological malig-

nancies [6].

Systemic therapy with fumaric acid esters (FAEs) has

been licensed in Germany since 1994 for the treatment of

moderate to severe psoriasis [18]. Licensed preparations

fumaderm initial and fumaderm are available. Both contain

a mixture of dimethylfumarate (DMF), and three salts of

ethyl hydrogen fumarate. DMF is considered to be the

active ingredient. FAEs are thought to have immunomod-

ulatory, anti-inflammatory, antiproliferative and apoptotic

actions on activated T cells [9]. A standard dose protocol

(Fig. 1) is recommended whereby the dose is gradually

increased to improve tolerance. Individual dose adjustment

is then made according to therapeutic response; the highest

daily recommended dose is 1.2 g (equals 720 mg DMF, 6

tablets) [18]. During therapy full blood count, liver

enzymes, urine sediment and serum creatinine must be

recorded (Fig. 2).

In the UK and Ireland the use of FAEs is on an irregular

and unlicensed basis [9]. It is unclear why fumaric acid

esters are not yet licensed for the treatment of moderate to

severe psoriasis in Ireland, while they have been success-

fully used to manage psoriasis in Germany for over

30 years. The use of such agents could offer the promise of

a safe, and effective long term treatment modality which is

more cost efficient than biological agents [11]. They also

have a 60 % 4-year drug survival, comparable with bio-

logical agents [11].

Fig. 1 FAE dosage scheme. With permission, Pathirana et al. [18]

162 Ir J Med Sci

123

While there have been some systematic reviews and

meta analyses on the safety of treatments for moderate to

severe psoriasis [15, 22], the author is unaware of any

literature reviews looking exclusively at the efficacy and/or

safety of FAEs in the management of moderate to severe

psoriasis in adult patients. The aim of this literature review

is to evaluate the efficacy and safety of FAE therapy in the

management of moderate to severe psoriasis in adult

patients.

Methods

One reviewer independently performed a literature review

of studies investigating the efficacy and/or safety of

fumaric acid ester use in the treatment of moderate to

severe psoriasis in adult patients published between Jan-

uary 1972 and December 2014. Case studies pertaining to

adult patients with moderate to severe chronic plaque

psoriasis which included evidence on safety and potential

adverse events were also selected for inclusion.

The PubMed, TRIP, Embase and Cochrane Collabora-

tion databases were systematically searched using the fol-

lowing combination of Medical Subject Headings (MeSH):

‘Psoriasis or Psoriatic AND fumaric acids or Fumarate

esters or fumarates or dimethylfumarate or fumaderm or

FAE AND toxicity or toxic or toxin or toxins or effect or

effects or outcome or outcomes or follow up or follow-up’.

The literature search was limited to articles written in

English. All references obtained from the databases were

screened. After all articles were identified, the reference

lists of each article were screened for additional relevant

articles.

Relevant studies were initially detected by reviewing the

title and abstract, and for the remaining studies by

reviewing the complete article. The literature review

included randomised controlled trials, case control studies,

cohort studies and case reports.

Inclusion criteria (Fig. 3) were adults over 18 years of

age, with a diagnosis of moderate to severe chronic plaque

psoriasis (and other variants if included), who were treated

with fumaric acid esters and no other systemic anti-psori-

atic agents concurrently. Exclusion criteria (Fig. 3) were

studies involving children, mild psoriasis, studies which

did not include patients with chronic plaque psoriasis, the

use of FAE for the management of illnesses other than

psoriasis, and patients treated with more than one systemic

antipsoriatic agent concurrently. A statement from German

experts reported that FAEs should not be used in combi-

nation with other systemic agents due to a lack of clinical

evidence [14]; for this reason studies in which patients

were treated with more than one systemic antipsoriatic

agent concurrently were excluded from this literature

review. Figure 4 summarises the study selection process.

Results

A total of 248 articles were retrieved during the database

search, 44 of which were duplicates. Of the 204 articles,

156 were excluded by title (Fig. 5). 107 of these papers

did not answer the research question, 28 articles were

unavailable in English, 3 papers evaluated the use of

FAE therapy in patients with psoriasis and multiple

sclerosis, and 9 papers looked exclusively at the use of

FAEs in the management of multiple sclerosis. A further

6 papers were excluded by title as they evaluated the use

of FAE therapy in granulomatous skin disease, granu-

loma annulare, autoimmune myocarditis, necrobiosis

lipoidica, or sarcoidosis. A further 3 papers were

excluded by title as they evaluated the use of FAE

therapy in children.

24 articles were excluded after reading the abstract (see

Fig. 5), and 6 articles were excluded on reading the full

text. 2 of these articles evaluated the use of FAEs in

patients with mild psoriasis, and 4 studies included patients

treated with FAEs and another systemic antipsoriatic agent

concurrently.

On hand searching the reference lists of selected articles,

1 further study was selected for inclusion in the review.

Fig. 2 FAE laboratory controls. With permission, Pathirana et al. [18]

Ir J Med Sci 163

123

In light of the specific aims of the study and strict

inclusion criteria, only 19 articles were finally included for

full review. The final studies included were 2 randomised

placebo controlled trials, 1 non-randomised comparative

study, 7 retrospective cohort studies, 2 prospective cohort

studies and 7 case studies. On completion of the study

selection process, data concerning all outcomes of interest

were extracted from all eligible studies and entered into

table format for evaluation (see Tables 1 and 2).

Discussion

In answer to the review question on the efficacy and safety

of fumaric acid esters in the management of moderate to

severe psoriasis in adult patients, this review found 19

studies that met the inclusion criteria. These included 2

randomised placebo controlled trials, 1 non-randomised

comparative study, 7 retrospective cohort studies, 2

prospective cohort studies and 7 case studies. The search

was limited to papers in the English language, which may

have introduced language bias. The references of each

article were searched; however, key people within the field

of psoriasis were not contacted to see if they had any

unpublished literature which could be included in the

review.

