Rev. Bras. Reumatol. vol.57 número2

r e v b r a s r e u m a t o l . 2017;57(2):182–184

ww w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Brief

communication

Salivary

␤

_{2-microglobulin}

_positively

_correlates

with

ESSPRI

in

patients

with

primary

Sjögren’s

syndrome

A

␤2-microglobulina

salivar

se

correlaciona

positivamente

com

o

ESSPRI

em

pacientes

com

síndrome

de

Sjögren

primária

Felipe

Garza-García

_,

_Guillermo

_{Delgado-García}

,

Mario

Garza-Elizondo

,

Luis

Ángel

Cece ˜nas-Falcón

_,

_Dionicio

_{Galarza-Delgado}

,

Janett

Riega-Torres

b_{UniversidadAutónomadeNuevoLeón,HospitalUniversitario,ServiciodeReumatología,Monterrey,Mexico}

c_{UniversidadAutónomadeNuevoLeón,HospitalUniversitario,ServiciodeAnatomíaPatológica,Monterrey,Mexico}

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Articlehistory:

Received20June2016 Accepted27September2016 Availableonline14December2016

PrimarySjögren’ssyndrome(pSS)isasystemicautoimmune disorderlargelydistinguishedbylymphocyticexocrinopathy.1 Salivaryand lachrymalglandsare mainlyimpaired inpSS. Salivaisthereforeconsideredanoptimalbiologicalfluidthat closelyreflectstheunderlyingautoimmuneexocrinopathy.1,2 For instance, in those with pSS, ␤2-microglobulin (B2M) is increased in whole saliva.2 _{This protein is significantly} correlated with lymphocytic infiltration in labial salivary glands.3 _{The EULAR Sjögren’s syndrome Patient Reported} Index(ESSPRI)isapatient-centered measureofsymptoms. This index has been recently shown to be valid, reliable and sensitive tochange in a largecohort of patients with pSS.1_{TheESSPRIcorrelatedsignificantlywithserumB2Min} patients with pSS.4 _{However, serum and salivary levels of} B2Mwerenotcorrelatedinapreviousstudy.5_{Itiscurrently} unknownwhethertheESSPRIisalsocorrelatedwithsalivary

∗ _{Correspondingauthor.}

E-mails:grdelgadog@gmail.com,guillermo.delgadogr@uanl.edu.mx(G.Delgado-García).

B2MinthosewithpSS.Thisisofparticularimportancesince, if thesetwoparameters areindeedassociated,atreatment whichcould decreaseinflammatoryactivitywould improve the patients’symptoms,and alsobecausethe treatmentof chronicdiseases finallyaimstoimprove qualityoflifeand patient-perceivedhealthstatus.6_{Duetotheaboveissues,this} studywasconducted.SalivaryB2Mwasfurthersubanalysed according to the patient-acceptable symptom state (PASS). A cut-off value for salivary B2M to distinguish those who were abovethe thresholdof unsatisfactorysymptom state (ESSPRI≥5)wasalsodetermined.

Inthis observationalstudy,adultpatients(≥18-year-old) with pSSwere enrolled.Thosewithhistory ofHIV, hepati-tis Band C,head and neck radiation therapy, sarcoidosis, amyloidosis, chronic kidney disease, lymphoma, or multi-plemyelomawereexcluded.pSSwasdiagnosedaccordingto

http://dx.doi.org/10.1016/j.rbre.2016.11.001

rev bras reumatol.2017;57(2):182–184

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theAmericanCollegeofRheumatology(ACR)/Sjögren’s Inter-nationalCollaborativeClinicalAlliance(SICCA)criteria.7 _All patientscompletedthe ESSPRI.Thisindexisameanscore of0–10numericalscales forpain, fatigueanddryness fea-tures(includingoral,ocularandglobaldryness).1_PASSwas definedasthevaluebeyondwhichpatientsconsider them-selveswell(i.e.,ESSPRI<5).6_{Thedegreeofhistopathological} changewasassessedusingthegradingstandardforlabial sali-varyglandbiopsy.8_{Writteninformedconsentwasobtained} fromall patients, andthe studywas approvedbythe local ethicscommittee.

Ourstudyprotocolwassimilartothatdescribedpreviously byCastroetal.5_{Salivasampleswerecollectedover15minby} passivespittinginto containers.Unstimulatedwhole saliva samples were centrifuged at 14,000×g for 20min at +4◦_C priortoassaying.B2Mwasdeterminedbyanenzyme-linked immunosorbentassay (Abcam,Cambridge, UK) and results were expressed as nanograms per milliliter (ng/mL). This assaywasperformedaccordingtothemanufacturer’s instruc-tionmanual.

