Anais
Brasileiros
de
Dermatologia
www.anaisdedermatologia.org.br
INVESTIGATION
Analysis
of
cardiovascular
risk
and
carotid
intima-media
thickness
in
patients
with
psoriasis
夽,夽夽
Elaine
Cristina
Faria
Abrahão-Machado
a,∗,
José
Alexandre
Mendonc
¸a
b,
Ana
Carolina
Belini
Bazán
Arruda
c,
Luciana
Bertoldi
Nucci
d,
Marcel
Alex
Soares
dos
Santos
eaDermatologyOutpatientClinic,HospitaldaPontifíciaUniversidadeCatólicadeCampinas,Campinas,SP,Brazil bRheumatologyOutpatientClinic,PontifíciaUniversidadeCatólicadeCampinas,Campinas,SP,Brazil
cPsoriasisOutpatientClinic,HospitaldaPontifíciaUniversidadeCatólicadeCampinas,Campinas,SP,Brazil dPostgraduateProgram,PontifíciaUniversidadeCatólicadeCampinas,Campinas,SP,Brazil
eDisciplineofDermatology,FaculdadedeMedicinaSãoLeopoldoMandic,Campinas,SP,Brazil
Received15January2019;accepted11July2019
Availableonline31January2020
KEYWORDS Cardiovascular diseases; Carotidintima-media thickness; Methotrexate; Moleculartargeted therapy; Psoriasis; Ultrasonography Abstract
Background: Psoriasisisassociatedwithatherosclerosisandincreasedcardiovascularrisk.
Cur-rently,anautomatedultrasound,calledquantitativeintimamediathickness,hasproventobe
ausefulmethodtoevaluatesubclinicalatherosclerosis.
Objectives: Tocompareincreasedcardiovascularriskinpsoriasispatientsreceivingtwotypes
oftreatments:Methotrexateandtumornecrosisfactorinhibitorandtoevaluatethecorrelation
betweentheFraminghamscoreandquantitativeintimamediathickness.
Methods: Fifty patients with plaque psoriasis were selected from June 2017 to July 2018,
dividedintotwogroups,receivingmethotrexateandtumornecrosisfactorinhibitor.
Measure-mentofabdominalcircumference,bloodpressure,bodymassindexandpresenceofmetabolic
syndromewereperformed.Afterwards,thepatientswereevaluatedforincreased
cardiovas-cularriskwiththeFraminghamscoreandforthequantitativeintimamediathicknessofthe
carotidarteries.
Results: Themeanagewas54.8(±12.5)withaslightmalepredominance(58%).Overall,84%of
thepatientshadelevatedwaistcircumference,82%hadabodymassindexaboveideal,and50%
hadametabolicsyndrome.Forthecorrelationbetweenquantitativeintimamediathickness
andFraminghamScore,Pearson’slinearcorrelationcoefficientwas0.617(p<0.001),indicating
amoderatetostrongpositiveassociation.
夽 Howtocitethisarticle:Abrahão-MachadoECF,Mendonc¸aJA,ArrudaACBB,NucciLB,SantosMAS.Analysisofcardiovascularriskand
carotidintima-mediathicknessinpatientswithpsoriasis.AnBrasDermatol.2020;95:150---7.
夽夽StudyconductedattheHospitaldaPontifíciaUniversidadeCatólicadeCampinas,Campinas,SP,Brazil. ∗Correspondingauthor.
E-mail:elaineabrahao@yahoo.com(E.C.Abrahão-Machado).
https://doi.org/10.1016/j.abd.2019.07.004
0365-0596/©2020SociedadeBrasileiradeDermatologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BYlicense(http://creativecommons.org/licenses/by/4.0/).
Studylimitations: The protectiveeffect ofthetherapies cited inrelationtothe increased
cardiovascularriskwasnotevaluated.
Conclusions: AmoderatetostrongpositiveassociationwasfoundcorrelatingtheFramingham
Scorevalueswiththequantitativeintimamediathicknessmeasurementanditisnotpossible
tostatewhichdrughasthehighestincreasedcardiovascularrisk.