All studies examined the efficacy and/or safety of

fumaric acid use in the treatment of adults with moderate to

severe psoriasis. While all studies included participants

with chronic plaque psoriasis, some studies also included

patients with nail psoriasis, palmopustular and guttate

psoriasis. The majority of studies included patients treated

Fig. 3 Inclusion and exclusion

criteria

164 Ir J Med Sci

123

with FAE according to a standard dose protocol as previ-

ously described. The bulk of the studies were completed in

tertiary referral centres (Table 2).

Efficacy

Treatment with FAEs is suggested for adults with moderate

to severe psoriasis [18]. While they are employed as a first

line therapy in Germany, their use in Ireland remains

unlicensed [9]. Two randomised controlled trials [1, 16]

met the inclusion criteria for this literature review and both

demonstrated a statistically significant treatment response

for FAE therapy. Furthermore, all other included studies

demonstrated an improvement in the majority of psoriasis

patients managed with FAE therapy, however, there was

significant heterogeneity between the outcome measures of

treatment efficacy in the included studies.

The majority of patients were managed according to a

standard dose protocol as previously outlined [18]. Treat-

ment response varied from 82 % [4, 7] to 55 % [8]. Disease

flare on treatment initiation leading to discontinuation was

rarely reported [8, 9, 23]; however, this may have been due

to discontinuation of other systemic antipsoriatic agents

[23].

In addition, a previous lack of response to other sys-

temic agents did not prevent a good treatment response to

FAEs [8]; therefore, they may be a valuable treatment

option for patients who fail to respond to other agents.Fig. 4 Selection process for relevant citations

Fig. 5 Overview of study

selection process

Ir J Med Sci 165

123

Table

1Summaryofincluded

articles

Title

andauthor(s)

Studydesign

No.ofpatients

Intervention

Outcomemeasuresreported

Results

HeelanandMarkham

(2012).‘Fumaric

acid

esters

asa

suitable

firstline

treatm

entforsevere

psoriasis:an

Irish

experience’[9]

Retrospective

cohortstudy.

Single

regional

referral

centre

45(28men,17women).Age

range21–71years.42had

chronic

plaque,

2had

palmoplantarand1had

nail

psoriasis

Standarddose

protocol.The

mediantreatm

entdurationof

thecohortincludingthe

ongoingtreatm

entwas

11.2

months

Notreported

32Patients

(71%)showed

asignificant

improvem

entin

theirpsoriasis

Noim

provem

entwas

seen

in7patients

(16%).1(2

%)showed

worseningof

thedisease,and5(11%)wereunableto

tolerate

treatm

ent

Adverse

events

occurred

in66%—

diarrhoea

(44.4

%),abdominal

cram

ps

(40%),flushing(40%)andheadaches

(6.7

%).Adverse

eventsledto

treatm

ent

discontinuationin

33%

Lymphopenia

developed

in24%

(treatmentwas

discontinued

in1of

thesepatients).Eosinophilia

occurred

in

18%

(warrantedtreatm

entwithdrawal

in1patient).Trace

transientproteinuria

occurred

in3patients,proteinuria(1?)

occurred

in1patient

Nopatientrequired

treatm

entstoppage

dueto

deterioratingrenal

function.1

patienthad

atransientincrease

in

creatinine,

whichnarmalised

spontaneously

Reich,K

etal.(2009).

‘Efficacy

andsafety

of

fumaric

acid

esters

in

thelongterm

treatm

entof

psoriasis—

a

retrospectivestudy

(FUTURE)[20]

Retrospective

multicentre

cohortstudy

(163centres

included)

984patients58.2

%(572)were

male,

41.8

%(411)female.

Themeanagewas

50.5

years.87.3

%ofthe

included

patients

had

chronic

stable

psoriasis,38.3

%scalp

psoriasis,22.6

%nail

psoriasis

StandardFAEdose

protocol.

71%

were

treatedcontinually

withFAE

forat

least2years.Mean

treatm

entdurationforthis

patientcollectivewas

50months.Therapywith

FAEover

more

than

3years

(withinterruptionsnolonger

than

6months)

was

administeredto

46%

ofthe

patients.Meantreatm

ent

durationforthiscollective

was

66months

Leucocytes,lymphocytes,

eosinophils,granulocytes,

serum

creatinine,

glutamyltransf-erase,alanine

aminotransfera-se

and

aspartate

aminotransfera-se.

Severityofskin

symptoms

was

assessed

byPhysician’s

Global

Assessm

ent(PGA)

andPsoriasis

Areaand

severityindex

(PASI).Data

werereported

from

baseline

andafter3,6,12,24,and36

ormore

monthsoftherapy

After

3monthsoftherapy30.8

%of

patientswere‘‘markedly

improved’’or

‘‘clear’’andan

additional

50%

of

patients‘‘slightlyim

proved’’

After

6monthsoftherapy67%

of

patientswere‘‘markedly

improved’’or

‘‘clear’’;after1yearthisdegreeof

improvem

entwas

documentedin

76%

ofpatients

41%

ofpatientshad

lymphcytopenia

(after

24months)

and12%

leucopenia

(after

24months)

Anelevationofliver

enzymes

(GGT,

ALATorASAT)occurred

in13%

of

patients(after

3months)

Anelevationofthecreatininelevel

occurred

in6%

(after

24months)

166 Ir J Med Sci

123

Table

1continued

Title

andauthor(s)

