REVISTA
BRASILEIRA
DE
REUMATOLOGIA
ww w . r e u m a t o l o g i a . c o m . b r
Review
article
Polyunsaturated
omega-3
fatty
acids
and
systemic
lupus
erythematosus:
what
do
we
know?
夽
Mariane
Curado
Borges
a,∗,
Fabiana
de
Miranda
Moura
Santos
a,b,
Rosa
Weiss
Telles
c,
Maria
Isabel
Toulson
Davisson
Correia
d,
Cristina
Costa
Duarte
Lanna
eaProgramofSciencesAppliedtoAdultHealth,FacultyofMedicine,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil bHospitaldasClínicas,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil
cDepartmentofInternalMedicine,FacultyofMedicine,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil dDepartmentofSurgery,FacultyofMedicine,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil
eDepartmentofMusculoskeletalSystem,FacultyofMedicine,UniversidadeFederaldeMinasGerais,BeloHorizonte,MG,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received16October2013 Accepted10December2013 Availableonline23October2014
Keywords:
Systemiclupuserythematous(SLE) Polyunsaturatedfattyacidsomega-3 Eicosapentanoicacid(EPA)
Docosahexanoicacid(DHA) Antioxidantsanddiet
a
b
s
t
r
a
c
t
Variousstudieshavedemonstratedtheimpactofomega-3fattyacidsontheconcentration ofCreactiveprotein(CRP),pro-inflammatoryeicosanoids,cytokines,chemokinesandother inflammatorymediators.Therefore,thesupplementationofthesetypesoflipidsmay rep-resentadditionaloptiontreatmentforchronicsystemicdiseases,suchasSystemicLupus Erythematousandother rheumaticdiseases. Theroleoftheselipidshasnot beenwell established,yet.However,itseemsthereisadirectrelationshipbetweenitsintakeand thedecreaseofthediseaseclinicalmanifestationsaswellasoftheinflammatorystatus ofthepatients.Thus,theaimofthismanuscriptistopresentathoroughreviewonthe effectsofomega-3fattyacidsinpatientswithSLE.BibliographicdatasetastheMedical Lit-eratureAnalysisandRetrievalSystemOnline(MEDLINE)andLiteraturaLatino-Americana edoCaribeemCiênciasdaSaúde(LILACS)weresearchedusingaskeywords:systemic lupuserythematous(SLE),polyunsaturatedfattyacidsomega-3,eicosapentanoicacid(EPA), docosahexanoicacid(DHA),antioxidantsanddiet.ManuscriptspublisheduptoSeptember 2013wereincluded.Therewere43articlesrelatedtothetopic,howeveronly15pertained humanstudies,withthreereviewarticlesand12clinicalstudies.
©2014ElsevierEditoraLtda.Allrightsreserved.
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.rbr.2013.12.002. 夽
Institution:FromtheClinicofRheumatology,HospitaldasClínicas,UFMG/DepartmentofMusculoskeletalSystemandDepartmentof Surgery,FacultyofMedicine,UFMG,Post-graduationPrograminSciencesAppliedtoAdultHealth,FacultyofMedicine,UFM,majorarea inClinicalSciences.
∗ Correspondingauthor.
E-mail:maricurado@gmail.com(M.C.Borges). http://dx.doi.org/10.1016/j.rbre.2013.12.002
Ácidos
graxos
poli-insaturados
ômega-3
e
lúpus
eritematoso
sistêmico:
o
que
sabemos?
