DepressionandSubclinicalVascularDiseasesinPsoriasis

NehalN.Mehta,MDMSCEFAHASectionChief,InflammationandCardiometabolicDiseases

NationalHeart,Lung,andBloodInstitute,USA

LaskerClinicalScholarInvestigatorNationalInstitutesofHealth,USA

ClinicalProfessorofMedicine

CaseReview:History

• 44previouslyhealthyfemalewithpsoriasisfor5years

• “cardiovascularevaluation”– Self-referred

• Beenfeeling“down”and“slow”recently

CaseReview:History• PMH:untreatedpsoriasis

• Medications:none

• Fhx:none

• SHx:+tobaccoofabout½PPD

• ROS:nocomplaints

VS:144/89;84bpm(reg);96%;height:61inches;weight:214lbsàBMI32waist:36inches;hip:35inchesàWHR~1.0

Neck:JVPat6cmH20,nocarotidbruitsLungs:clearbilaterallyCV:RRR,normalS1/S2,nomurmurs,rubsorgallopsAbd:NoHSMorpulsatileliverExt:NoedemabilaterallowerextremitiesVascular: Pulses2+inbothUEandLESkin:plaquepsoriasisontrunk,elbows,kneesandscalp;estimated~9%

BSA

CaseReview:Examination

CaseReview:LaboratoryDataLipids:• TC:186(4.8mmol/L)• LDL:129(3.6mmol/L)• TG’s:144(4.4mmol/L)• HDL:45(1.14mmol/L)Chemistry:• FastingGlc 106(2.8mmol/L)

CaseSummary• 44femalewithuntreatedmoderatepsoriasis

• +tobaccouse

• +highbloodpressure

• BMIof32(obese)

• ‘feelingdown’consistentwithpossibledepression

Whataboutinflammationassociatedwithherpsoriasis?

InflammationmattersinCVDisease

Libby, P and Ridker P. Am J of Medicine. 2002.116(6) 9-16.

Inflammation:criticalinatherosclerosis

1° & MessengerInflamm. Chemokines

• IL-1• TNF-a

• IL-6• IL-18

• MCP-1

Cellular AdhesionMolecules

• sICAM• sVCAM

• sSelectins• sESAMAcute (& chronic) Phase Reactants

hs-CRP, SAA, Lp-PLA2, WBC

Plaque Destabilization

• MMPs• IL-18• MPO

Plaque Rupture•CD40L

•EPCs

EndothelialFxn

Stary, et al. Circulation. 1995;92:1355-1374.

SeverePsoriasis• 50%increasedriskof

mortality• 5yearsoflifelost

CVDiseaseinPsoriasis

Outcome Hazard Ratio(adjusted for CV risk

factors)MI1 1.58Stroke2 1.43CV Death3 1.57MACE4 1.53

Figure. Abuabara K, et al. Br J Dermatol. 2010 Sep;163(3):586-92. 1. Gelfand, JM et al. JAMA. 2006;296:1735-1741.

2. Gelfand, JM et al. J Invest Dermatol .2009; 129:2411-2418. 3. Mehta, NN et al. Eur Heart J. 2010;31:1000-6

4. Mehta, NN et al. Am Journal Of Medicine . 2011; 776: 1-7.

Perpetuation

KeyImmuneFactorsinPsoriasis

Modifiedfrom:NestleFO,etal.NEnglJMed2009;361:496–509.

Initiation

KeratinocyteIL-1βIL-6

TNF-αTNF-αIFN-γ

TNF-α

IFN-αActivation

Natural killer T cell

Plasmacytoid dendritic cell

Myeloid dendritic cell

Macrophage

Th1 cell TNF-α IFN-γ

Antimicrobial peptides

IL-1βIL-6

TNF-αS100

CXCL8CXCL9CXCL10CXCL11CCL20

IL-17AIL-17FIL-22

Keratinocyte

Th17 cell

IL-23

IL-12

Hypothetical model based in part on non-clinical data

Libby. Circulation. 1995;91:2844–2850.