©2020SociedadeBrasileira deDermatologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan
openaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
Introduction
Psoriasis(Ps)isachronicandrecurrentinflammatorydisease associated witha wide range of systemic manifestations. Itaffectsapproximately2---3%ofthepopulation.1Systemic
drugs,includingmethotrexate,acitretin,cyclosporineand immunobiologicaldrugs, areusedaloneor incombination withother treatment modalities. The choice of the most appropriate therapy for each case involves an analysisof theseverity ofthe diseasetogether withthepresence or absenceofcomorbidities.2
SystematicreviewsevidencedtheassociationofPswith increasedprevalenceandincidenceofMetabolicSyndrome (MS), as well as its individual components: obesity, dys-lipidemia, Type 2 Diabetes Mellitus (DM2), and Systemic Arterial Hypertension (SAH) and increased Cardiovascular Risk (CVR).3 They also demonstrated that patients with
severePscomparedtothosewiththemildformofthe dis-easepresentedhigherchancesforthedevelopmentofMS. Therefore, PS hasbecome an independent risk factor for cardiovascularevents.4
The Framingham score is the most widely used theo-retical frameworkthatdemonstratesacausalrelationship with Cardiovascular Disease (CVD) and justifies the ade-quate stratification of CVR for the future occurrence of CVD.5 Carotid Ultrasound (US) can be usedas oneof the
mainmethodsofnoninvasiveevaluationinthediagnosisof atheroscleroticcarotiddisease.Itischaracterizedbybeing agood,dynamic,radiation-freeandlow-costmethod.6
Theuseofthesameforcalculatingcarotidintima-media thicknessby an automated ultrasoundcalled Quantitative IntimaMediaThickness(QIMT)isanimportantparameterto identifysubclinicalatheroscleroticdiseaseinpatientswith or withoutrisk factors.Differently fromtheother carotid arterythicknessassessmenttechniques,thismethodisnot examiner-dependentbecausetheresultisgivenbythis soft-wareandnotmeasuredmanually.7
In Ps,theinflammatoryevents thatareperpetuatedin the bloodstream probably influence the onset of lesions in the vascular endothelium and the development of atherosclerosis.Fromthissametheory,thehypothesisarises that,bydecreasingtheinflammatoryload,itwould conse-quentlydecreasetheriskoftheonsetofCVD.8Theconcept
ofPsasasystemicdiseasedirectedthescientific commu-nitytoinvestigatetheinfluence oftherapies forPsin the evolutionofthesemoreprevalentcomorbidities.
ThepurposeofthisstudyistocompareCVRinpsoriasis patients receivingtwotypes of treatments:methotrexate (MTX) and tumor necrosis factor inhibitor (TNF-i) and to evaluatethecorrelationbetweentheFraminghamscoreand QIMT.
Methods
Thisstudywasacross-sectionalobservationalstudy,carried outfromJune2017toJuly2018inPUC-Campinas,with50 patientswithmoderatetosevereplaquepsoriasisPsoriasis AreaSeverityIndex (PASI)≥10 and aged20 years or over weredividedintotwogroups:
Group 1: 25 patients receiving MTX for more than 6 months;
Group2:25patientsreceivingTNF-i(infliximabor adali-mumab)formorethan6months.
We evaluated the measurement of abdominal circum-ference, Blood Pressure (BP), Body Mass Index (BMI) and presenceof MS.Afterwards;theywere evaluatedfor car-diovascularriskwiththeFraminghamscoreandtheQIMTof thetwocommoncarotidarteries.
Several groups have developed criteriafor the diagno-sisofMS,but theNational Cholesterol Education Program (NCEP-ATP III) definition is the most widely used and recommended by the Brazilian Guideline on Diagnosis and Treatment of MS. Through a clinical and labora-tory investigation, it aims to confirm the diagnosis of MS and to identify associated cardiovascular risk factors. Therefore, a combination of three of the following five parameters is required: triglyceride levels≥150mg/dL; HDL<40mg/dL for men and <50mg/dL for women;waist circumference>88cm for women and>102cm for men; fastingblood glucose≥100mg/dLandhigh bloodpressure (BP≥130×85mmHg).
The Framingham score is calculated using information on age, LDL and HDL cholesterol, blood pressure, dia-betes mellitus, and smoking for men and women. From the sum of the points of each factor is estimated the CVRin 10 years.Carotid ultrasoundwas performed using the gray scale or B-mode (SG), on the EsaoteMylab 50 machine, with a high resolution linear probe and fre-quency ranging from 3.5 to 10MHz. The angulation to calculate the common carotid of the artery was less than60◦.CarotidIntima-MediaThickness(IMT)was deter-mined using automated software that evaluates IMT by radiofrequency(QIMT).9 To obtain the QIMT,specific
soft-ware was used to perform the semi-automatic reading and calculation of the expected relationship for each patient.
