Therapeutics and Clinical Risk Management

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Optimal management of fatigue in

patients with systemic lupus
erythematosus:
a systematic review
This article was published in the following Dove Press journal:
Therapeutics and Clinical Risk
Management 1 October 2014
Number of times this article has been viewed

Hon K Yuen1
Melissa A Cunningham2
1

Department of Occupational
Therapy, School of Health
Professions,
University of Alabama at
Birmingham,
Birmingham, AL, 2Division of
Rheumatology and Immunology,
Department of Medicine, Medical
University of South Carolina, SC,
USA

Abstract: Among the host of distressing pathophysiological and psychosocial symptoms,

fatigueisthemostprevalentcomplaintinpatientswithsystemiclupuserythematosus(SLE).This
reviewistoupdatethecurrentfindingsonnonpharmacological,pharmacological,andmodality
strategies to manage fatigue in patients with SLE and to provide some recommendations on
optimalmanagementoffatiguebasedonthebestavailableevidence.Weperformedasystematic
literature search of the PubMed and Scopus databases to identify publications on fatigue
managementinpatientswithSLE.Basedonthestudiesreportedintheliterature,weidentified
nineinterventionstrategiesthathavethepotentialtoalleviatefatigueinpatientswithSLE.Ofthe
ninestrategies,aerobicexerciseandbelimumabseemtohavethestrongestevidenceoftreatment
efficacy.NacetylcysteineandultravioletA1phototherapydemonstratedlowtomoderatelevels
ofevidence.Psychosocialinterventions,dietarymanipulation(lowcalorieorglycemicindexdiet)
aiming for weight loss, vitamin D supplementation, and acupuncture all had weak evidence.
Dehydroepiandrosteroneisnotrecommendedduetoalackofevidenceforitsefficacy.Inaddition
totakingtreatmentefficacyandsideeffectsintoconsideration,cliniciansshouldconsiderfactors
such as cost of treatment, commitments, and burden to the patient when selecting fatigue
managementstrategiesforpatientswithSLE.Anycomorbidities,suchaspsychologicaldistress,
chronicpain,sleepdisturbance,obesity,orhypovitaminosisD,associatedwithfatigueshouldbe
addressed.

Keywords: healthrelatedqualityoflife,vitality,systemiclupuserythematosus,clinical
effectiveness,rheumatology

Introduction

Correspondence: Hon K Yuen

Department of Occupational
Therapy, School of Health
Professions, University of
Alabama at Birmingham,

Systemic lupus erythematosus (SLE) is a chronic, multisystem, inflammatory, auto

immune connective tissue disorder. It is characterized by production of pathogenic
autoantibodiesanddysregulatedimmuneresponsesbyBcells,Tcells,dendriticcells,
andotherimmunecells,resultinginnumerousclinicalandserologicalmanifestations. 1
Abroadarrayofclinicalpresentationsrangingfromrash,oralulcers,andarthralgiasto
lifethreateninginternalorganinvolvementsuchaslupusnephritisiscommon. 2 The
courseofSLEisextremelyvariableandischaracterizedbyintermittentandunpredict
ableremissionsandexacerbations(ie,flares)duringwhichtheimmunesystemattacks
variousorgans.3Withrecurrentflares(approximately65%ofpatientsperyear), 3SLE
canleadtoprogressivedisability.ThecauseofSLEisunknown,butislikelytobean
interaction of genetic, environmental, and hormonal factors. 1 SLE affects mostly
women,withanincidenceaboutninetimeshigherthaninmen,andalsohasahigher
prevalenceinnonCaucasianpopulations.4

1720 Second Avenue South,

Birmingham, AL 35294, USA
Tel 1 205 934 6301
Fax 1 205 975
7787 Email
yuen@uab.edu

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Yuen and Cunningham

Duetoearlierdiagnosisandbettertreatmentoptionsto
control the disease and its complications, the 5year
survivalofpatientswithSLEhasexceeded90%inmost
centers.5Withasignificantimprovementinsurvivalinthis
population,attentionhasadditionallybeendirectedtoward
improvinghealthrelatedqualityoflife.Amongthehostof
distressing pathophysiological and psychosocial
symptoms, fatigue is the most prevalent complaint
in
approximately50%90%ofpatientswithSLE,6withmore
than50%ofpatientsratingfatigueasthemostdebilitating
symptom they experience.7 Fatigue manifests as an
overwhelming sense of extraordinary tiredness or8
exhaustionthatisnotcompletelyrelievedbyrestorsleep.