Palavras-chave:
Lúpuseritematososistêmico (LES)
Ácidosgraxospoli-insaturados ômega-3
Ácidoeicosapentaenoico(EPA) Ácidodocosahexaenoico(DHA) Antioxidantes
r
e
s
u
m
o
Diversosestudostêmdemonstradoa habilidadedosácidosgraxosômega-3emreduzir as concentrac¸ões de proteína C-reativa (PCR), eicosanoides pró-inflamatórios, citoci-nas, quimiocinas e de outrosbiomarcadores da inflamac¸ão. Poressas propriedades, a suplementac¸ãocomessaclassedelipídeospoderepresentarterapiaadicionalao trata-mentodedoenc¸asinflamatóriascrônicassistêmicas,comoolúpuseritematososistêmico (LES)eoutrasdoenc¸asreumáticas.OpapeldessaclassedelipídeosnoLESaindanãoestá bemestabelecido.Noentanto,parecehaverrelac¸ãoentreoconsumodestetipodegordura eadiminuic¸ãodasmanifestac¸õesedaatividadeinflamatóriadadoenc¸a.Sendoassim,este artigoapresentarevisãodaliteraturacientíficasobreosefeitosdosácidosgraxosômega-3 empacientescomLES.Realizou-selevantamentobibliográficojuntoaosbancosdedados MedicalLiteratureAnalysisandRetrievalSystemOnline(MEDLINE)eLiteratura Latino-AmericanaedoCaribeemCiênciasdaSaúde(LILACS),utizando-secomopalavras-chave: lúpuseritematososistêmico(LES), ácidosgraxospoli-insaturadosômega-3,ácido eicos-apentaenoico(EPA),ácidodocosahexaenoico(DHA),antioxidantesedieta.Foramincluídos artigospublicadosatésetembrode2013.Quarentaetrêsartigosrelacionadosaotemaforam encontrados.Apóslimitarabuscaapenasparaestudosrealizadosemsereshumanosforam encontrados15artigos,sendotrêsderevisãoe12ensaiosclínicos.
©2014ElsevierEditoraLtda.Todososdireitosreservados.
Introduction
Beneficialeffectsofomega-3polyunsaturatedfattyacidshave beenextensivelystudied,mostlythoseactingonthe cardio-vascularsystem.1–4Overthelastfewyears,theinterestinthe
roleofthisnutrientinreducinginflammationhasgrown.5
Thesefattyacidsareconsideredessentialandshouldbe providedbythedietorfromsupplements.Theycompetewith thearachidonicacid(AA),amemberoftheomega-6family throughthesameenzymaticpathwayandstimulateseries3 prostaglandinsandseries5leukotrienes,whichhavealower inflammatoryactionthanthoseAA-derivedeicosanoids.6
Several studies have demonstrated that omega-3 fatty acids can reduce the concentrations of C reactive protein (CRP),proinflammatoryeicosanoids,cytokines,chemokines, andotherinflammatorybiomarkers.7–10 Inaddition,
eicosa-pentaenoicacid(EPA)anddocosahexaenoicacid(DHA),both membersofomega-3family,areprecursorsofthelipid medi-atorsresolvinsandprotectins,whichhaveanti-inflammatory andimmunomodulatorycharacteristics.11–13
Inviewoftheseproperties,supplementswiththis class oflipids mightrepresentanadditionaltherapyofsystemic chronicinflammatorydiseases,suchassystemiclupus ery-thematosus (SLE) and other rheumatic conditions. Studies conducted insubjects with rheumatoid arthritis report an improvementingeneralphysicalevaluation,pain, morning stiffnessandreducedanti-inflammatoryagentusefollowing supplementationwithomega-3.14–16
TheroleofthesefattyacidsinSLEisnotfullyestablished yet.However,theintakeofthiskindoffatseemstoberelated tothereductionindiseasemanifestationsandinflammatory activity.17–25
Theauthorspresentaliteraturereviewontheeffectsof omega-3fattyacidsonpatientswithSLE.
Method
A literaturesearchon MEDLINEand LILACSdatabases was performed with the following keywords: systemic lupus erythematosus (SLE), omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), antioxidants, and diet.Articles publishedup to September 2013wereincluded. Forty-threearticlesrelatedtothetopic havebeenidentified.Afterthesearchwaslimitedtostudies conductedinhumans,15articleswerefound,withthreeof thembeingreviewarticlesand12clinicaltrials.