The imagewasobtained inthecommoncarotidartery, bilateral,10mm proximallytothecarotidbulbandinthe finaldiastolicphase.Theevaluationwasperformedwiththe measurementofthearterialthickening.
Allexaminationswereperformedbythesamedoctorwith 10yearsofexperienceinultrasonography.Thepatientwas inthesupineposition≤45◦ tothecontralateralsideofthe
carotidarteryunderstudyandbothcarotidandtransverse scanswereevaluated.
All patients read and signed the Free and Informed Consent Form, approved by the ResearchEthics Commit-tee (voucher number: 061354/2017 and opinion number: 2,209,814)ofthehospitalinvolved.
Statisticalanalysis
Descriptiveandanalyticalstatisticalanalyzeswerecarried outaccordingtotheproposedobjectives.Allanalyzeswere performedusingSPSSStatisticssoftware,version17.0.
Forthequantitativevariablesitwasinitiallyevaluated if they presented Normal distribution through descrip-tive analysisand the normality test of Shapiro---Wilk. The patient’s age variable was described by the mean (± standard deviation), as it presented approximately Nor-mal distribution and the time of drug use and the PASI values,with asymmetric distributions, were described by the median (interquartile range). Categorical variables were described by absolute (n) and relative (%) frequen-cies.
In the comparison analysis between the groups, Stu-dent’s t-tests for the variable age of the patient, the Mann---WhitneytestforthetimeofdruguseandthePASI val-ueswereperformed.Fortheothercategoricallydescribed variables,Chi-Squaretestsor theFisher’sexact testwere used.
FortheevaluationoftheCVRaccordingtothetreatment and the association between the CVR classifications, uni-variateandmultivariablelogisticregressionanalyzeswere performed.Thecrudeandadjustedoddsratios(OR---Odds Ratio)werecalculatedandtheirrespective95%Confidence Intervals(95%CI).
The concordance between the CVR measured by the FraminghamscoreandtheQIMTcategoricallywasassessed by the Kappa coefficient and 95% CI. The calculations of sensitivity, specificity and accuracy were also performed. Inaddition,we assessedthe association of CVRmeasured continuouslybytheFraminghamscoreandtheQIMTvalues throughsimpleandmultiplelinearregressionanalysis.The levelofsignificance(a)adoptedwas5%,beingconsidered statisticallysignificantvaluesofp<0.05.
Results
FiftypatientswithmoderatetoseverePswereevaluated, 50%wereusersofMTX(Group1)and50%of TNF-i(Group 2).Thecharacteristics ofthe studiedpopulation are sum-marized in table 1. The majority of the patients were male(58%),white(88%)andmeanage54.8(±12.5)years. Thetimeof useofthemedicationswasdescribedthrough themedian(1st---3rdquartiles)witharesultof36(12---60) months.
The mean age of patients in the MTX group was 59.4 (±10.7)yearsandtheTNF-igroupwas50.1(±12.6)years. Themediantimetouseofthedrugrangedfrom24(12---60) monthsfor MTXusers to 48 (21---84) months for the TNF-igroup. Through BMI,worrying results were shown, since 82%ofthepatientsinthestudywereoverweight.Only16% of Group 1 and 20% of Group 2 had the ideal weight for
height.ThePASIindexatthestartoftreatmentwasgreater than10%for60%ofthepatients,andintheMTXgroupthis percentagewas40% andin the TNF-igroup was80%.The overall mean was14.7 (±5.7), with11.8 (±3.0) in Group 1 and 17.5 (±6.8) in Group 2. Due to the non-normality of the data, the Comparison of PASI between groups was performedusinganon-parametrictest,describingthe medi-ans(1st---3rdquartiles),indicatingastatisticallysignificant difference(p<0.001)(Table1).
Table2shows the comorbiditiesof thesepatientswith Ps.Almost40%ofthepatientshaddiagnosedSAHpresentin 48%ofGroup1and28%ofGroup2.DM2intreatmentwas observedin16%ofpatients,with20%ofMTXpatientsand 12%ofTNF-i.Sixteenpercentofstudyparticipantssmoked, withthe same valuewithin thegroups. Total cholesterol, HDL and LDL were altered in 50%, 76% and 30% of the patients, respectively, withno statisticallysignificant dif-ferencebetweenthegroups.Valuesoftriglyceridesgreater thanor equalto≥150mg/dL wereobservedin42% ofthe patients.Regardingpreviouscardiovasculardisease,14%of thepatientshadalreadypresentedapicture.Overall,84% ofthepatientspresentedhighwaistcircumferenceand82% wereoverweightinrelationtoheight,with30%already con-sidered obese, with no statistically significant difference betweengroups.Wealsoanalyzedthepresenceorabsence of MSinthesepatientswithPsandin 50%of themitwas present,withahigherpercentageofMTXusers(68%)than thosereceivingTNF-i(32%).