Inmostcasesthecauseoffatigueisunknown.Anumber
of factors associated with SLErelated fatigue have been
reported, including pathochronobiological factors (sleep
disturbance, physical inactivity), pathopsychosocial factors
(anxiety, depression), chronic pain (fibromyalgia), obesity,
andlackofperceivedsocialsupport. 914 Somestudieshave
shownanassociationbetweendiseaseactivity(ie,cytokine
and autoantibody levels) and fatigue,9,10,15,16 while others
havereportedthatfatigueisnotassociatedwithanydisease
markers.17,18 Furthermore, fatigue was also reported in
patients without clinical or laboratory evidence of active
disease.7

FormanypatientswithSLE,fatiguedisruptsnormal
dailyfunctioning,decreasestheabilitytoconcentrate,and
affects work, leisure, and6,19
social activities, leading to
diminishedqualityoflife,
ahighprevalenceofwork
disability,20,21 andhigherhealthcareutilization. 22 Atthe
same time, more than 80% of patients with SLE have
reportedthatfatigueisnotadequatelyaddressedintheir
healthcaremanagementplan.23,24
Theaimofthisreviewistoupdatethecurrentfindings
on several nonpharmacological, pharmacological, and
modalitystrategiestomanagefatigueinpatientswithSLE
andtoprovidesomerecommendationsonoptimalfatigue
managementbasedonthebestavailableevidence.

Materials and methods

Literature search strategy
This systematic review was conducted according to the
guidelines ofthe Preferred ReportingItems for Systematic
ReviewsandMetaAnalyses.25 Theprocessbeganwiththe
firstauthor(HKY)performingasystematicelectroniclitera
turesearchofthePubMedandScopusdatabasesfromtheir
inception(1966and1996,respectively)toMay2014.Que
riestoidentifypotentiallyrelevantpublicationsonfatigue

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managementinpatientswithSLEwerebasedonBoolean
combinationsofthefollowingsearchterms:((lupus[tiab]
ORSLE[tiab])AND(fatigue[tiab]ORvitality[tiab]OR
SF36[tiab]ORqualityoflife[tiab])).Wealsoidentified
appropriate articles that were cited in review papers
relatedtofatigueandlupus.

Study eligibility criteria

WelimitedthisreviewtopublicationsthatwereintheEng
lishlanguage,withfulltextavailable,themajorityofpatients
diagnosed with SLE, and adults (ie, 18 years), although
childrencouldconstituteaminorityoftheparticipantsina
study.Onlyinterventionandobservationalstudiesreportinga
fatigueorvitalitymeasureasoneoftheprimaryorsecond
aryoutcomeswereincluded.Studieswereexcludedifthey
werecasereports,dissertations,editorials,commentaries,or
review articles, or if they employed primarily qualitative
researchmethods.

Data extraction
Thefirstauthor(HKY)screenedthetitlesandabstractsofall
thearticlesthathadbeenretrievedtodetermineiftheymet
theeligibilitycriteria,andappraisedthemethodologicalqual
ityandevidenceofeachselectedstudy.Thesecondauthor
(MC)subsequentlyreviewedtheaccuracyandqualityofthe
appraisal.Anydisagreementswerediscusseduntilconsensus
was reached. The flow diagram in Figure 1 describes the
processusedtoselectarticlesforthisstudy,andtheresultsof
thisliteraturesearch.

Results
Basedonthestudiesreportedintheliterature,weidentifiednine
interventionstrategiesthathavethepotentialtoalleviatefatigue
in patients with SLE. These strategies were psychosocial
intervention, exercise, diet manipulation, vitamin D
supplementation, Nacetylcysteine (NAC), dehydroepi
androsterone (DHEA), belimumab, ultravioletA1 (UVA1)
phototherapy,andacupuncture.Theresultsofourcriticalreview
on the clinical efficacy evidence of each strategy to improve
fatigueorvitalityaresummarizedasfollows.

Psychosocial intervention
Approximately 40% of patients who have SLE remain dis
tressed over time, and since there is a significant association
between distress and fatigue, these patients may benefit from
psychosocial interventions.26 Psychosocial interventions for
fatigue management in patients with SLE included cognitive
behavioraltherapy,27,28psychoeducation,29,30counseling,30,31
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Optimal management of fatigue in

Identification

patients with SLE

Records identified through

database searching
(n=911 from PubMed, n=1,051 from
Scopus)

Additional records identified

through review papers
(n=20)

Included

Eligibility

Screening

Records after duplicates removed

(n=1,164)

Records screened
(n=1,164)

Full-text articles assessed

for eligibility

(n=30)

Records excluded
(n=1,134)

Full-text articles
excluded (n=4) due to:
The drug, epratuzumab, has
not been approved by the
FDA to treat SLE
No vitality measure as the
outcome was reported
Same analysis was conducted
using a subset of data from a
previously published RCT

Studies included in
quantitative synthesis
(n=26)

Only 28% of the sample was

diagnosed with SLE

Figure 1 Flow diagram of the selection process and study search results.
Abbreviations: FDA, US Food and Drug Administration; SLE, systemic lupus erythematosus; RCT, randomized
controlled trial.