SystemicLupusErythematosus
Systemic lupus erythematosus (SLE) is a multisystemic autoimmuneinflammatorydiseasewithalargespectrumof manifestationsthatisclinicallycharacterizedbyrelapsesand remissionperiodswithavaryingcourseandoutcome.The dis-easeseverityrangesfrommildtosevere.However,complete andprolongedremissionisrare.26
Although SLE etiology is not known, an interaction of genetic, hormonal and environmentalfactors are probably involvedinthediseasedevelopment,thusleadingtoalossof cellimmunoregulationbalance.27Thisimmunedisturbance
occursthroughlossoftolerancetonuclearantigens,poorly regulatedactivationofB-andTlymphocytesandsubsequent B-lymphocyte polyclonalactivation, with largenumbers of reactive self-antibodies being produced and immune
self-antibodies,areprimarilyresponsiblefortissuelesionand organdamage.28
This complex process involves interaction of various cytokines, chemokines, adhesion molecules, and pattern-recognitionreceptors(PRRs)triggeringcellactivation.29
TlymphocyteswithaTH1functionalresponseare stimu-latedbyinterleukin(IL)-12toproducetumornecrosisfactor alpha(TNF-),interferongamma(IFN-),andIL-2.Ontheother hand,TH2lymphocytes produceIL-4, IL-5,and IL-13when stimulated by IL-4. A significant cytokine elevation result-ing from the TH1 response is observed in the serum of patientswithSLE,thusindicatingadisturbanceinTH1/TH2 responsepattern is likely.28 The TH17functional response
and serum levels of other cytokines, such as IL-23, IL-18, IL-21,and IL-23arealsoelevated, but theirrole inthe dis-easepathogenesisisstillunderinvestigation.28Manyofthese
cytokinesareelevatedintheserumofpatientswithSLEand areassociatedwithahigherdiseaseactivityorcertainclinical manifestations.29–32
Fewstudiesanalyzedtherole ofnutritioninSLE patho-genesistothismoment.Omega-3polyunsaturatedfattyacids mighthavebeneficialclinicaleffectsonSLEbecauseoftheir anti-inflammatoryactions,whichwouldwarranttheiruseas anothertreatmentoptionforthedisease.13
Omega-3polyunsaturatedfattyacids
Fattyacidsmaybeclassifiedassaturated(nodoublebonds betweenindividualcarbonatoms)fattyacidsandmono-or polyunsaturatedfattyacidsaccordingtothenumberof dou-ble bondsinthe chain. Themost commonsaturated fatty acidsinhumanfoodare:lauric,myristic,palmitic,andstearic acids(rangingfrom12to18carbonatoms).Unsaturatedfatty acidsareclassifiedintotwomaincategories:polyunsaturated fattyacids,representedbyomega-6fats(withmain represent-ativesbeinglinoleicandarachidonicacids)andomega-3fats (withmainrepresentativesbeing-linolenic,eicosapentaenoic [EPA],anddocosahexaenoic[DHA]acids)ormonounsaturated fattyacids,representedbytheomega-9(omega-9–oleic)fats. Omega-3andomega-6fattyacidsareconsideredessential,as theyarenotsynthesizedbythehumanbody.Thelinoleicacid (18:2omega-3)istheprecursoroftheotherpolyunsaturated fattyacidsinomega-6fats,whichhassoy,corn,andsunflower vegetableoilsastheirmainfoodsources.Intheomega-3 fam-ily,the -linolenicacid(18:3 omega-3)isfoundinanumber ofvegetables,suchascanolaandlinseed,whereasEPA(20:5 omega-3)andDHA(22:6omega-3)arefoundindeepseacold waterfish(mackerel,sardines,salmon,herring).Ontheother hand,oleicacid(18:1omega-9)canbesynthesizedbythebody anditsmaindietsourcesareoliveoil,canolaoil,olives, avo-cadoandnuts(peanuts,chestnuts,walnuts,almonds).33
Mechanismsofactionofomega-3fattyacids
Thefirst datasuggestinga possibleanti-inflammatoryrole for omega-3 fatty acids are derived from an epidemiolog-ical study in Greenland Eskimos conducted by Kronmann and Green in 1980. The authors found that the preva-lenceofdiseaseswithaninflammatorycomponent,suchas acutemyocardiuminfarction,diabetesmellitus(DM),multiple
Family w-3
Delta 6 desaturase
Delta 5 desaturase
Delta 6 desaturase
Family w-6 18:3 (α-linolenic acid) 18:2 (linoleic acid)
20:4 (arachidonic acid–AA) 20:5 (eicosapentaenoic acid–EPA)
22:6 (docosahexaenoic acid–DHA) 18:4
Elongase
Elongase
Elongase
Beta-oxidation 20:4
22:5
18:3
20:3
22:4
24:4
24:5
22:5 24:5
24:6
Figure1–Omega-3andomega-6fatty-acidmetabolism AdaptedfromLeonardetal.,2004.37.