ConsideringtheprevalenceofCVRaccordingtothe Fram-inghamscore,almostaquarterofthepatientspresenteda highrisk(oddsofgreaterthan20%presentingcoronary dis-easein10years),with28%ofGroup1and20%ofGroup2; and morethan 60%presented low risk, withaprobability oflessthan10%ofdevelopingacardiovasculareventin10 years,with56%intheMTXgroupand72%inthebiological group(Table3).
Analyzingthe carotidultrasound,theresultwas worri-somebecause64%ofthepatientspresentedQIMTabovethe upperlimitoftheage-adjustedvalues,signalingsubclinical cardiovasculardisease.InGroup1,56%ofthepatientshad thickeningofthecarotidintimal-mediallayerand28%inthe carotidplaques.InGroup2,72%ofpatientshadalteredQIMT resultsand20%hadcarotidplaques.However,noassociation wasfound betweenCVR,calculatedusingtheFramingham scoreandautomatedUSandstudieddrugs,inotherwords, nostatisticallysignificantdifferenceinriskbetweenthetwo groups(Table3).
SincetheQIMT is stillpoorlyexploredin patientswith Ps as a possible screening test for CVR assessment, we chose toevaluate the valuesfound in thisindex continu-ously,correlatingwiththevaluesoftheFraminghamscore. The linearcorrelationcoefficient ofPearson(r)was0.617 (p<0.001),indicatingapositiveassociationofmoderateto strong.Table4describesthecoefficientsofthemultivariate linearregressionmodel.
The association between the comorbidities of patients with Ps and the high CVR according to the Framingham score and the QIMT was evaluated and is described in
table 5 which summarizes the results found, in whichwe canverifystatisticallysignificantassociationsbetweenthe highFraminghamscorewithhypertension,diabetes, triglyc-erides≥150mg/dLandcardiovasculardisease.However,for
Table1 Characteristicsofpatientswithpsoriasis,totalsampleandaccordingtothetreatmentperformed.
Characteristicsa Total(n=50) MTX(n=25) TNF-i(n=25) p-Value
Age(years) 54.8(±12.5) 59.4(±10.7) 50.1(±12.6) 0.007 Gender 0.252 Male 29(58.0%) 12(48.0%) 17(68.0%) Female 21(42.0%) 13(52.0%) 8(32.0%) Skincolor 0.189 White 44(88.0%) 24(96.0%) 20(80.0%) Brown 1(2.0%) 0(0.0%) 1(4.0%) Black 5(10.0%) 1(4.0%) 4(16.0%)
Timeofuseofthedrug(months) 36(12---60) 24(12---60) 48(21---84) 0.094
Nutritionalstatus 0.564 Eutrophic 9(18.0%) 4(16.0%) 5(20.0%) Overweight 26(52.0%) 15(60.0%) 11(44.0%) Obese 15(30.0%) 6(24.0%) 9(36.0%) PASI 12(10---18) 10(10---12) 16(15---20) <0.001 Mild(=10) 20(40.0%) 15(60.0%) 5(20.0%) Severe(>10) 30(60.0%) 10(40.0%) 20(80.0%) 0.004
a Dataarepresentedasmean(±standarddeviation),absolutefrequency(%)ormedian(1st---3rdquartile).
PASI,PsoriasisAreaSeverityIndex;MTX,Methotrexate;TNF-i,infliximabandadalimumab.
Table2 Prevalenceofcomorbiditiesofpatientswithpsoriasis,accordingtothetreatment.