psychotherapy,29,32 and biofeedback,28 with the aim of

reducing interference by the disease with activities of
dailyliving,improvinginterpersonalrelationships,social
support, selfefficacy,
and coping skills for stress
management.33 Theseinterventionsfocusedprimarilyon
reducing psychological distress (ie, stress, anxiety and
depressivesymptoms),fatigue,andpain,andconsistedof
skillstraininginrelaxation,paincontrol,problemsolving,
coping, social interaction (eg, interpersonal relationship,
assertiveness),andcognitiverestructuring.
Ofthesevenpsychosocialinterventionstudiesidentified,
two were nonrandomized controlled trials (nonRCTs, one
beingasinglegrouppretestposttestdesignstudy29andone
Therapeutics and Clinical Risk Management 2014:10

beinganonequivalentcontrolgrouppretestposttestdesign
study),33 and five were RCTs.27,28,3032 The two nonRCTs
demonstrated
a decrease in fatigue or an improvement in
vitality.29,33 Of the five
RCTs, only one demonstrated a
reduction in fatigue.30 The other four trials showed that
psychosocial interventionsresulted ineither nosignificant
decrease
in fatigue when compared with standard usual
care27,28,32orwereequallyeffectiveinreducingfatiguewhen
comparedwithplacebo(ie,symptommonitoringonly). 28,31
TheRCTthatdemonstratedadecreaseinfatiguecom
pared a psychoeducational
intervention with an attention
placebocontrol.30 Patientsandtheirpartnersassignedtothe
interventiongroup(n64)receiveda1hoursessionwitha
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Yuen and Cunningham

nurseeducatorandsubsequentmonthlytelephonecounseling
for 6 months, whereas participants (n58) in the attention
placebogroupreceiveda45minutevideopresentationabout
lupusandmonthlytelephonemonitoring.Theauthorsuseda
fouritem visual analog scale (VAS) to assess levels of
patient fatigue when performing various daily activities. 34
Ratingonthescalerangedfrom0(nofatigue)to10(extreme
fatigue).Therewasnosignificantdifferenceinfatiguescores
betweentheinterventionandplacebogroupsat6months(ie,
immediate posttelephone counseling); however, a sig
nificant difference in fatigue scores was observed between
theinterventionandplacebogroupsat12months(6months
withoutinterventionforbothgroups),withtheintervention
group reporting less fatigue.30 This phenomenon may sug
gestthatthefindingswerenotreliableandsimplyreflected
sampleattrition.

Overall, there was only a 0.7point improvement in

fatigue score from
baseline to 12 months in the
intervention group.30 This amount of reduction did not
reachtheminimalclinicallyimportantdifference(MCID)
for the35 fatigue VAS, which was estimated to be 1.3
points. Furthermore,
as revealed in a previous meta
analysis study,36 pooled analysis of the effects of
psychosocialinterventionsonfatiguewithanotherRCT 28
indicated that no significant difference in fatigue scores
betweentheinterventionandcontrolgroupswasobserved.
Basedontheavailable evidence,psychosocialinterven
tions seem effective inreducing psychological distress and
pain,36andinimprovingproblemfocusedcopingability,self
efficacy,andperceivedsocialsupport. 33 However,evidence
tosupportpsychosocialinterventionsinalleviatingfatiguein
patientswithSLEwasveryweak.Furthermore,noimmediate
or sustained (12month followup) effects of psychosocial
intervention on physical function, mental health, and SLE
diseaseactivitywereobserved.36

Exercise
Since physical inactivity was found to be significantly
associatedwithfatigueinpatientswithSLE, 9,12exerciseisa
logical strategytoalleviate fatigue.Studiesofexercisefor
patientswithSLEusedprimarilyaerobicexercise,inwhich
the exercise was conducted either at a specific site (ie,
supervised) or at home (ie, unsupervised) with weekly
telephone monitoring. Typically, exercise was performed
threetimesperweekfor3050minutes,achievinganinten
sity of60%80%oftheparticipantsmaximumheartrate,
andthedurationofthestudyrangedfrom8to12weeks.The
primaryaimsoftheexerciseprogramsweretoincrease

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exercise tolerance, aerobic capacity, and perceived

physicalfunction,andtoreducefatigue.
Ofthesevenexercisestudiesidentified,threewerenon
RCTs (one being a 37nonequivalent control group pretest
posttestdesignstudy 38,39
andtwobeingsinglegrouppretest
posttestdesignstudies),
andfourwereRCTs.34,4042Three
34,40,42
of the37 RCTs
and the nonequivalent control group
study demonstrated that exercise significantly reduced
fatiguewhencomparedwiththecontrols.TheRCTthatdid
notshowasignificantdifferenceinfatiguewaslikelydueto
inadequatestatisticalpowerasthesamplesizeofeachgroup
was only 5.41 For this trial,41 following the 2month
supervisedexerciseprogram,themagnitudeoffatiguereduc
tion, as
measured by the nineitem Fatigue Severity Scale
(FSS),43exceededthethreshold(ie,0.6points)oftheMCID
fortheFSS.35,41Bothsinglegroupstudiesshowedsignificant
improvementinfatigueafterexercise. 38,39 Inaddition,exer
cisehasbeenshowntobesafeanddoesnotaggravateSLE
diseaseactivity.34,38,4042
Thefindingsofthesestudieshighlightedtheroleofexer
ciseinreducingfatigueinpatientswithSLE;however,few
studies evaluated longterm exercise adherence in patients
with SLE or the sustained effect of exercise on reducing
fatigueinthispopulation.Therefore,largescaleRCTswith
longtermfollowupareneededtosupportthisconclusion.