sclerosis,bronchialasthma,andthyrotoxicosis,waslowerin the studypopulationthan inWesterncountry populations. Eskimosdiethavealargeamountofseafood,whichisasource ofpolyunsaturatedfattyacids.34 Thereafter,several studies
wereconductedtofindtheroleoftheselipidsinmanychronic diseasesinwhichinflammationplaysamajorpathogenetic role.
Theomega-3andomega-6families,throughtheir mem-bersEPA,DHA,and arachidonicacid (AA),are theessential lipidclassesforeicosanoidsynthesis.Eicosanoidsareamong the major inflammation mediators and regulators. They includeprostaglandins(PG),leukotrienes(LT),thromboxanes, andotheroxidizedderivatives.Theyareproducedbyoxidative pathwaysoftheenzymescyclooxygenase(COX)and lipoxyge-nase(LOX).35
Due to their molecular similarity, linoleic acid and -linolenicacidcompeteforthesameenzymes tosynthesize derivatives with20 carbonatoms: AA(20:4omega-6), eico-sapentaenoicacid(EPA)(20:5omega-3)eeicosatrienoicacid (ETA) (20:3 omega-9). The -linolenic acid has a 22-carbon atomderivative,thedocosahexaenoicacid(DHA)(22:6
omega-3)33,36,37(Fig.1).
A high intake of linoleic acid favors an increased AA content in membrane phospholipids, thus increasing the productionof series2 and 4eicosanoids (prostaglandinE2 and leukotriene B4) through cyclooxygenaseand lipoxyge-nase enzymatic pathways, respectively. A high production ofeicosanoidsisrelated tothe occurrenceofimmune dis-orders, cardiovascular and inflammatory diseases. On the other hand,the intakeofomega-3family fatty acids,such as -linolenic acid, EPA or DHA, which compete with AA for the same enzymatic pathways, competitively inhibits thearachidonicacidoxidationbycyclooxygenase(COX)into prostaglandins and their conversioninto leukotrienes (LTs) via5-lipoxygenase(LOX)pathway.6,33Theomega-6fattyacid
Arachidonic Acid
EPA
DHA
Series-2 PGs Series-4 LTs Series-3 PGs Series-5 LTs Series-E resolvins Series-D resolvins and protectins
COX LOX COX LOX COX and LOX
COX and LOX
High proinflammatory potential Low proinflammatory potential Anti-inflammatory and resolution
of inflammation potentials
-
-Figure2–SynthesesandactionsoflipidmediatorsproducedbyAA,EPA,andDHA
AA,arachidonicacid;EPA,eicosapentaenoicacid;DHA,docoxahexaenoicacid;COX,cyclooxygenase;LOX,lipoxygenase; PG,prostaglandins;LT,leukotrienes
AdaptedfromCalderetal.,2010.13.