Comorbidities Totaln(%) MTXn(%) TNF-in(%) p-Value
Hypertension 19(38.0%) 12(48.0%) 7(28.0%) 0.145a Diabetes 8(16.0%) 5(20.0%) 3(12.0%) 0.702b Smoking 8(16.0%) 4(16.0%) 4(16.0%) 1.000b Totalcholesterol≥200mg/dL 25(50.0%) 13(52.0%) 12(48.0%) 0.777a HDL≤60mg/dL 38(76.0%) 17(68.0%) 21(84.0%) 0.185a LDL≥130mg/dL 15(30.0%) 7(28.0%) 8(32.0%) 0.758a Triglycerides≥150mg/dL 21(42.0%) 10(40.0%) 11(44.0%) 0.774a Cardiovasculardisease 7(14.0%) 6(24.0%) 1(4.0%) 0.098b
Highabdominalcircumference 42(84.0%) 23(92.0%) 19(76.0%) 0.247b
Overweight+Obesity 41(82.0%) 21(84.0%) 20(80.0%) 1.000b
Obesity 15(30.0%) 6(24.0%) 9(36.0%) 0.355a
Metabolicsyndrome 25(50.0%) 17(68.0%) 8(32.0%) 0.011a
a Chi-squaretest. b Fisher’sexacttest.
highQIMT values,theonlystatisticallysignificant associa-tionwasfoundwithLDL≥130mg/dL.
Discussion
TheassociationbetweencardiovasculardiseaseandPswas described almost 50 years ago, but in the last decade there has been an increase in the investigation of this correlation.10,11
The inflammatory response in Ps leads to insulin resistance, endothelial dysfunction, oxidative stress and developmentofatherosclerosisthatculminateswithAcute MyocardialInfarction(AMI)orstroke.Therefore,thePsmay beconsideredanindependentriskfactorforcardiovascular events.12
In2018,Fernandes-Armenterosetal.publishedan obser-vationalstudythroughadatabasewith398,701individuals,
including6868casesofPs,ofwhich7.3%wereconsidered moderate to severe Ps, the MS was higher prevalence in patientswithPs(28.3%×15.1%,OR=2.21).13Another
cross-sectionalstudycontaining244patientswithPsandanother 163 in a control group found a significant prevalence of MSinthePsgroup(45.1%vs.19.6%),regardlessofdisease severity.14Inthisstudy,50%ofpatientswithMSwerefound,
allwithmoderatetoseverePs,demonstratingthe associa-tionofPsandMS.
Asurveyof6549Americansaged20---59yearsshowedthat theprevalenceofMS(according totheNCEP ATPIII crite-riareviewed) was40% amongindividuals withPsand 23% amongthosewithoutPs,againapproachingthedatafound inthis study with 50% of patients withMS. Andthe most commonMScharacteristicamongthepatientswasobesity, followedbyhypertriglyceridemiaandafterlowlevelsofHDL cholesterol.15
Table3 PrevalenceofcardiovascularriskaccordingtotheFraminghamscore,carotidradiofrequencyultrasound(QIMT)and
presenceofcarotidplaques.
Totaln(%) MTXn(%) TNF-in(%) p-Value
Framinghamscore 0.533b Low 32(64.0%) 14(56.0%) 18(72.0%) Intermediate 6(12.0%) 4(16.0%) 2(8.0%) High 12(24.0%) 7(28.0%) 5(20.0%) QIMT 0.239a Normal 18(36.0%) 11(44.0%) 7(28.0%) Changed 32(64.0%) 14(56.0%) 18(72.0%)
Presenceofcarotidplates 0.508a
Yes 12(24.0%) 7(28.0%) 5(20.0%)
No 38(76.0%) 18(72.0%) 20(80.0%)
aChi-squaretest. b Fisher’sexacttest.
Table4 AssociationoftheFraminghamscorevsQIMT.
Variables Adjusted(95%CI)a p-Valueb
QIMT 8.77(0.15,17.39) 0.046
Age(years) 0.27(0.17,0.367) <0.001
95%CI,95%confidenceinterval.
aAdjustedlinearregressioncoefficients b MultipleLinearRegression(R2=0.601)
TheconsequencesofcomorbiditiesofPs,suchashigher valuesofMS,atherosclerosisandCVR,leadtoanincreasein mortalityintheseindividuals.Gelfandetal.reportedthat menwithseverePsdie3.5yearsearlierthanmenwithout Psand women withsevere Ps died 4.4 yearsearlier than thosewithoutPs.Therefore,modificationoftheriskfactor isnecessarytoreduceCVR.1
Theoretically,theinflammatoryeventsthatarepresent in the blood circulation of individuals with Ps may influ-encetheappearanceofvascularendotheliallesionsandthe developmentofatherosclerosis.Therefore,thehypothesis that reducing the inflammatory load would consequently decreasetheriskofcardiovasculardisease.16,17 Therefore,
themedication chosen for the treatment of Ps shouldbe analyzed not only to improve the skin disease, chronic inflammationandmicrocirculation,preventingfuture dam-agetotheindividual.