Inaddition,thereareissuesrelatedtodifficultymea
suringfatigueandinterpretingfindingsinthesestudies.
Most exercise studies included several measures for
fatigue,butoftenonlyonefatiguemeasurewasfoundto
besignificantlydifferentbetweentheexerciseandcontrol
groups.34,37,40,42 Inaddition,amongthesestudies,noone
particular fatigue measure consistently showed a
significantdifferencebetweengroups.Forexample,there
were two exercise studies of similar research
design
conductedbythesamegroupofresearchers; 34,40bothused
twofatiguemeasures,ie,thesevenitemfatiguesubscale
44
oftheProfileofMoodStates
andafouritemVASfor
fatigue. 34 Onestudyfoundthat thefatigue subscale of
ProfileofMoodStatesscores,butnottheVASfatigue
scores,were significantlydifferent betweenthegroups,
whiletheotherstudyfoundtheopposite.34,40
Willingnesstoparticipate inanexercise programorto
continue exercise regularly after the study program ended
wasasignificantproblem.Inonehomebasedexercisestudy,
patients received a free Wii console and Wii Fit balance
board,mitigatingtheneedfortraveltoafitnesscenterfor
exercise, and the accrual rate was only 43%. 39 In another
exercisestudy,theresearchersrecruited93patientsto

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patients with SLE

participate,butmentionedthat31eligiblepatientsdeclinedto
participateduetolackoftime.42Inaddition,aboutonefifth
(18%)oftheparticipantsassignedtotheexercisegroupdid
notattendanysupervisedexercisesessions. 42Thisappearsto
indicatealackofenthusiasmonthepartofpatientswithSLE
toparticipateinexercisetraining.Finally,lessthanaquarter
(24%)oftheparticipantsinthatstudycontinuedtoexercise
regularlyatthe3monthfollowup.42

Manipulation of diet
Between40%and50%ofadultswithSLEareclassifiedas
obese.14,4547 Obese patients with SLE are more likely to
experience higher levels of fatigue. 13,14 Davies et al con
ductedarandomizedcomparativetrialtoexplorethesafety
andbenefitsofspecialdietswithregardtoweightlossand
fatiguereductioninpatients withSLE.48 Theycompareda
lowglycemicindex(GI)diet(n11)versusalowcaloriediet
(n12) in 23 patients for 6 weeks. Fatigue was measured
usingtheFSS.43 Theresults indicatedthatbothdietswere
equallyeffectiveinreducingfatigueandhelpingpatientsto
loseweight.Fatiguereductionwasreportedbysevenofthe
elevenparticipantsinthelowGIdietgroup,andfourofthe
12 in the low calorie diet group. The fatigue score was
reducedby0.5pointsinthelowGIdietgroup,and0.3points
in the low calorie diet group. However, the amount of
reductiondidnotreachtheMCIDof0.6pointsfortheFSS. 35
Both diets were well tolerated, with mild adverse effects
(headache, constipation, increased bowel frequency,
bloating),andSLEdiseaseactivityremainedunchanged.

Vitamin D supplementation
Sunlightavoidance,useofsunscreen,renalinsufficiency,
anddrugs(suchaschloroquineandprednisone)prescribed
to treat the symptoms of SLE interfere with vitamin D
metabolismandputpatientswithSLEatriskforvitamin
Ddeficiency.49 Infact,hypovitaminosisDiscommonin
patientswithSLE.49
EvidenceregardingtheassociationbetweenvitaminD
deficiency and fatigue is inconsistent. In an openlabel
observational study, 60 patients with SLE took dietary
vitamin D3 supplements (4001,200 IU per day) for 2
years,bywhichtimesignificantimprovementinfatigue
scores,asmeasuredbya10pointVASforfatigue,was
observed.50Therewasa0.8pointimprovementinfatigue
score,butthisdidnotreachtheMCIDof1.3pointsforthe
fatigueVAS.35Duetothelackofacontrolgroupandthe
unmasked nature of this openlabel study, strong bias
relatedtoselfreportedfatiguelevelswasunavoidable.
Therapeutics and Clinical Risk Management 2014:10

Optimal management of fatigue in

Inthatstudy,asignificantassociationbetweenserum
25(OH)Dandfatiguelevelsat2yearfollowupwasalso
observed.50 In contrast, the majority of crosssectional
studiesdidnotfindanysignificantrelationshipbetween
vitamin D and fatigue levels.5154 Participants in these
crosssectionalstudiesdidnotknowtheirserum25(OH)D
level or the purpose of the investigation.5154 Although
fewinnumber,thefindingsofthesestudiesdonotsupport
vitaminDsupplementationashavingasignificantdirect
effectonimprovingfatigueinpatientswithSLE.