(LTB4)].PGE2inducesanumber ofproinflammatoryeffects, suchasincreasedvascularpermeability,vasodilation, hyper-emia,andhiperalgesia.38–40TXA2promotesthesynthesisof
inflammatory cytokines, IL-1 and TNF-␣ by mononuclear phagocytes.39,41 On the other hand, LTB
4, in addition to
causingincreasedvascularpermeabilityandhyperemia,isa powerfulleukocytechemotacticagentinducingthe produc-tionoflysosomalenzymesandincreasingtheproductionof reactiveoxygenspeciesandcytokines,suchasTNF-,IL-1,and
IL-6(Fig.2).39,40
Thus,theomega-3fattyacidactsbyreducingthe forma-tionofeicosanoidswithinflammatorycharacteristics,since it competes with omega-6 fatty acids for the same enzy-maticpathway,leadingtotheinhibitionofTNF-,IL-1andIL-6 synthesisandreducingtheintercellularadhesionmolecule-1 (ICAM-1)expression.42Itisalsoasubstrateforthesynthesis
ofseries3and5eicosanoids,whichhavelessinflammatory characteristics(Fig.2).6
Studiesinculturedcellshavefurtherdemonstratedthat EPAandDHAcaninhibittheproductionofclassic inflamma-torycytokines,suchasTNF-,IL-1,IL-6,andothers.40,43–45In
healthysubjects,reducedproductionofTNF-,IL-1andIL6by monocytesandmononuclearcellshasalreadybeen demon-strated following fish oil supplementation,9,10,46 although
otherstudieshavenotconfirmedthosefindings.8,47,48These
differencesmighthaveoccurredbecauseofthedifferentdoses used,thedurationoftreatment,andnon-representative sam-ples.
T-cellproliferationinhibitionandIL-2productionwerealso foundinculturedcellsfollowingsupplementationwithEPA andDHA.49However,thesefindingsareinconsistentinhuman
studies.
Inaddition,EPAandDHAareprecursorsofthelipid medi-atorsresolvinsandprotectins.Thepathwayforproduction ofthesesmediatorsalsoinvolvestheenzymes cyclooxygen-ase and lipoxygenase (Fig. 2). In cultured-cell and animal studies,bothresolvinsandprotectinsdemonstratedtohave anti-inflammatory and immunomodulating actions.11–13,50
ResolvinsE1andD1andprotectinD1caninhibitneutrophil
transendothelialmigration,thuspreventingtheinfiltrationof immunecellsattheinflammationsite.ResolvinE1can fur-therinhibitIL-1productionandprotectinE1inhibitsIL-1and TNF-production.50Thus,theselipidmediatorscanplayarole
intheresolutionphaseofinflammationandinlimitingtissue damage.