In addition to receiving MTX in Ps therapy as an anti-inflammatory, antiproliferative and immunosuppres-sive agent, there is considerable evidence of its anti-atherosclerotic effect. A study involving 1240 patients observedover6yearsshowedthatinbothpatientswithPs andthosewithrheumatoidarthritis,MTXreducedtherisk ofcoronaryheartdiseaseandalsoreducedtheriskofdeath fromCVDby70%comparisonwithpatientsnottreatedwith MTX.18
There is a study evaluatingthe effects of MTX onthe developmentofatherosclerosis inpatients withPs,which describesitsimpactonendothelialfunctioninthe microcir-culationasanearly markerof atherosclerosis.After8---10 weeksoftreatment,nosignificantchangesin microcircula-tionwereobserved.19Asthepresentcross-sectionalstudy,
Table 5 Prevalence of comorbidities of patients with
psoriasisandhighcardiovascularrisk,classifiedbythe
Fram-inghamscoreandQIMT.
Comorbidities Highrisk
Framingham
HighriskQIMT
Hypertension 11(61.1%)a 14(43.8%) Diabetes 7(38.9%)a 6(18.8%) Smoking 5(27.8%) 7(21.9%) Total choles-terol≥200mg/dL 8(44.4%) 13(40.6%) HDL≤60mg/dL 15(83.3%) 25(78.1%) LDL≥130mg/dL 5(27.8%) 5(15.6%)a Triglycerides≥150mg/dL 11(61.1%)a 13(40.6%) Cardiovasculardisease 6(33.3%)a 6(18.8%) Highabdominal circumference 16(88.9%) 28(87.5%) Overweight+obesity 13(72.2%) 28(87.5%) Obesity 4(22.2%) 11(34.4%) Metabolicsyndrome 12(66.7%) 17(53.1%) a p<0.05(Chi-squaretest).
this limitation occurred to assess whether MTX or TNF-i wouldreduceCVRafteragiventimeofusemedication.
Several recent publications have suggested that TNF-i alsohasabeneficialimpactonCVR.20---22Inameta-analysis,
Westlake etal. summarized the potential effectsof anti-TNF-␣inpatientswithpsoriaticarthritisonmajoradverse cardiovascularevents(MACE)andontheriskofdeveloping cardiovasculardiseaseagain.Theresultsshowedapotential cardioprotectiveeffectofanti-TNF-␣,butnotaseffective asthatobservedwiththeuseofMTX.23
Anotherstudywith2400 patientswithsevere Psfound that patients treated withMTX or immunobiologicals had low rates of cardiovascular events compared to other therapies.24
Asystematicreviewandmeta-analysisshowedthe rela-tionship between the use of TNF-i, MTX, non-steroidal anti-inflammatorydrugs and corticosteroids and the pres-ence of cardiovascular events in 236,525 patients with rheumatoid arthritis and 220,209 patients with psoriatic
arthritisandPs.In rheumatoidarthritis,abeneficial asso-ciationofMTXwithcardiovascularriskreductionwasfound (RR=0.72,95%CI0.57---0.91,p=0.007).However,MTXwas notassociatedwithreducedrisk ofstroke andMACE.The useofTNF-iwasassociatedwiththereductionoftheCVR (RR=0.7, 95% CI0.54---0.9, p<0.005), suchasAMI, stroke andMACE.IntheanalysisofpsoriaticarthritisandPs,the data were sufficient to evaluate the effect of systemic therapycomparedwithnon-useofitoronlytopical medica-tion.SystemictherapywasassociatedwithdecreasedCVR (RR=0.75,95%CI0.63---0.91,p=0.003).25
Carotid US measuringthe medial-intimal thickness are a non-invasive method to evaluate the initial changes of the atherosclerotic vascular wall. When these values are increased, they reflect local abnormalities that correlate withhistologicallyprovenatherosclerosis.26Measurementof
thisthicknesshasapredictivevalueintermsof cardiovas-cularevents,regardlessoftraditionalriskfactors.27
Considering the fact that US is the most operator-dependent imaging technique and US vascularization requires experienceand expertise, a method that allows an automated measurement of IMT can facilitate its use, suchasautomatichigh-accuracyandreal-timeevaluationby radiofrequency,throughasoftware,calledQIMT.The man-ualmeasurementsareinfluencedbysubjectiveparameters suchasthedifficultyofthehumaneyetodifferentiatethe interfacesof thelayersandconsequently thethresholdof theinterfaceoftheechooftheeyeandthesensitivityofthe handofthesonographerinthepositioningoftheelectronic meters.BytheQIMTmethodthereisnosuchinfluenceon theB-modeimagequality,whichmakesitlessdependenton theoperator.7