N-acetylcysteine
NAC,anaminoacidprecursorofglutathione,servesasan
inhibitorofautoimmuneinflammatoryprocesses. 55 Thedata
suggest that patients with SLE have low levels of
glutathione.56 Lai et al conducted a doubleblind, placebo
controlled,randomizedtrialtoexplorethesafetyandbenefits
oforallyformulatedNACinpatientswithSLE. 57Thirtysix
patientsreceivedeitherplacebo(n9)oroneofthreedaily
doses(1.2g,2.4g,or4.8g)ofNACfor3months(n9in
eachdosegroup).After13months,significantimprovement
wasachievedwiththetwohigherNACdoses,ie,2.4g/day
and 4.8 g/day,intermsof antiDNA, disease activity, and
fatigueasmeasuredbytheFatigueAssessmentScale 58when
comparedwithplacebo.Inaddition,forthe2.4g/daygroup,
the amount of fatigue reduction exceeded the MCID of 4
pointsfortheFatigueAssessmentScale.59

Regardless of the mean baseline score, participants

whoreceivedNAC2.4g/dayor4.8g/day,orplaceboall
ratedtheirfatiguelevelreducedtoabout24at3months.
However, the mean standard deviation score on the
Fatigue Assessment Scale in a random
sample from an
adultDutchpopulationwas19.26.5.58Accordingtothis
pioneerwork,a2.4g/daydoseofNACiseffectivefor
reducingfatiguebutmaynotbepotentenoughtoreduce
fatigueinpatientswithSLEtoalevelthatiscomparable
withthat inthegeneral population.The2.4g/daydose
wastoleratedbyallparticipants,butthe4.8g/daydose
waslesswelltolerated,withonethirdoftheparticipants
reportingheadache,heartburn,nausea,andvomiting.57

Dehydroepiandrosterone
DHEA is a naturally occurring
mild androgen with immu
nomodulatoryproperties.60 Thedatasuggestthatpatientswith
SLEhavelowermeanserumDHEAlevels,61andlowerlevelsof
DHEA might relate to increased fatigue.62 Beneficial health
effectsofDHEAsupplementationinpatientswithSLEinclude
reducingdiseaseactivityandimprovingglobal

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Yuen and Cunningham

wellbeing and functioning.6366 However, several double

blind,randomized,placebocontrolledtrialshaveassessedthe
effect of orally formulated DHEA (200 mg per day) on
fatiguespecifically,andconcludedthatDHEAhaseitherno
effectonreducingfatigueorthesameeffectasplacebo. 6669
PossiblesideeffectsinDHEAusersincludeacne,hirsutism,
weightgain,andmenstrualchanges,makingthistherapyless
attractivetofemalelupuspatients.60

Belimumab
Belimumabisafullyhumanizedmonoclonalantibodythat
binds to the soluble form of Blymphocyte
stimulator
proteinandinhibitsitsbiologicalactivity. 70Blymphocyte
stimulatorprotein,alsoknownasBcellactivatingfactor,
isanimmunomodulatorycytokinethatpromotesBcell
proliferation and survival.71 Blymphocyte stimulator
proteinlevelsarehighinpatientswithSLEandcorrelate
withchangesindiseaseactivity.72
Two large multisite international collaboration trials
assessed the efficacy ofbelimumabin patients with active
SLE.73,74Theycomparedtwodosesofbelimumab(1and10
mg/kg)withplaceboover1year.Thepooledanalysisofdata
fromthesetworandomized,doubleblind,placebocontrolled
clinical trials in 1,684 patients showed that both doses of
belimumab administered intravenously once a month
significantlyreduceddiseaseactivityandcorticosteroiduse,
and improved scores in the fouritem vitality scale of the
MedicalOutcomeStudy36itemShortFormHealthSurvey
(SF36) and Functional Assessment of Chronic Illness
Therapy Fatigue (FACITFatigue) scale at week 52 when
comparedwithplacebo.75Meanscoreimprovementsinboth
FACITFatigue and SF36 vitality scales exceeded the
MCIDsoftheirrespectivescales. 75 TheSF36vitalityscale
scoreatweek52wascomparablewithagematchedandsex
matched US norms.75 In fact, significant differences in
FACITFatigue scale scores were observed between beli
mumabandplacebobeginningatweek8.76

In addition, extending the first phase of these two

trials,296patientswhocompletedthe52week,double
blindtreatmentcontinuedtoreceivemonthlybelimumab
10mg/kgfor4yearsinanopenlabelstudy. 77Theresults
indicatedthatthenumberofpatientsexperiencingfatigue
after4yearsofbelimumabtherapydecreasedbyfourfold
(to7.3%)comparedwithplaceboorbaseline.77
Belimumabiseffectiveforreducingfatigueinpatientswith
active SLE and without severe nephritis or central nervous
system involvement.78 Adverse effects in belimumab users
includeheadache,insomnia,arthralgia,gastrointestinal

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complaints(nausea,diarrhea),infection(upperrespiratory
tract, urinary tract infections), cellulitis, psychiatric
disorders (anxiety, depression with 77,79
increased suicidal
ideation),andtransientischemicattack.