Studydesign

No.ofpatients

Intervention

Outcomemeasuresreported

Results

Brewer

andRogers

(2007).‘Fumaric

acid

esters

inthe

managem

entofsevere

psoriasis’[3]

Retrospective

cohortstudy

31patients(21men,10

women).Agerange

27–78years

old.93.5

%had

chronic

plaquepsoriasis

and

6.5

%had

palmoplantar

pustularpsoriasis

Standarddose

protocol

Fullbloodcount(FBC),urea,

electrolytes,creatinine,

liver

functiontests(LFTs),

urinalysis—

measuredat

baseline,

then

once

weekly

for1month,fortnightlyfor

2months,then

once

every

2months.Response

was

described

as‘excellent’ifthe

skin

was

clear/minim

al

psoriasis,‘good’ifa

significantim

provem

entwas

noted,and‘failed’ifthere

was

noresponse/intolerance

2Patientswithdrew

from

thestudyat

the

beginning(1

dueto

noncompliance,1

dueto

breastcancer)

Oftheremaining29patients,17(58.6

%)

showed

goodto

excellentim

provem

ent

4Patients

did

notrespondto

treatm

ent

27patients

(87.1

%)experiencedside

effects—

flushing(67.8

%),abdominal

cram

ps(48.4

%),diarrhoea

(61.3

%),

andnausea(16.1

%)

Side-effectsledto

withdrawal

of

treatm

entin

8patients(27.6

%)afteran

averageof3months.Gastrointestinal

(GI)(3),lymphopenia

(2),flushing(1),

fatigue(1),generalised

rash

(1)

Lymphopenia

occurred

in19patients

(61.3

%)—

This

resulted

in

discontinuationoftreatm

entin

2

patients

Leucopenia

developed

in5patients

(16.1

%),eosinophilia

in10(32.3

%)

Atransientrise

inliver

enzymes

occurred

in4(12.9

%)

Nochangein

serum

creatinineoccurred

inanypatient

Fikaet

al.

(2006).‘Fumaric

acid

esters

inpsoriasis’[7]

Retrospective

cohortstudy

11(5

men,6women).Age

range19–59years.73%

had

chronic

plaquepsoriasis

and

27%

guttatepsoriasis

Patients

weretreatedwithan

FAEregim

eaccordingto

published

guidelines

Clinical

exam

inationonly

9Patients(82%)showed

improvem

entin

theirpsoriasis.3patients

(27%)

discontinued

treatm

ent—

dueto

side

effectsin

2(22.2

%),lack

ofefficacy

(1)andlack

ofcompliance

(1).Side-

effectswereseen

inallpatients—

GI

(82%),flushingin

18%.

Lymphocytopenia

developed

during

treatm

entin

6patients(54%).

Transienteosinophilia

was

noticedin

3

patients(27%).Nosignificant

abnorm

alitieswerenotedin

renal

or

liver

function

Ir J Med Sci 167

123

Table

1continued

Title

andauthor(s)

Studydesign

No.ofpatients

Intervention

Outcomemeasuresreported

Results

Sladden

etal.(2006).

‘Fumaric

acid

esters

forseverepsoriasis:

theLeicestershire

experience’[23]

Retrospective

cohortstudy.

Single

centre

30patients(21men

and9

women).Agerange

31–62years.Allpatients

had

moderateorseverechronic

plaquepsoriasis

StandarddosingProtocol

Notreported

8Patients(27%)discontinued

FAE

therapy(range2–6weeks),alldueto

GI

side-effects.2patientsstopped

dueto

disease

flare(H

owever

both

had

recently

withdrawnmethotrexateoracitretin)

Treatmentwas

withdrawnin

1dueto

glomerulonephritis(noproven

causal

linkwithFAE)

Oftheremaining19patients,4showed

someim

provem

entin

theirpsoriasis,

and15were‘clear

orvirtually

clear’

13(of19)developed

lymphocytopenia,2

patientsrequired

dose

reductionas

a

result.2patents

developed

microscopic

haematuriabut,afternephrologyand

urologyreview,continued

FAE

treatm

ent

Harries

etal.(2005)

‘Fumaric

acid

esters

forseverepsoriasis:a

retrospectivereview

of58cases’

[8]

Retrospective

single

centre

cohortstudy

58patients25women

and33

men.Themeanageofthe

patients

was

47.2

years

(range14–77years).94%

had

chronic

plaquepsoriasis,

3%

guttatepsoriasis,3%

palmoplantarpustular

psoriasis

Eachpatientfollowed

an

individually

tailoredFAE

dose

regim

enbased

ona

standardprotocol

Notreported

32Patients

(55%)showed

improvem

ent

intheirpsoriasis.Noim

provem

entwas

seen

in28%

ofpatients.16%

showed

disease

worsening.Themeantimeto

initialim

provem

entwas

5.6

weeks

(range2–20weeks)

32(55%)discontinued

FAEtreatm

ent

dueto

subjectiveadverse

events

(15),

lack

ofefficacy

(12)andlaboratory

abnorm

alities(4)

Theremaining26patients

(45%)

continued

FAEtreatm

ent

Side-effectswerereported

intwo-thirds

ofpatients—

abdominal

pain(61%),

diarrhoea

(55%),flushing(45%),

nausea(21%)andmalaise

(15%)

Lymphocytopenia

developed

during

treatm

entin

57%.This

prompteddose

reductionin

2patients,andeventual

treatm

entwithdrawal

in1ofthese

patients

Atransienteosinophiliaoccurred

in31%;

thisrevertedto

norm

alin

allcases

4patientsshowed

elevated

liver

enzymes

promptingtreatm

entdiscontinuationin

3cases

168 Ir J Med Sci

123

Table

1continued

Title

andauthor(s)

Studydesign

No.ofpatients

Intervention

Outcomemeasuresreported

Results

Carboniet

al.(2004).