Thus, the ratio between daily intake of omega-6 and omega-3 fatty-acid sources assumes great importance in humannutrition.36However,theWesterndietischaracterized
byahighomega-6polyunsaturatedfattyacidintakeandhigh omega-6/omega-3ratio,whichfavorspathogenesisina num-berofconditions,includingcardiovascular,inflammatory,and autoimmunediseases,aswellascancer.The omega-6/omega-3 ratio in Western diet is estimatedto be 15-20:1. On the otherhand,anincreasedomega-3intakeandareducedratio betweenthesefattyacidsasaconsequenceseemstoexerta suppressiveeffectondiseasepathogenesis.51
Omega-3andSystemicLupusErythematosus
Fewstudiesinvestigatingomega-3fattyacideffectson sub-jectswithSLEhavebeenconductedtothismoment.However, afewtrialssuggestthatsupplementationwiththisclassof lipids can represent an additionaltherapy to the standard pharmacologicaltreatmentofthisdiseaseduetotheir anti-inflammatoryproperties.17–25
SLEandahistoryofCVDhadhigherlevelsofplasma monoun-saturated fatty acids and higher levels of omega-6 family polyunsaturatedfattyacidsthanthosewithoutCVD.Patients takingprednisone had higher levels ofomega-3and lower AA/EPAratios comparedwiththose nottakingprednisone. However,thesedifferenceswerenotstatisticallysignificant.23
Low levels of omega-3 could contribute to worsen the inflammationalready present inthese patients, thus indi-catingthatthenutrientsupplementation,onitsturn,would contributetoimprovetheinflammatoryprofileand, conse-quently,thediseaseactivity,assubstantiatedbyElkanetal. (2012) in a study conducted in 114 patients with SLE and 122 subjects without the disease. The authors found that higherlevelsofEPAandDHAinfatcellsofpatientswithSLE were negativelyassociatedwithdisease activity (measured bySystemicLupus ErythematosusDisease Activity Index– SLEDAI)andthepresenceofatheroscleroticplaques.Onthe other hand, higher omega-6 levels were positively associ-atedwithahigherdamageindex(evaluatedbytheSystemic LupusInternationalCollaborationClinics/AmericanCollegeof RheumatologyDamageIndex–SLICC/ACR)andthepresence ofatheroscleroticplaques.Inthisstudy,foodintakeevaluation identifiedthat subjects withSLEdescribed a higher carbo-hydrateintakeand alower fiberand polyunsaturatedfatty acid(omega-6andomega-3) intakethan controls. Carbohy-drateintake was positively associatedwith the amount of omega-6fattyacidspresentinadiposetissue.Anassociation betweencarbohydrate,fiber,saturatedandmonounsaturated fattyacidintakeanddiseaseactivityordamageindexcould notbefound.24
Thefirststudyevaluatingtheeffectofomega-3fattyacids on patients with SLE taking fish oil supplementation was reported in 1989 by Clark et al. Theauthors analyzed the effectsofomega-3(EPAandDHA)on12subjectswithSLEand nephritisandconcludedthatdietsupplementationwithfish oilcanaffectthemechanismsinvolvedininflammationand atherosclerosis.Thepatientswere givenasupplementation overfiveweekswithdailydosesof6goffishoil,followedby aperiodoffiveweekswithoutthesupplementationandthen fivemoreweekswith18goffishoildaily.AriseinEPAandDHA levelsinmembranephospholipidsandreducedAA incorpora-tionwerefound.Thesechangeswereassociatedwithreduced plateletaggregationandbloodviscosityandwithanincrease inredcellflexibility.LTB4productionbyneutrophilswasalso significantlyreduced.Thehigher fishoildose induced38% reductionintriglyceridelevelsanda39%reductionin VLDL-cholesterol,associatedwitha28%increaseinHDL-cholesterol levels.Theeffectsontheanti-DNAantibodiestitleand albu-minuriawasnotverified.17