Normality of data distribution was assessed using the Shapiro–Wilktest.Themeasurementofthestrength ofthe association between the variables was explored using the Kendall’s correlationcoefficient. Continuous variables were comparedbetweengroupswiththeMann–WhitneyUtest.A receiveroperatingcharacteristic(ROC)curvewasgeneratedto determinethecutoffvalueintheB2Mwiththehighestlevelof accuracyinidentifyingpatientswithunsatisfactorysymptom state(ESSPRI≥5).Sensitivityandspecificitywerethus calcu-lated.Unless indicatedotherwise, all resultsare expressed asmean±standarddeviationormedian(interquartilerange). StatisticalanalyseswereconductedusingSigmaStat(v.3.5, Erkrath,Germany)orMedCalc (v.14.12.0,Ostend,Belgium), andap-valuebelow0.05(p<0.05)wasconsideredsignificant. Weincluded71consecutivefemalepatientswithpSSaged 53.05±12.19years.Theyhad siccasyndromefor48(24–81) months.Inourpatients,themedianESSPRIwas6.3(3.3–8.6), whilethemedianB2Mwas0.671(0.284–1.072)ng/mL.A signifi-cantpositivecorrelationbetweenESSPRIandsalivaryB2Mwas found(0.759,95%CI0.656–0.837,p<0.0001)(Fig.1).Thedegree ofhistopathologicalchangewasnotsignificantlycorrelated withsalivaryB2M(0.0485,95%CI−0.123to0.237,p=0.55).Data werethensubanalysedintoPASS(n=28)andnon-PASSgroups (n=43).SalivaryB2Mwascomparativelyhigherinthosewho were above the thresholdofunsatisfactory symptom state (0.878[0.682–1.263]vs0.219[0.10–0.324]ng/mL,p<0.0001).The ROCcurveanalysisforsalivaryB2Mshowedanareaunderthe curveof0.965(95%CI0.891–0.994,p<0.0001)withanoptimal cutoffvalueof0.472ng/mL(Fig.2).Sensitivityandspecificity were97.67%and96.30%,respectively.

B2M isanonglycosylated low-molecular-weightprotein, which is part of the major histocompatibility complex I and is particularlyexpressed in lymphocytes. This protein is regulated by interferon and, in turn, this pathway acti-vation is thought to be related to the disease progression ofpSS.9,10 _{TheincreasedexpressionofB2Minwholesaliva} might thus represent both systemic Bcells activation and increasedintraglandular immunoglobulin synthesis, which are peculiarfacetsof pSS.10,11 _{As notedbefore, the ESSPRI} hasbeenvalidatedrecentlyinaninternationalmulticenter

3.0

2.5

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B2M (ng/mL

)

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0.0

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0

ESSPRI

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6 10

Fig.1–Asignificantpositivecorrelationbetweenthe ESSPRIandsalivaryB2Mwasfound(Kendall’stau0.759, 95%CI0.656–0.837,p<0.0001).

cohortofpatientswithpSS.TwoSpanish-speakingcountries were includedinthelatterstudy (includingonefromLatin America).1_{TheESSPRIhasbeenalsovalidatedintoBrazilian} Portuguese.12_{ThemedianESSPRIinourstudyissimilartothat} alreadydescribedbySeroretal.intheirinternational multi-centerstudy.1_{ThePASSissimilartotheconceptoflow-disease} activityfortheEULARSSdiseaseactivityindex(ESSDAI;i.e., ESSDAI<5).Nevertheless,thesetwoindexesdidnot necessar-ilyoverlap,particularlyinpSSwherediseaseactivity(ESSDAI) andpatients’symptoms(ESSPRI)didnotcorrelate.6,13_Hence, thesetwoindexescomplementeachotherintheevaluation ofpatientswithpSS.1

B2M (ng/mL)

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Fig.2–ROCcurveanalysisforsalivaryB2M.Itshowedan areaunderthecurveof0.965(95%CI0.891–0.994,

p<0.0001)withanoptimalcutoffvalueof0.472ng/mL.

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OurresultssupportthenotionthatsalivaryB2Mmightact asabiomarkerforanunsatisfactorysymptomstate(Fig.2). PatientswithsystemicfeatureshavehigherscoresonESSPRI, which means that they are more symptomatic.1 Addition-ally,asignificantassociationbetweensalivaryB2M(measured by enzyme-linked immunosorbent assay) and serum anti-Ro/SSA antibodies has been previously reported.11 _{This is} relevantbecause,inpatientswithpSS,theseantibodiesare likelytobestronglyinvolvedinthe clinicalseverityof ker-atoconjunctivitissicca,14 _{and alsobecause higher levels of} these antibodies have been reported in patients with sys-temicfeatures(e.g.,purpura).15_{Therefore,consideringthese} twofindingstogether,higherconcentrationsofsalivaryB2M mayalsodistinguishthosewithsystemicfeatures,whocould benefitmostfromtreatment.6

In summary, there is a significant positive correlation betweenthe ESSPRIand salivaryB2M.Inaddition, salivary B2M iscomparatively higher inthose who were abovethe thresholdofunsatisfactorysymptomstate.Ourresults sug-gest that, inpSS,the intensity ofthe symptoms isindeed associatedwithsB2M.sB2Mmightthusrepresentasimpleand objectivemethodtoaidintheidentificationofthosewithan unsatisfactorysymptomstate.Thelatterisespecially impor-tantinchronicdiseases,suchaspSS,sincetheirtreatment aimstoimprovepatients’qualityoflife.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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