‘Fumaricacid

estersin

thetreatm

entof

psoriasis:an

Italian

experience’[4]

Prospective

cohortstudy

40patients(25males

and15

females).Agerange

18–72years.Moderateto

severeplaquepsoriasis

Dim

ethylfum-arate

was

given

atadaily

dose

of30–360mg

foraminim

um

of6months,

accordingto

astandarddose

protocol.Doseswere

gradually

reducedas

soonas

remissionoccurred

PASIscore.Clinical

and

photographic

documentation.

Bloodandurineat

0,15,30,

90and180daysandthen

every3months.

Haemachrome,

renal

and

hepatic

functiontests

33Patients

(82.5

%)achieved

complete

clinical

remissionwithFAEtreatm

ent:

8after3monthsand25after6months

Adverse

events,such

asintolerable

abdominal

cram

psandincoercible

diarrhoea,occurred

in4patientswho,

forthisreasoninterruptedtherapy

Hoefnagel

etal.(2003).

‘Longtern

safety

aspects

ofsystem

ic

therapywithfumaric

acid

esters

insevere

psoriasis’[10]

Retrospective

cohortstudy

66patients,41men

and25

women.94%

had

psoriasis

vulgaris,5%

had

guttate

psoriasis

and1patienthad

arthropathic

psoriasis

All66patientsweretreated

withindividually

differing

dosesofFAE.Attheonsetof

therapywithFAEthedose

was

gradually

builtupto

a

maxim

um

of6highstrength

tablets

in27(41%)of66

patients.Themean

maintenance

dosagewas

between3–4highstrength

tablets

per

day

Laboratory

param

eterswere

monitoredmonthly

duringthe

first6monthsoftreatm

ent

andthereafter

at3-m

onthly

intervals.Theseincluded

total

leucocyte

count,relative

percentages

oflymphocytes

andeosinophils,serum

creatinine,

andliver

enzymes

(ALT,GGT)

Adverse

events

werereported

in73%

andledto

treatm

entwithdrawal

in9

patients.Thesewereusually

mild—

flushing(55%),diarrhoea

(42%),

nausea(14%),tiredness(14%)and

stomachcomplaints

(12%)

In22(35%)arelativelymphocytopenia

existedat

thestartoftherapy.Ofthe41

patientswithoutarelative

lymphocytopenia

atthestartoftherapy,

31(76%)developed

thisaftertherapy

onset.Therapywas

permanently

discontinued

in4,temporarily

discontinued

in1,andthedose

reduced

in5.In

8patientsnoactionwas

taken,

andlymphocyte

countsincreased

spontaneouslyto[10%

Thecourseofthemedianleucocyte

count

duringaperiodof12years

oftreatm

ent

did

notshow

anymarked

alterations

Eosinophilia

occurred

in14%—

transient

inall,requiringnoaction

Elevated

LFTsoccurred

in25%.In

14an

isolatedelevationofGGTwas

observed.This

resolved

spontaneously

ornarmalised

afterdose

reductionin

all

but3patients.In

2patients

elevated

LFTswerethereasonto

withdraw

therapypermanentlyandin

1patientto

withdraw

temporarily

Elevated

serum

creatinineoccurred

in1

patient.ReintroductionofFAEsdid

not

altercreatininelevelsin

thispatient

Ir J Med Sci 169

123

Table

1continued

Title

andauthor(s)

Studydesign

No.ofpatients

Intervention

Outcomemeasuresreported

Results

Mrowietz

etal.(1998).

‘Treatmentofsevere

psoriasis

withfumaric

acid

esters:scientific

backgroundand

guidelines

for

therapeuticuse’[14]

Prospective

multicentre

study(12

dermatological

centres

in

Germany)

101patients,68male,

31

female.

Agerange

21–69years.Patients

with

severepsoriasisofdifferent

clinical

types

(e.g.,psoriasis

vulgaris.Guttatepsoriasis,

exanthem

atic

psoriasis)were

included

inthestudy

Standarddose

protocol.

Treatmentdurationwas

16weeks

PASIscore

was

assessed.

Pruritus,jointpainandnail

involvem

entwereassessed

usingascore

from

0to

4.

Patients

wereasked

for

adverse

events

atvisits.At

baselineandtreatm

entend

complete

skin

&physical

exam

wereperform

edto

detectanychanges

relatedto

therapy.Lab

values

measured

ateach

visitincluded:serum

creatinine.

Bloodureaand

nitrogen

(BUN),serum

glutamic

oxaloacetic—

transaminase,

serum

glutamic—

pyruvic

transaminase,GGT,uricacid,

LDH,alkalinephosphatase,

cholineesterase,bilirubin.

Serum

cholesteroland

triglycerides,electrolytes,

urinechem

istry,FBC

and

differential

count.Blood

pressure

andbodyweight

werealso

measured

70Patients

completedthestudy

31Discontinued

thestudydueto

adverse

events(G

Iin

5,flush

1,increasing

pruritus1,lack

ofefficacy

2,jobreasons

2,non-compliance

20)

Evaluationofoverallefficacy

showed

a

decreasein

PASIof80%

after

4monthsofFAEtherapy

Adecreaseoflymphocytesmore

than

50%

below

baselineoccurred

in10

patients

Duringweeks4and8meaneosinophil

countswereabovethenorm

alrange,but

allreturned

tonorm

alat

theendof

therapy

Nopatientshowed

changes

inrenal

function

Adverse

events

werereported

in69%

mainly

consistingofGIcomplaints

(56%)andflushing(51%)

170 Ir J Med Sci

123

Table

1continued

Title

andauthor(s)

Studydesign

No.ofpatients

Intervention

Outcomemeasuresreported

Results

Altmeyer

etal.(1994).