In this study subclinical changes consistent with atherosclerosis were seen based on an increased mean QIMT. A previous study with 30 patients with Ps (n=15) andpsoriaticarthritis(n=15)demonstratedtherelationship between such disordersand an increased risk of subclini-calatherosclerosisandcardiovasculareventsusingtheQIMT method. Statistically significant values showed that 60% of patients withPs and80% with psoriatic arthritishad a greatermeasureofIMTthanexpected.28
Thevaluesfoundinthisstudyweresimilartothose pub-lished in the literature, in which 64% of the 50 patients with Ps presented altered QIMT levels (56% of MTX users and72%ofindividualsreceivingTNF-i),whileonly36%had intermediateor highriskintheFraminghamScore(44%of Group1and28%ofGroup2).Thisshowstheusefulnessof IMTforalertnessofatherosclerosisnotyetclinically appar-entandinthetherapeuticdecisioninitiativeofthepatient with a chronic inflammatory disease such as Ps. The dif-ference between the QIMT measurement values between thetwodruggroups(56%ofMTXusersand72%of individu-alsreceivingTNF-i)canbeattributedtoamoreimportant inflammatory process in patients in the group of TNF-i, whichhad80%PASI>10andonly40%oftheMTXgrouphad PASI>10.RecallingthatallpatientspresentedPASIequalto orgreaterthan10,beingevaluatedasmoderatetosevere Ps.Inaddition,itisknownthatinclinicalpracticeTNF-iis usedforpatientswithmoresevereconditionsofPsor ther-apeuticfailureswithothermedicines,inother words,itis apatientprobablywithlongerdiseaseandgreatersystemic inflammation,characterizingamoreevidenced
atheroscle-rotic process. However,longitudinal studies witha larger numberofparticipantsshouldbeperformedtoconfirmthese data.
Inasystematicreviewoftheliterature,twenty-four arti-cleswereanalyzed(1120patientsand943fromthecontrol group)toassesstherelationshipbetweenIMTandankylosing spondylitis,andtreatmentwithTNF-isuggestedan improve-mentordecreaseinprocessprogressionofatherosclerosis, whereasinflammatorydiseasesmayinducethedevelopment ofatherosclerosis.9,29
AprospectiveSpanishstudyof53patientswith moder-atetoseverePs,alsousedQIMT,automatedradiofrequency method, before and after 8 months of systemic therapy. QIMTofimmunobiologicaluserstendedtodecrease,insulin and glycemia levels decreased with TNF-i and patients undergoingMTXtreatmentshowedasignificantdecreasein QIMT,concludingthatcarotidthicknessanditsconsequences maybebenefittedfromtheuse ofsystemicdrugs suchas biologicalandMTX.30 Theseresults arein agreementwith
previousstudiesinpatientswithrheumatoidarthritis2,31and
emphasizethatMTXtreatmentservesasaprotectivefactor duringthedevelopmentofMACEs.32
In a pilot study with 16 patients with severe Ps, carotidIMTwascalculatedbyconventionalultrasonographic methodbeforeandafter6monthsoftreatmentwith TNF-i.AsignificantdecreaseinIMTwasobserved,showingthat effectiveinhibitionoftumornecrosisfactordecreasesIMT inpsoriaticpatients,andalsorevealedalteredcarotidIMT in84%ofpatients.33
Previously,DiMinnoetal.hadpresentedacross-sectional studycomparingIMTlevelsofpatientsreceivingTNF-iand anti-rheumaticdiseasemodifyingdrugsforpsoriatic arthri-tisandshowedthatpatientsreceivingthebiologicalhada decreaseinIMTvalues.34
Therefore,itiswelldocumentedthatIMTofthecommon carotidarteryshowspositivecorrelationswiththeduration ofinflammation,laboratoryparameters,ageandtraditional risk factorsfor CVD.35,36 Cardiology societies suggest that
theIMTassessmentofthecarotidarteryshouldbepartof the medicalevaluation of patients withincreased CVR,37
andtheguidelinesfor rheumatologysuggest thatpatients withinflammatoryarthritisshouldundergoultrasonographic evaluationofthecarotidarteries.38However,intheareaof
dermatologythereisnopositioningregardingthisevaluation imaging,andknowntobea chronic inflammatorydisease andanindependentriskfactorforCVD,thissubjectshould beaddressedandtargetedtotheexpertsintheareaassoon aspossible.