– Tlymphocyte

– Macrophagefoamcell(tissuefactor+)

– “Activated”intimalSMC(HLA-DR+)

– NormalmedialSMC

FibrouscapMedia

LumenAreaofdetail

LumenLipidcore

Lipidcore

VulnerablePlaque

StablePlaque

CellmediatedinflammationdrivesCVDSlide courtesy of Jam

es DeLem

os, MD

Whataboutinflammationassociatedwithherpsoriasis?

Whatabouther‘mood’and‘feelingslow’?

DepressionandAnxietyinPsoriasis

KurdSK,Troxel AB,Crits-Christoph P,Gelfand JM,ArchivesofDermatology,2010

DepressionandAnxietyinPsoriasis

KurdSK,Troxel AB,Crits-Christoph P,Gelfand JM,ArchivesofDermatology,2010

MI,StrokeandCVDeathareincreasedinacutedepressioninpsoriasis

Egeberg,A.ActaDermVenereol.2016Feb;96(2):218-21

LinkingPsoriasisandMoodDisorders

ConnorCJ,LiuV,Fiedorowicz JG.DermatologyResearchandPractice,2015

ConceptualFramework

Depression/Anxiety

Psoriasis

CardiovascularDiseaseInflammation

IL-6,TNF-α,GM-CSF,IL-17

IL-1β,IL-2,IL-6,TNF-α,PGE2,CRP

Canweutilizesubclinicalvasculardiseasestounderstandthis

relationship?

CT Coronary Angiography

(CCTA)

FDG PET-CT&

FDG PET-MR

Estimates direct coronary artery “plaque burden”

Estimates “inflammatory burden” and “functional

consequences”

Vascularimaginginpsoriasis:Howdoweapproachit?

FDGPET/CT– ANovelBiomarker• 18-Fluorodeoxyglucose(FDG)istakenupbycellsinproportion

totheirmetabolicactivity• Biomarkerformacrophagesinearlyatheroscleroticplaques

• recentdataàsmooth muscleorendothelialcells• Visualizesandquantifiesvascularinflammationinvivo

asStandardizedUptakeValue(SUV)

• Demonstratesfunctionalandanatomicaldata

1

5

2

4

3

FDGPETCTImageQuantification:

Figueroa et al JACC Imaging 2013

VascularInflammationAssociateswithFutureCVDEventsinNon-Psoriasis

CoronaryComputedTomographyAngiography(CCTA)– Axialimagesand3Drendering

diagonalbranches

Video provided by: Karen Rodriguez, Dr. David Bluemke

CCTAAnalyticalApproach

Lumen Volume

TotalVolume Plaque Volume

- =Plaque volume = (Artery volume) – (Lumen volume)

Plaque Index = Sum of all plaque volumes of segmentLength of segment

StudyDesign

• Cross-sectional,observational;nestedcohortstudy

• Hypothesis:Subclinicalatherosclerosis,asmeasuredbyFDGPET/CTandCCTA,willbeincreasedinpatientswithpsoriasisandcomorbiddepressionand/oranxietyascomparedtopatientswithpsoriasisalone.

Methods

159patientsprospectivelyenrolledincohortstudy

41patientsreportedhistoryofdepressionoranxietyonbaselinesurvey

40PSOpatientswithreportedcomorbiddepressionand/oranxiety

40PSOpatientsreportingnohistoryofcomorbidpsychiatricillnessmatchedbyageandsex

1patientrandomlydropped

StudySample

Self-reporteddepressionincreasesvascularinflammationinpsoriasis

Aberra,TfromMehtaLabNHLBI.Atherosclerosis.2016Aug;251:219-25.

Self-reporteddepressionisassociatedwithhighercoronaryplaqueburden

Aberra,TfromMehtaLabNHLBI.Atherosclerosis.2016Aug;251:219-25.

Non-calcifiedplaqueàacutemyocardialinfarction

Limitations/FutureDirections

• Samplesize• Cross-sectional• Limitedcharacterizationofpsychiatricdiagnoses

• Mechanism??

Conclusions

• Selfreporteddepressioninpsoriasiswasassociatedwithincreasedvasculardiseases.

• BetterriskstratificationofpsoriasispatientsbyunderstandingtheimpactofpsychiatricillnessonearlyCVdiseasemaybewarranted.

• Earlyidentificationandinterventionmaycontributetoreducingtheburdenofcardiovasculardiseases.