Ultraviolet-A1 phototherapy
Withthediscoveryoftheimmunosuppressivepropertiesof
longwavelengthultravioletradiation(ie,aUVA1rangeof
340400 nm), this modality serves as a potential adjuvant
therapyforSLE.80Poldermanetalconductedarandomized,
doubleblind, placebocontrolled crossover trial to evaluate
the safety and benefits of UVA1 phototherapy. 81 In two
consecutive 12week periods, eleven patients with mild to
moderate SLE received lowdose (6 J/cm2) wholebody
UVA1phototherapyandaplacebolighttreatmentfivetimes
perweekforthefirst3weeks,orviceversa.Patientswho
received the UVA1 phototherapy showed a significant
improvementintheSF36vitalityscalescorecomparedwith
thesamepatientswhoreceivedplacebo.A16pointincrease
invitalityscoreafterUVA1phototherapywasobserved. 81
Scoreimprovementexceededthethreshold(ie,35points)of
theMCIDfortheSF36vitalityscale. 35,82However,noneof
the other seven subscales or total SF36 scores showed a
significant difference following UVA1phototherapywhen
compared with placebo. Based on the Pvalue (0.03)
provided,thecomparisonbetweenthevitalityscorefollowing
UVA1phototherapyandplacebowouldnotbestatistically
significant,hadcorrectionsforchancebeenmade.
UVA1 phototherapy did not achieve a significant
improvementindiseaseactivitywhencomparedwithplacebo; 81
however,asubsequentstudyconductedbythesamegroupof
researchersreportedthatUVA1(whendoublingtheintensity)
was more effective than placebo in reducing SLE disease
activity.83 Nosignsofphotosensitivityorotheradverseevents
were reported at the lower dose; 81 however, as might be
expected, two of 12 patients in the subsequent study had
transientskinreactions(ie,erythema).83 Seriousadverseeffects
ofUVA1mayincludephotocarcinogenesis,phototoxicity,and
induction of photodermatoses.84 Contraindications to UVA1
phototherapyaredisordersofphotosensitivity,longtermuseof
immunosuppressantsandphotosensitizingagents,historyofskin
cancer,orreceivingradiationtherapy. 84 ItappearsthatUVA1
phototherapy may be effective in reducing fatigue in patients
withSLE,althoughlargerscaleRCTswithlongtermfollowup
wouldbeneededtoconfirmthepreviousfindingsandensureits
safetyinlupuspatients,whichisuncertain.

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patients with SLE

Acupuncture
A systematic review on the effectiveness of acupuncture in
reducing fatigue in patients with chronic fatigue syndrome
indicatedthatabout92%ofpatientspooledfrom13studieswho
received acupuncture alone or augmented with moxibustion
reported effectiveness in fatigue reduction.85 Greco et al
conducted amodified doubleblindRCT toexplore thesafety
and benefits of acupuncture in reducing fatigue and pain in
patientswithSLE.86 They compared standardized acupuncture
with minimal needling (sham) and usual care in 24 patients
(eightineachgroup)duringtensessionsoverapproximately5
weeks.86 Fatigue was measured using the FSS43 and SF36
vitality scale.87 The results indicated that acupuncture and
minimal needling were significantly superior to usual care in
reducingfatigue.However,acupunctureandminimalneedling
wereequallyeffective.ThemeanimprovementscoresonFSS
and SF36 vitality scale were 0.35 points and 1.6 points,
respectively.However,theamountofreductiondidnotreachthe
MCID of0.6points forthe FSSor 35points forthe SF36
vitality scale.35,82 Only one of eight (13%) participants in the
acupuncture group achieved clinical improvement in fatigue
(vitality).Approximately40%ofparticipantsintheacupuncture
group reported an improvement in pain score, but no
improvementindiseaseactivitywasobserved.

Only transient adverse events, including local bruising,

painduringneedleinsertion,dizziness,andlightheadedness
were reported in the acupuncture and minimal needling
groups.86AcupunctureisnotrecommendedforSLEpatients
withadvancedvisceralorganinvolvement.88

Discussion
Since fatigue management is part of the overall treatment of
patients with SLE, selection of fatigue management strategies
may oftenbe dictatedby thetreatment thattargets controlof
SLEdiseaseactivity.Strategiesforfatiguemanagementshould
beselectedusingthosethatareleastinvasiveandwiththefewest
side effects. In addition to taking treatment efficacy and side
effectsintoconsideration,cliniciansshouldconsiderfactorssuch
ascostoftreatment,commitment,andburdentothepatientwhen
selectingfatiguemanagementstrategieswithSLE(seeTable1).
Theseimportantfactorsneedtobeassessedwhenevaluatingany
strategies for fatigue management in patients with SLE using
welldesigned, largescale RCTs with longterm followup in
ordertoproviderobustclinicalevidence.