Inthepresent study,therewasamoderatetoastrong positiveassociationafter assessingtheQIMT values corre-latedwiththeFraminghamscorevalues(p<0.001),showing thatQIMT canbeconsidered a possiblescreening test for cardiovascular risk assessment in patients with Ps. More than70%ofthepatientsinGroup2hadITQIaltered,while 56%of Group 1 presented alterations,showing lowerCVR in patients submitted to MTX treatment. However, when assessedbytheFraminghamscore,Group1presented28%of highCVRandGroup220%,notingthattheuseof ultrasonog-raphybyradiofrequencytechnologyshouldbeconsideredas aninstrumentfortheearlydetectionofatherosclerosis,still withoutsignsclinicalorlaboratory.
Therearesomelimitationsinthisstudythatincludethe heterogeneityof age andtimeof useof the medications. Whilethefindingsofourstudyprovidesupportingevidence, itisimportanttonotethatcross-sectionalanalysisdoesnot provideinformationoncausalityandtheprotectiveor non-protectiveeffectofthetherapies citedinrelation toCVR hasnotbeenevaluated.Anotherlimitingfactoristhesmall numberofparticipants,duetothecostofbiological medi-cationsandtofollowcriteriafortheintroductionofthese medications.
Ourstudy isone ofthe fewtopresent newultrasound variables, including an automated measurement of the carotidandmiddlelayerofthecarotidarteryby radiofre-quencyandthecorrelationwithothervariablesinpatients withPs.Allultrasoundmeasurementswereperformedbya physicianwithextensiveexperienceinUS,andithasbeen shownthatphysicianswhoarenotspecialistsinvascularUS canperformreliableassessmentsofcarotidQIMT.9
The evaluation of the possible atherogenic damages caused by an inflammatory process suchas that resulting fromPsandtheidentificationofsubclinicalCVDshouldbe madebyallprofessionalsinthe areaandshouldalertthe patienttotherisksofCVD andifnecessaryreferthem to thespecialistforfollow-upandtherapyofcomorbidities.
The useofUS indermatology isstilluncommon, butit isa non-invasive,low-cost andwidely accessiblemethod. The techniques are evolving and spectral Doppler ultra-sound using the QIMT technique is the most appropriate for inflammatory reactions, allowing the visualization of atherosclerotic changes in the vessel wall caused by the chronic inflammatoryactivity that occursin some derma-tologicaldiseases,suchasPs.
Conclusion
There was no statistically significant difference between CVR(measuredbyFraminghamandQIMT)inrelationtothe treatmenttwogroups(MTXandTNF-i),soitisnotpossible tostatewhichdrughasthehighestCVR.
Inthisstudy,theassociationofPsandMSwasverified,as wellasveryalteredresultsforobesity,waistcircumference andBMI.
Wealsofoundamoderatetostrongpositiveassociation correlatingtheFraminghamscorevalueswiththeQIMT mea-surement,providing evidencefor theuseof ultrasoundin clinicalpractice.
Financial
support
Nonedeclared.
Authors’
contributions
ElaineCristinaFariaAbrahãoMachado:Approvalofthefinal versionofthemanuscript;conceptionandplanningofthe study;elaborationandwritingofthemanuscript;obtaining, analysis,andinterpretationof thedata;effective partici-pationinresearchorientation;intellectualparticipationin thepropaedeuticand/ortherapeuticconductofthestudied
cases;criticalreviewoftheliterature;criticalreviewofthe manuscript.
José Alexandre Mendonc¸a: Approval of the final ver-sion of the manuscript; conception and planning of the study; obtaining,analysis,andinterpretation of thedata; effectiveparticipationinresearchorientation;intellectual participationin thepropaedeuticand/or therapeutic con-ductofthestudiedcases;criticalreviewofthemanuscript. AnaCarolinaBeliniBazánArruda:Conceptionand plan-ning of the study; effective participation in research orientation; intellectual participationin the propaedeutic and/ortherapeuticconductofthestudiedcases.
LucianaBertoldiNucci:Statisticanalysisconceptionand planningofthestudy;obtaining,analysis,andinterpretation ofthedata;criticalreviewofthemanuscript.
MarcelAlexSoaresdosSantos:elaborationandwritingof themanuscript;criticalreviewofthemanuscript.
Conflicts
of
interest
Nonedeclared.
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