‘Antipsoriatic

effect

offumaric

acid

derivatives:resultsof

amulticenterdouble-

blindstudyin

100

patients’[1]

Randomised

double

blind

study

comparingthe

use

offumaric

acid

derivatives

withplacebo

100patients.Agerange

18–70years.

Psoriasis[

10%

ofbody

surfacearea,including

chronic

plaque,

exanthem

atic

guttate,

pustular,and

psoriatic

erythrodermaforat

least2years

Either

placeboordrugin

tablet

form

accordingto

auniform

randomisationschedule.The

drugwas

available

in‘initial’

and‘forte’

tablets.Thedose

was

escalatedaccordingto

a

standardprotocol.Patients

given

placebowere

administeredthesame

amountoftabletsas

thedrug

group

Laboratory

studiesmeasuredon

day

0,andafter

2,4,6,8,12,16weeks

including:haemoglobin,

erythrocyte,leucocyte,and

differential

counts;platelet

count;levelsofbilirubin,

creatinine,

urea,

uricacid,

glucose,alkaline-

phosphatase,

transaminases,

gam

ma-GT,cholesterol,

triglycerides,calcium,

sodium,potassium

and

urinalysis.Creatinine

clearance

was

determined

at

Oweeksandafter16weeks.

PASIscore

was

completed.

Pruritus,arthralgia,andnail

deform

itieswereassessed

on

thebasis

ofaclinical

score

from

0to

4.Ateach

visitboth

thephysician

andthepatient

wereasked

toassess

the

outcomeoftherapyandany

sideeffects

Asignificanttreatm

entdifference

usingthe

PASIscore(p\

0.0001)was

foundin

favourofthedruggroup.Inthedruggroup

71.3

%ofpatientsshowed

remission,

18%

showed

noresponse

and10.2

%

showed

deterioration.82%

oftheplacebo

groupremained

unchanged

ordeteriorated

Adverse

reactionsoccurred

in75.5

%of

thedruggroupand16%

oftheplacebo

group.Therewerenochanges

in

haemobin

orerythrocyte

countduring

the16weeks.Leucocytesshowed

a

milddecreasein

week8in

both

groups,

withnofurther

changes

afterthis

Eosinophilsshowed

asignificantincrease

inthedruggroupfrom

2%

(weekO)to

3.4

%(w

eek2)(p\

0.05)

Platelets,bilirubin,urea,

creatinine,

glucose,alkalinephosphatase,

transaminases,gam

maG

T,cholesterol,

triglycerides,andurinalysisdid

not

changesignificantlyin

either

group

Therewerenosignificantdifferencesin

creatinineclearance

ineither

group

KolbachandNieboer

(1992).‘Fumaric

acid

therapyin

psoriasis:

Resultsandside

effectsof2years

of

treatm

ent’[13]

Non-randomised

comparative

study(choice

oftherapywas

determined

by

patients

insurance)

196patients[18years

with

nummularandplaquetype

psoriasis

withat

least10%

involvem

entofbodysurface

TheDMFAEgroup(n

=129)

received

60mgcapsulesof

dim

ethylfuma-ricacid

esters,

increasedweekly

by60mgto

amaxim

um

of240mg/day.

TheFACgroup(n

=67)was

treatedwithfumaderm

‘mite’

initially,increasingto

fumaderm

‘forte’,whichwas

increasedweekly

toa

maxim

um

of4‘forte’

tablets

per

day

Therapeuticevaluationwas

doneat3–6.6–12,12–18,and

18–24months.Resultswere

scoredaccordingto

a

simplified

severityscore.

Improvem

entof[75%

was

sufficient,less

extensive

improvem

ent,deterioration

andexacerbationwerecalled

insufficient.Sideeffectswere

noted.Lab

testsincluded:

urinalysis,whitebloodcell

countwithdifferential,

haemoglobin,serum

creatinine,

bloodurea

nitrogen

(BUN),transaminase

andalkalinephosphatase

levels

After

24months55%

oftheFACgroup

continued

treatm

entas

opposedto

16%

oftheDMFAEgroup

50%

OftheFACgroupattained

sufficient

results.Thiswas

statisticallysignificant.

18%

oftheFACgroupstopped

dueto

sideeffects,26%

intheDMFAEgroup

Inthefirst6monthsGIcomplaints

were

most

frequentin

both

groups

Milddeviationsofliver

andrenal

function

wereseen

in3patientsin

theDMFAE

groupand1patientin

theFACgroup.

They

disappearedafterdiscontinuation.

Leucocytopenia

occurred

in4%

(not

specified

inwhichgroup)

After24months86%oftheDMFAEgroup

and81%

oftheFACgrouphad

lympho-

penia,discontinuationledtonorm

alisation

inmostcasesafterupto6months

Ir J Med Sci 171

123

Table

1continued

Title

andauthor(s)

Studydesign

No.ofpatients

Intervention

Outcomemeasuresreported

Results

Nugteren-H

uyinget

al.

(1990).‘Fumaric

acid

therapyforpsoriasis:

Arandomised,double

blind,placebo

controlled

trial’[16]

Randomised

double

blind,

placebo

controlled

trial

39psoriasispatients

(12

women

and27men).Age

range20–73years.Severe

psoriasis[

10%

body

surfacearea

Patients

wererandomly

assigned

to3groups.Group1

(n=

12)weretreatedwith

oralentericcoated

tablets

containingamixture

of

dim

ethylfuma-rate,and

magnesium,calcium

andzinc

monoethylfu-m

arate.Group2

Patients

weretreatedwith

oralentericcoated

tablets

containingoctylhydrogen

fumarate,andmagnesium

and

zincmonoethylfu-m

arate.