Even though evidence of the efficacy of psychosocial

interventions for reducing fatigue in patients with SLE is
weak, such interventions are effective in reducing psycho
logicaldistressandpaininthispopulation,36andshouldbe
Therapeutics and Clinical Risk Management 2014:10

Optimal management of fatigue in

integrated into fatigue management. Based on the existing

evidence, optimal management of fatigue for patients with
SLE should start with lifestyle changes, which include
aerobicexerciseanddietarymanipulationwiththeaimsof
increasingphysicalactivityandweightcontrol,respectively.
Althoughcliniciansshouldalwaysencouragehealthychoices
by their patients, there are, undeniably, many barriers to
modifyinglifestyleandthusthesechangesareoftendifficult
forpatientswithSLEtoimplementandsustain.

SincevitaminDsupplementationforSLEpatientswith
hypovitaminosis D is associated
with significant
improvement in disease activity,89 clinicians frequently
prescribe vitamin D supplementation as an adjuvant
therapyforpatientswithSLEwhoarealsodiagnosedwith
lowlevelsofserum25(OH)D.Therefore,hypovitaminosis
DassociatedfatigueshouldbemanagedwithvitaminD
supplements.
EventhoughevidenceforefficacyoftheNACsupple
mentinreducingSLEdiseaseactivityandfatigueisstill
in the early phase of clinical trials, its use in fatigue
managementforpatientswithSLEisencouraging.Given
that NAC supplements at 2.4 g/day have minimal side
effects,andthecostofthissupplement isaffordable, it
maybeincludedinfatiguemanagement.
Belimumab is a prescription medication that has been
approvedbytheUSFoodandDrugAdministrationtotreat
SLE,andhasbeenshowntoreducefatigue(ie,toincrease
vitality). However, side effects and the high cost of this
medicationaretwofactorsthatneedtobeconsideredwhen
prescribingbelimumabforfatiguemanagement.

TheuseofUVA1phototherapytomanagefatiguefor
patientswithSLEissomewhatencouraging,butthedata
are limited and safety concerns remain, as it may
exacerbateSLE.Thelongtermefficacyandsideeffectsof
UVA1areunknown,socautionshouldbeexercisedin
prescribingthismodalitytotreatSLE.Furthermore,not
all rheumatology clinics have the appropriate apparatus
andpersonneltoprovidethisservice.
For SLE patients with pain as a contributing factor
associated with fatigue who do not want to rely on
medicationstocontrolpain,acupunctureisanoptionto
managefatigue.Evidencetosupportitsefficacyinfatigue
reduction for patients with SLE is weak, and patients
mustbeunafraidofacupunctureneedlingandbeableto
affordtopayoutofpocketasitisnotwidelycoveredby
insurance plans for treating SLE. Pain can also be
simultaneouslymanagedusingmeditationorbiofeedback
(partofpsychosocialintervention).

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Table 1 Considerations of various intervention strategies on fatigue management in patients with SLE
Consideration

Efficacy

Evidence

Sample

Treatment

size

duration

TG 64

6 months

Dosage or
frequency
of
administration

Intervention
Psychosocial

Weak, not reaching

MCID
threshold

Exercise
Dietary manipulation

Only one RCT

showed
delayed
positive
effect30
Four RCTs34,40

Moderate-strong
Weak, not reaching
MCID

42

threshold

pilot RCT48

Only one
small

n 60

7 months

A single 1-hour inperson

session and 6
monthly
telephone
counseling
sessions
Three times/week,
30 minutes each
For low GI diet:
limited
to 45 g/day
carbohydrate
For low calorie diet:
limited to 2,000
kcal/day
4001,200 IU daily,
orally

TG1 9
TG2 9
TG3 9
PG 9
TG 366
PG 303

3 months

1.2 g, twice daily,

orally

12 months

200 mg daily, orally

TG1 559
TG2 563
PG 562

8 weeks

10 mg/kg, monthly,
intravenously

n 11

12 weeks

PG 58

n 160

8 weeks

TG1 11

6 weeks

TG2 12
Vitamin D
supplementation

N-acetylcysteine

Very weak, not reaching

MCID threshold

Moderate

No RCT
available,
one
observational
study50
Only one
small
pilot RCT57

DHEA

Not effective

Four RCTs6669

Belimumab

Very strong, reduces

Two multisite
Phase III
RCTs75,76

fatigue to a level that is

comparable with the
norm

Ultraviolet-A1

Weak-moderate

pilot RCT81

phototherapy

Acupuncture
small

Only one
small

Weak, not reaching MCID

Only one

threshold, only one of eight pilot RCT86

patients showed clinical
improvement

TG 8
Sham 8
CG 8

5 weeks

3 weeks, 5
days/week
(or 200 second
exposure time);
total
body irradiation of
UVA-1 (340400 nm)
with 6 J/cm2
10 sessions