Ontheotherhand,inanothertrialconductedbythesame group of investigators, different results were found. In 21 patientswithastablelupusnephritiswhoweregivenadaily doseof15gfishoilorplacebocontainingoliveoiloverone year,animprovementinkidney function orinthe disease activitywasnotfoundinthefishoilgroupcomparedwiththe placebogroup.Asforbloodlipids,onlyVLDL-cholesteroland triglycerideshadasignificantreductionfollowingthe treat-mentwithfishoil,whereasLDLandHDLfractionsremained unchanged.19
Westbergetal.(1990)evaluatedtheeffectsofomega-3fatty acids supplementationwith capsulescontaining fish oilor capsulesofoliveoilasaplacebo in60patientswith mod-eratelyactiveSLE.Overthefirstthreemonths,thepatients receivingomega-3supplementationhadsignificant improve-mentinclinicalandlaboratoryparameters.However,aftera six-monthsupplementation,nodifferencesbetweengroups couldbedetected,whichsuggests,accordingtotheauthors, thesupplementeffectsareshort-lived.18
In 2004, Duffy et al. published another trial evaluating theeffectofomega-3supplementsand/orcopperinpatients with SLE. Fifty-two patients were divided into four treat-ment groups. One of the groups was given 3 g of fish oil in capsules (EPA 540 mg+DHA 360 mg/capsule)and 3mg of copper; the second groupwas given 3 gof fish oil and copperasaplacebo;thethirdgroupreceivedasupplement with3mgofcopperand fish oilplacebo; the fourthgroup receivedplaceboinsteadofbothnutrients.Afterasix-month supplementation,areduceddiseaseactivityfrom6.12to4.69 (P < 0.05), measured by the Systemic Lupus Activity Mea-sure(SLAM)score,wasfound.Theintegument,neuromotor, and laboratory domains ofSLAM-R were most affected by supplementation.20
Omega-3 beneficial effects on reducing lupus nephritis activitywereevaluatedbyNakamuraetal.(2005).Theauthors examined theeffectofdailysupplementationwith1.8gof purifiedEPAinsixpatients withlupusnephritisdiagnosed bykidneybiopsy.Aftera3-monthsupplementation,reduced AA levels and increasedlevels ofEPA inplasma phospho-lipidsweredetected,inadditiontoreducedurinarylevelsof 8-isoprostane (from550113pg/mg CRto23549pg/mg CR, P=0.02).Intheauthors’opinion,thesefindingsindicatethat EPAcanpromotedecreasedoxidativestress,withconsequent benefits forlupusnephritis treatment. On the other hand, whenimmuneparameterswereevaluated,nosignificant dif-ferences were found in anti-DNA and serum complement valuesafteromega-3treatment.21
Wrightetal.(2008)comparedtheeffectsofdailyintakeof3 gofomega-3(1.200mgofDHA+1.800mgofEPA)withplacebo ofolive oilin 60 patientswith SLEover a 24-weekperiod. They noted that the omega-3 supplementationin patients withSLEcouldnotonlyhaveatherapeuticeffectonthe dis-easeactivitymeasuredthroughtheSystemicLupusActivity Measure(SLAM-R)andBritishIslesLupusAssessmentGroup (BILAG)indexes,butalsopromoteimprovementinendothelial functionandreducedoxidativestress,thusconferring cardio-vascularbenefits.22
Recently,Belloetal.(2013)havepublishedadouble-blind, placebo-controlledtrialinwhich85patientswithSLEwere randomizedtoreceiveeither3gofomega-3supplementsor placebo.Aftera12-weeksupplementation,nosignificant dif-ferencesbetweenthegroupswerefoundfordiseaseactivity, serumlevelsofinflammatorymarkers(ICAM-1,VCAM-1,and IL-6),andendothelialfunction.Asforthelipidprofile,patients receivingomega-3hadasignificantincreaseinLDLcholesterol levels,whereasthoseintheplacebogrouphadasignificant reductionofthislipoprotein.25
Table1–Interventionalstudieswithomega-3fattyacidsinpatientswithsystemiclupuserythematosus(SLE).