Group3Patientsweretreated

withaplacebo.Alltablets

had

thesameappearance,size

andcolour

Extentandactivityofskin

disease

was

assessed

by

estimatingthepercentageof

bodysurfaceaffected

with

psoriasisandbyscoringthe

degreeofinfiltrationand

scalingoftheplaques

(from

0

noinfiltrationorscaling,to

8

verysevereinfiltratingor

scaling).Thefollowinglab

investigationswere

perform

ed:ESR,leucocyte

differential

count,

haemoglobin,haematocrit,

urea,

creatinine,

AST,ALT,

lactate-dehydrogenase,

alkaline-phosphatase,

gam

ma

glutamyltransfe-rase,total

bilirubin,glucose

andprotein.

Urinalysisforlevelsof

glucose

andprotein

and24h

creatinineclearance

rate

Nodifferencesfoundbetweengroupsat

baseline.

Of39patients,34completed

thestudy

Group1—

themeanpercentageofbody

surfaceaffected

withpsoriasiswas

reducedfrom

21%

(atbaseline)

to

6.7

%after16weeks.Thiswas

statisticallysignificantfrom

groups2

and3(p

B0.01)

After

16weeksthescore

forscalingin

group1was

significantlylower

than

in

groups2and3(p

B0.0.1)

Ingroup1,6patients

showed

complete

clearance,and3showed

improvem

ent.

Ingroup2nosuch

resultsoccurred

and

ingroup3only

1patientshowed

improvem

ent.In

group1themainside

effectswereflushing(12),diarrhoea

(13),fatigue(7),andnausea(6).One

patientbecam

eilldueto

renal

insufficiency

Atransientrise

inliver

functiontests

occurred

in8patientsin

group1,and4

patientsin

group2

Transienteosinophilia

occurred

in5

patientsin

group1

Lymphopenia

occurred

in4patients

in

group1

172 Ir J Med Sci

123

Table

2Summaryofincluded

Casestudies

Title

andAuthor(s)

Patient(s)

Intervention

Casesummary

Erm

iset

al.(2013).‘PMLin

apatienttreated

withfumaric

acid’[5]

One74yearold

man

OralFAEtherapyfor3years

indosesofupto

120mgofdim

ethyl—

fumarateand95mgof

monoethyl—

fumarate,

each

taken

twicedaily

PMLwas

diagnosedduringtherapywithFAE,treatm

ent

was

discontinued.Differential

bloodcountrevealed

grade3lymphocytopenia.(Retrospectiveanalysis

revealedthat

thelymphocytopenia

had

reached

an

unrecognised

grade3statuswithin

1yearafterthe

initiationoftreatm

entwithFAE)

Reidet

al.(2013).‘D

eToniFanconiSyndrome

secondaryto

fumaric

acid

esters’[21]

Onefemaleage

37years

FAE240mgthreetimes

daily.18monthsoftherapy,

heldfor15monthswhilepregnant,reintroducedfor

7monthsbefore

thedevelopmentofDeToni

Fanconisyndrome

DeToniFanconisyndromedeveloped

duringFAE

therapy,thisresolved

within

4weeksoftreatm

ent

cessation.Thepatienthad

norm

allabparam

etersbefore

commencingtherapy

van

Oosten

etal.(2013).‘PMLin

apatient

treatedwithdim

ethylfumaratefrom

a

compoundingpharmacy’[25]

One43yearold

lady

420mgofPsorinovo(D

imethylfumaric

acid)

per

day

for6years

AdiagnosisofPMLwas

madewhilereceivingFAE

therapy,thiswas

subsequentlystopped.Haematologic

studiesrevealedapreviouslyunrecognised

lymphopenia,

withacountof200lymphocytesper

cubic

millimetre

(norm

alrange,

600–2900)

Barth

etal.(2011).‘M

alignantmelanoma

duringtreatm

entwithfumaric

acid

esters-

coincidence

ortreatm

entrelated?’

[2]

Patient1:45yearold

malePatient2:

74yearold

male

Both

patientsweretreatedwithFAE(unspecified

dose),Patient1for4yearsandPatient2for8years

Patient1Nosignificantrisk

factors

formelanoma.

A

nodularmelanoma(Breslow

depth

2.4

mm,Clark

level

IV)was

foundin

theleftpectoralregion.Follow-up

excisionandtwosentinel

lymphnodes

werefree

of

tumour.Patient2Developed

apigmentedskin

lesion

Breslow

depth

0.35mm,Clark

level

II(U

nderlyingrisk

factors

included

ahistory

ofchronic

actinic

dam

age,

squam

ouscellcarcinoma(SCC),methotrexate,

acitretin

andciclosporinuse.In

additiontherewas

ahistory

of

PUVA

andsunlampuse)

Ogilvie

etal.(2011).‘Proteinuriawithfumaric

acid

estertreatm

entforpsoriasis’[17]

Patient1:A

55year

old

malePatient2:

N/A

Patient3:A

58-yearold

lady

Patient1and3—

StandardFAEdose

protocolas

per

manufacturer

Patient1Had

developed

areducedglomerularfiltration

rateonciclosporin9yearspreviously,andhad

apossible

IgA

nephropathy.Within

2weeksofFAEtherapyhe

developed

proteinuriawithatraceofbloodonurinalysis.

FAEwas

stopped

butinvestigationsdid

notuncover

any

abnorm

alfindings.Within

2weeksofstoppingtheFAE,

proteinuriahad

resolved,andFAEwas

restarted

4monthslater.Within

3weeksofrestartingproteinuria

was

detected(‘???’).Once

more,discontinuationof

treatm

entwas

followed

byresolutionofproteinuria.