Abbreviations: GI, glycemic index; FDA, US Food and Drug Administration; MCID, minimal clinical important difference; OTC, over the counter; RCT,
randomized controlled trial; UVA-1, ultraviolet-A1; CG, control group; PG, placebo group; TG, treatment group; SLE, systemic lupus erythematosus;
DHEA, dehydroepiandrosterone.

Limitations
Given that this review was limited to papers published in the
Englishlanguage,withfulltextavailable,itispossiblethatwe
mayhavemissedsomeimportantstudieswritteninlanguages
otherthanEnglish,notindexedinthesetwodatabases(PubMed
and Scopus), or as part of reporting bias. To reduce the
probability of excluding appropriate studies relevant to this
review, we used the tracking citations function of Scopus to
locate additional appropriate articles that cited our selected
studies.Wedidnotincludeorevaluateastudyofepratuzumab,
an experimental drug administered at a dose of 360 mg/m 2,
whichhasbeenshowntoimprovetheSF36vitalityscalescore
at week 48, exceeding agematched and sexmatched US
normativevalues,90asepratuzumabhasnotyetbeenapproved

bytheUSFoodandDrugAdministrationtotreatSLE.We
alsodidnotincludeanotherRCTonthebenefitofexpressive
writing on reduction of fatigue because only about one
quarterofpatientsinthatstudyhadSLE(54/75[72%]ofthe
participantshadrheumatoidarthritis)andnodiseasegroup
stratum was formed before randomization, 91 so it is not
possible to accurately interpret the beneficial findings of
expressivewritingandattributethattoSLEparticipantsonly.

Conclusion
Oftheninestrategiesforfatiguemanagementinpatients
with SLE reviewed in this study, aerobic exercise and
belimumab seem to have the strongest evidence for
treatment efficacy. NAC and UVA1 phototherapy
demonstrated

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Therapeutics and Clinical Risk

Management 2014:10

Optimal management of fatigue in

patients with SLE

Dovepress

Cost

Not normally covered by

health insurance if just
for
fatigue management
Minimal to free for
walking
and basic aerobic
exercise
Minimal (may need
initial
educational counseling
from
dietitian or nutritionist)

Common side effects

None

Acceptability to

Availability

patients

Required
lifestyle
change

Acceptable

Minimal

Not available in clinic for

group treatment

Muscle aches and joint

May not sustain

Major

Easily available

May not sustain

Major

Easily available

pain (transient)
Headache and
gastrointestinal
discomfort (transient)

Minimal

None

Acceptable

No (except take
the pills)

OTC

Minimal

Headache, heartburn,
nausea, vomiting

Acceptable if not
experiencing side
effects

No (except take
the pills)

OTC

Minimal

Acne and hirsutism

No (except take

Prescription/OTC

Expensive even with

health
insurance

Headache,
gastrointestinal
complaints, infection,
increased suicidal
ideation,
and transient ischemic
attacks

Not acceptable by
most young
females
Acceptable by
most
patients

May not be covered by

health insurance; not
approved by FDA for its
use to treat SLE

Erythema, pruritus,
hyperpigmentation,
and induction of
photodermatoses,
phototoxicity, and
photocarcinogenesis

Acceptable if not
experiencing side
effects

No

Not normally covered by

Dizziness,

health insurance plan

lightheadedness, and
local bruising, pain
during
needle insertion

Acceptable if no
fear

the pills)
No (except take
the pills)

No

of needles

lowtomoderate levels of evidence. Psychosocial

interventions, dietary manipulation (low calorie or
glycemic index diet), vitamin D supplementation, and
acupunctureallhadweakevidence.Finally,DHEAisnot
recommendedduetolackofevidenceforitsefficacy.
SLErelatedfatigueisacomplexphenomenonandabroad
arrayoffactorsiscommonlyassociatedwithfatigue.Optimal
fatiguemanagementshould,therefore,startwithacomprehen
siveevaluationofthepatientasrelatestothesefactors.Ideally,
treatmentstrategiesshouldbetailoredtotheindividualpatients
physical and psychosocial health status, and their cultural
background.Anycomorbiditiessuchaspsychologicaldistress,
chronicpain,sleepdisturbance,obesity,andhypovitaminosisD
thatareassociatedwithfatigueshouldbeaddressed.

Required prescription

Not available in every

major
lupus center

Available in many areas,

efficacy may depend on
the
expertise of the
acupuncturist

Disclosure

Theauthorsreportnoconflictsofinterestinthiswork.

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