Study n Studydesign Results
Clarketal.,198917 12subjectswithlupus
nephritis
6gofomega-3supplements/day overfiveweeks,followedbyfive weekswithnosupplementsand additionalfiveweekswith18gof omega-3/day
RiseinEPAandDHAlevelsin membranephospholipidsand decreaseinAAlevels
Decreasedplateletaggregationand bloodviscosity
Increasedred-cellflexibility ReducedLTB4productionby neutrophils
38%reductionintriglyceridelevels and39%reductionofVLDL-Clevels 28%increaseinHDL-Clevels Noeffectsonanti-DNAand albuminurialevels Westbergetal.,199018 60subjectswith
moderatelyactiveSLE
Omega-3supplementsvs.placebo Supplementsforsixmonths
Improvementinclinicaland laboratoryparametersoverthefirst threemonthswithsupplements Unchangedaftersixmonthswith supplements
Clarketal.,199319 21subjectswithstable
lupusnephritis
Supplementswith15goffishoil vs.oliveoilplaceboforoneyear
Unchangedkidneyfunctionand diseaseactivity
ReducedVLDL-Candtriglyceride serumlevels
UnchangedLDL-CandHDL-Clevels Duffyetal.,200420 52subjectswithSLE Fourgroups:(1)3gofomega-3+3
mgofcopper;(2)3gof
omega-3+copperplacebo;(3)3mg ofcopper+omega-3placebo;(4) omega-3andcopperplacebo Supplementsforsixmonths
Reduceddiseaseactivityingroups receivingomega-3
Nakamuraetal.,200521 Sixsubjectswithlupus
nephritis
Supplementswithdailydosesof 1.8gofpurifiedEPA
Supplementsforthreemonths
ReducedAAlevelsandincreased EPAlevelsinmembrane phospholipids
Reducedurinelevelsof8 isoprostane
Unchangedanti-DNAandserum complementvalues
Wrightetal.,200822 60subjectswithSLE Supplementswith3g/dayof
omega-3vs.oliveoilplacebo Supplementsforsixmonths
Reduceddiseaseactivity Improvementofendothelial function
Reducedoxidativestress Aghdassietal.,201123 32subjectswithSLEand20
controlswithoutthe disease
Fattyacidcontentsinredcellsand plasmafrom:womenwithand withoutSLE;betweenSLEpatients withandwithoutahistoryofCVD; betweenpatientstaking
corticosteroidsornotwere compared
Loweromega-3levelsinred-cell membraneofsubjectswithSLE thaninthosewithoutthedisease Higherplasmaomega-6fatty-acid levelsinpatientswithSLEanda historyofCVD
Higheromega-3levelsinpatients takingcorticosteroids
Differences,however,werenot statisticallysignificant Elkanetal.,201224 114SLEpatientsand122
subjectswithoutthe disease
Omega-3andomega-6contentsin adiposetissuecellsofpatients withSLEwereevaluated
Negativeassociationbetween higherEPAandDHAlevelsin adiposetissuecellsanddisease activityandpresenceof atheroscleroticplaques
Positiveassociationbetweenhigher omega-6levelsinadiposetissue cells,damageindex,andpresence ofatheroscleroticplaques Belloetal.,201325 85subjectswithSLE Supplementswith3gof
omega-3/dayvs.placebo Supplementsfor12weeks
Unchangedendothelialfunction anddiseaseactivity
IncreasedLDL-Clevelsinsubjects receivingomega-3
Unchangedlevelsofinflammatory markers(IL-6,ICAM-1,and VCAM-1)
Finalremarks
Clinicalstudiessuggestthatsupplementationwithomega-3 polyunsaturatedfattyacidscanrepresentanadditionaloption toSLEstandardpharmacologicaltreatmentbecauseoftheir anti-inflammatoryproperties.17–25 Thislipidclassisrelated
totheproductionofeicosanoidswithalowerinflammatory actionthanthose producedbyfatty acidspertainingtothe omega-6family,additionallyreducingserumlevelsof inflam-matorycytokinesandTlymphocyteactivation.
Clinical trialsconducted usedvery different doses, ran-gingfrom 1.8 gto18 goffish oil, and differenttreatment lengths,rangingfromfiveweeksto12months.Whether pos-itive effectsare causedby EPAintake, DHA intakeor by a combinedactionofbothfattyacidsisquestionable.In addi-tion,moststudieshavesmallnumbersofsubjectsincluded, thereforeleadingtolimitedconclusions.
Thus, further studies with a larger number ofsubjects areneededtoevaluatetherealeffectofthesefattyacidsin patientswithSLE,theeffectivedose,andthedurationof treat-ment.
Funding
This research project received funding from Fundac¸ão de AmparoàPesquisadoEstadodeMinasGerais(Fapemig).
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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