Patient3Within

1month

afterreachingthestandard

maxim

um

dose

ofFAE,thepatientdeveloped

proteinuria(‘???’)whichresolved

within

3monthsof

treatm

entcessation

Ir J Med Sci 173

123

A meaningful disease improvement may be seen after

6–8 weeks of therapy when FAEs are administered

according to a standard dose protocol [18], however, some

studies [20] demonstrate that a significant clinical effect

can be expected between weeks 12 and 24. Reich et al.

(2009) reported that rates of improvement and disease

clearance continued to increase up to 1 year after com-

mencing treatment. This information is important to ensure

that a final judgment of therapy success is not made pre-

maturely. Treatment failure should therefore not be

determined before 6 months of continuous treatment [20].

Safety and tolerability

Gastrointestinal symptoms and flushing

According to European guidelines, gastrointestinal adverse

effects may occur in up to 60 % of psoriasis patients

treated with FAEs, particularly in the first few weeks after

initiation of therapy [18]. Flush symptoms such as feeling

warm, reddening of the face, and headache lasting for

minutes to hours are also common upon treatment initia-

tion [18]. These symptoms were an extremely common

occurrence upon treatment initiation in the studies included

in this literature review [1, 3, 7–10, 13, 14, 16, 23].

Treatment withdrawal due to such adverse events ranged

from 33 % [9] to 18 % [13]. The literature review has

shown that these side effects are extremely common and

may be better tolerated, if therapy is commenced at a low

dose and gradually increased over a period of weeks [18].

Once remission has been achieved, the dose may be

reduced to a lower maintenance dose to maintain clinical

response while minimising the risk of side effects.

Alterations of full blood count

Leucocytopenia, lymphocytopenia and eosinophilia can be

observed during therapy with FAEs. If leucocytes drop

below 3000/lL and lymphocytes below 500/lL, the dose

must be reduced or the treatment stopped [18].

An increase in eosinophils is temporary and usually

observed between weeks 4 and 10 of treatment [18]. There

were no associated adverse events reported in any of the

studies described. Eosinophilia was frequently self-limiting

and rarely necessitated treatment withdrawal

[1, 3, 7, 8, 10, 14, 16]. However, Heelan and Markham

(2012) reported one patient who required treatment dis-

continuation due to eosinophilia.

The most frequently occurring change in blood count

was a relative lymphocytopenia [3, 7–10, 13, 14, 20, 23].

This infrequently required dose reduction for some patients

[8, 10, 23] or rarely treatment withdrawal [3, 8–10]. It has

been suggested that lymphocytopenia could be influencedTable

2continued

Title

andAuthor(s)

Patient(s)

Intervention

Casesummary

JenningsandMurphy(2009).‘Squam

ouscell

carcinomaas

acomplicationoffumaric

acid

esterim

munosuppression’[12]

A49yearold

male

FAEtherapyfor7weeks,withslow

dose

titrationas

per

manufacturer’sinstructions

Improvem

entin

psoriasis

at6weeks,butdeveloped

3

SCCs.Totallymphocyte

countduringthisperiodwas

reducedandlymphocytesubsetsrevealedlowCD4,CD8

andCD19counts.Thepatienthad

ahistory

ofsun

exposure,an

outdoorlifestyle,actinic

dam

age,

PUVA

use,methotrexate,

ciclosporin,andahistory

ofSCC

on

ciclosporin.FAEwas

discontinued

andsix-m

onth

follow-uphas

notrevealedanynew

SCCs

RaschkaandKoch

(1999).‘Longterm

treatm

ent

ofpsoriasis

usingfumaric

acid

preparations

canbeassociated

withsevereproxim

altubular

dam

age’

[19]

A38yearold

female

420mgfumaric

acid

b.i.d

for5years

Thepatientcomplained

offatigueandweaknessfor

4monthsas

wellas

polydipsiaof3±

4lper

day.A

proxim

altubulardam

agewithglycosuria,

hypophosphatem

ia,proteinuriaandhypuricemia

after

long-term

therapywithfumaric

acid

was

diagnosed.

FAEwas

stopped

immediately;symptomspersisted

for

6monthsaftercessationoftherapy

174 Ir J Med Sci

123

by previous use of other systemic agents in a number of

patients, or it may be an intrinsic characteristic of psoriasis,

however, studies on this are lacking [10]. Harries et al.

(2005) suggested that there may be a link between a

reduced lymphocyte count and a beneficial response to

treatment, noting that the reduced lymphocyte count may

be part of the therapeutic process. Dose reduction or ces-

sation of therapy should be considered in the face of a

significant lymphocytopenia [10].

There are some case studies of malignancy [2, 12] as

well as infections such as PML [5, 25] occurring in patients

treated with FAEs. However, in the latter cases, the

patients had unrecognised lymphocytopenia, the levels of

which merited treatment withdrawal. In October 2015 the

European Medicines Agency [27] reviewed cases of PML

which occurred with Fumaderm and Psorinovo, both used

to treat psoriasis. The EMA recommended that a complete

blood count be performed at the start of treatment and

suggested that in the presence of values outside the normal

range, treatment should not be started. During treatment,

blood cell counts should be monitored every 4 weeks; if

the lymphocyte count drops below 0.7 9 109/L, the dose

should be halved. If, during a follow-up check after

4 weeks, the lymphocyte count remains below this value,

treatment must be discontinued. If therapy is continued in

presence of a lymphocyte count below 0.7 9 109/L, the

risk of PML cannot be excluded. If the lymphocyte count

drops below 0.5 9 109/L, treatment should be

discontinued.

Overall, there is no high level of evidence to suggest an

increased risk of malignancy or infections when treated

with FAEs. However, prescribers must be alert to the

possibility of such occurrences given the potential

immunosuppression. Differential white cell counts must be

closely monitored during FAE therapy, and treatment

withdrawn if leucocytes or lymphocytes drop below the

aforementioned levels.

Nephrotoxicity

European guidelines suggest that occasionally proteinuria

may occur during therapy, but disappears after dose

reduction or cessation of treatment [18]. Nephrotoxicity is

generally regarded as a rare event; however, there are case

reports of proteinuria [9, 17], reversible renal insufficiency

[16], microscopic haematuria [23] and proximal tubular

damage [19, 21] associated with FAE therapy. Both

Hoefnagel et al. (2003) and Heelan and Markham (2012)

found one patient to have a transient increase in serum

creatinine while on FAE therapy. In the latter case, this

normalised spontaneously, while in the former case it

resolved on treatment discontinuation and did not recur on

later reintroduction of treatment. Ismail et al. (2014) noted

that one patient in their retrospective study required dis-

continuation of therapy due to a reversible creatinine rise.

Similarly, Reich et al. (2009) noted an elevated creatinine

in 6 % of their cohort at 24 months.

The cases of such renal injury were all reversible upon

treatment cessation; however, their occurrence reinforces

the need for strict monitoring of renal function while

patients are receiving FAEs. Urinalysis is also important in

screening for proximal renal tubular dysfunction [21].

European guidelines [18] recommend renal function tests

prior to treatment, monthly for the first 6 months of treat-

ment, with further testing according to clinical signs or risk

factors. It has been suggested that renal impairment may be

associated with an initial overdose of FAEs, therefore, slow

dose titration as per protocol may also help to reduce the

occurrence of renal impairment [1, 10].

Hepatotoxicity

In rare cases, an isolated increase in ALT or bilirubin may

be seen while undergoing FAE therapy [18]. Hoefnagel

et al. (2003) found this to occur in 25 % of 63 patients;

however, they doubted an association with FAE therapy.

Similarly, Harries et al. (2005) reported three patients who

had to discontinue therapy due to abnormalities of liver

function. The liver enzyme abnormalities resolved spon-

taneously or on dose reduction in nearly all cases. There

were no case reports of any patient suffering hepatic

impairment as a result of FAE therapy. Despite limited

evidence to link raised liver enzymes to fumaric acid ester

therapy, vigilant screening of hepatic function should also

occur during therapy.

Limitations

Finally, it needs to be acknowledged that this literature

review has important limitations. Methodological short

comings of some of the included studies may have com-

promised the overall results. Most of the selected studies

were limited by small sample size. There was also a large

heterogeneity between studies concerning the type of

psoriasis treated, as well as follow up and outcome mea-

sures utilised. The majority of the studies were also short

term. The review also included a number of case studies

which represent a weak level of evidence.

In addition to the aforementioned weaknesses, a large

number of studies (28) had to be excluded from the review

as they were not available in English. This undoubtedly

introduced a language bias. Publication bias may also have

been a factor as only published articles available from the

aforementioned databases were included. Involving greater

than one reviewer may have enhanced the validity of the

Ir J Med Sci 175

123

review. In addition, the review may have been more

comprehensive, if grey literature was included and key

researchers in the area were contacted for additional

research papers.

Conclusions

In light of the chronic nature of psoriasis, safe and effective

long term treatment options are of major importance. The

aim of this literature review was to evaluate the efficacy

and safety of fumaric acid esters in the management of

moderate to severe psoriasis in adult patients. 19 articles

were selected for review. Overall, the use of fumaric acid

esters for the treatment of moderate to severe psoriasis has

been shown to be an effective and safe long term treatment

agent.

Gastrointestinal side effects and flushing are common at

treatment initiation and may limit treatment. The occur-

rence of serious adverse events such as hepatic or renal

injury appears to be very rare, and although there are some

case reports of renal injury, these were all reversible upon

cessation of treatment. Haematological disturbances such

as moderate lymphocytopenia are common; however, there

is no high level of evidence available to suggest any

increased risk of malignancy.

The characteristic spectrum of adverse events which

may occur enables easy monitoring of patients during the

course of treatment [14]. FBC, liver enzymes, serum cre-

atinine and urinalysis must be vigilantly recorded [18]. If

the drug is monitored as per the manufacturer’s protocols,

it is likely to be a safe agent. For patients who experience

adverse reactions or intolerance of other systemic antip-

soriatic agents, FAEs may be a viable treatment alternative.

While this literature review only included studies in

which fumaric acid ester therapy was used in isolation to

manage moderate to severe psoriasis, studies such as that

completed by Ismail et al. (2014) suggest that FAEs may

be used safely in combination with other systemic and

biological agents. When used in combination with other

therapies, they may in fact facilitate dose reduction of more

toxic agents [26]. The use of fumaric acid esters in com-

bination with other treatment modalities would be a valu-

able topic for future research.

Fumaric acid ester therapy has been utilised for over

30 years for the management of psoriasis [26]. Fumaderm

is licensed in Germany for treating adults with moderate to

severe plaque psoriasis in whom topical therapy is not

effective. The licensing of FAEs in Ireland for the treat-

ment of moderate to severe psoriasis would be desirable,

increasing available treatment options. This systematic

review suggests that they are an effective long term treat-

ment option. They may be safely used in practice when

administered in accordance with the European Medicine

Agency guidelines [27].

Acknowledgments With special thanks to Dr Bart Ramsay, Con-

sultant Dermatologist, University Hospital Limerick.

References

1. Altmeyer PJ, Matthes U, Pawlak F et al (1994) Antipsoriatic

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