Clinical immunology, Part 1

Systemic autoimmune diseases:

Systemic Lupus Erythematosus (SLE)

Györgyi Mőzes

Semmelweis University, 2nd Dept. of Medicine

Lecture outlineLecture outline

�� ImmunologyImmunology / / immuneimmune systemsystem: : conceptsconcepts, , functionsfunctions

�� SelfSelf--tolerancetolerance: : significancesignificance, , mechanismsmechanisms

�� AAutoimmunityutoimmunity: : definitiondefinition, , paradoxesparadoxes

�� AutoimmuneAutoimmune diseasesdiseases: : characteristicscharacteristics, , etiologyetiology

patternspatterns, , clinicalclinical featuresfeatures

�� SLESLEepidemiologyepidemiology

aspectsaspects of of etiopathogenesisetiopathogenesis

clinicalclinical manifestationsmanifestations

diagnosisdiagnosis / / criteriacriteria, , differentialdifferential diagnosisdiagnosis

management, management, therapeutictherapeutic approachesapproaches

prognosisprognosis

WHAT IS IMMUNOLOGY ?WHAT IS IMMUNOLOGY ?

FunctionsFunctions of of thethe immuneimmune systemsystem

� Traditional concept: iimmunemmune defensedefense

**protectionprotection against against infectioinfectionsns

�� ImmuneImmune homeostasishomeostasis::

**disdiscriminationcrimination of of selfself and and nonnon--selfself ((foreignforeign) ) antigensantigens

withwith ttoleraolerancence toto selfself componentscomponents

**preservationpreservation of of individualindividual antigenicantigenic identityidentity

**clearanceclearance of of injuredinjured oror senilesenile cellscells, , tissuetissue repairrepair

�� Immune surveillanceImmune surveillance::

**preventionprevention of of persistentpersistent infectionsinfections

**destructiondestruction of of transformedtransformed (tumor) (tumor) cellscells

Aspects of clinical immunology

*disorders of the immune system

failure: *immunodeficienciesaberrant rections: *allergic diseases

*autoimmune diseasesuncontrolled cell growth: *lymphoid malignancies

*disorders of other systems (where immune reactions play a significant part in pathophysiology)

*infections and immunity*cancer immunology*transplantation immunology*reproductive immunology

IImportancemportance of immune regulationof immune regulation

�� To avoidTo avoid eexcessive lymphocyte activation and tissue xcessive lymphocyte activation and tissue

damage during normal protectivedamage during normal protective responses against responses against

infectionsinfections

�� To preventTo prevent inappropriate reactions against self antigens (inappropriate reactions against self antigens (i.e. i.e.

toto maintainmaintain selfself--tolerancetolerance))

Failure of control mechanismsFailure of control mechanisms is the is the main main underlying underlying

cause of cause of immuneimmune--mediated inflammatorymediated inflammatory ((autoimmuneautoimmune))

diseasesdiseases

HOW TO MAINTAIN SELFHOW TO MAINTAIN SELF--TOLERANCTOLERANCEE

AND PREVENT AUTOIMMUNITYAND PREVENT AUTOIMMUNITY ??

ImmunImmunee tolerancetolerance

�� DefinitionDefinition: :

�� specific specific immuneimmune unresponsiveness to aunresponsiveness to a ((tolerogenictolerogenic))

antigen that is induced by exposure of lymphocytes to antigen that is induced by exposure of lymphocytes to

that antigen that antigen

�� SignificanceSignificance::

�� aallll individuals are tolerant individuals are tolerant toto their own antigens their own antigens

((„„selfself--tolerancetolerance””))

�� bbreakdownreakdown / / failurefailure of selfof self--tolerancetolerance--maintainingmaintaining

mechanismsmechanisms resultresultss in in autoimmunautoimmune e diseasedisease

Central and peripheral tolerance

Abbas, Lichtman and Pillai, Cellular and Molecular Immunology, 7th ed., 2011

Clonal ignorance

AutoimmunityAutoimmunity

�� DefinitionDefinition: : an an immune response against self (autoimmune response against self (auto--) ) antigeantigenn

�� CautionCaution (!)(!): : autoimmuneautoimmune responsesresponses dodo notnot necessarilynecessarily implyimply

thethe pathologicpathologic conditioncondition of of autoimmuneautoimmune diseasedisease

�� SignificanceSignificance -- paradoxesparadoxes::

� early idea: any forms of autoimmunity: aggressive !

� present days: natural autoimmunity: physiologic

-permanent, immunoregulatory

-non-self-destructive immune reactivity

(for providing self-identification and preservation)

-complex interconnected network of natural autoantibodies

CD5+ B1 cells: produce natural autoantibodies,

reactive with conserved, essential molecules

*heat shock proteins (hsp)*enzymes (CytC, SOD)

*plasma proteins (albumin, IgG)

*membrane proteins (β2 M) *cytoplasmic proteins

(actin)*nuclear antigens (DNA,

histones)

*cytokines, hormones

microbialantigens

humanantigens

Characteristics of autoreactive antibodies

Natural Pathogenic

Serum titre Low High

Affinity Low High

Isotype IgM>IgG>IgA IgG>IgM>IgA

Antigen specificity Low High

V-region Germline Somatic mutations

how does tolerance break down ?

Pathologic autoimmunity:

(T cell bypass) (epitope spreading)

AUTOIMMUNE DISEASESAUTOIMMUNE DISEASES

�� DefinitionDefinition of ADof AD: : cchronichronic disablingdisabling diseases resultdiseases resultinging from from

immune responses against self antigens with prominent immune responses against self antigens with prominent

inflammationinflammation and and tissuetissue damagedamage

�� aaffectffect ~ ~ 55--7 7 % of % of thethe worldworld ppopulationopulation

�� includeinclude over 120 over 120 conditionsconditions

�� oneone of of thethe „„top top tenten”” leadingleading causescauses of of deathdeath

�� patternspatterns: : organorgan--specificspecific, , nonnon--organorgan--specificspecific / / systemicsystemic

�� GeneralGeneral sharedshared characteristicscharacteristics::

�� ppathogenesisathogenesis: : mulifactorialmulifactorial

�� familialfamilial clusteringclustering

�� gendergender, , ageage of of onsetonset

�� polyautoimmunitypolyautoimmunity

�� responseresponse toto immunimmunoosuppressisuppressiveve treatmenttreatment

Nature Immunology, 2001

******EpigeneticsEpigenetics

Infective agents,

hormones, UV-light,

dietary factors, drugs,

chemicals, stress, etc.

AD: multifactorial

AD: AD: ggeneticsenetics

MainlyMainly polygenicpolygenic !!

AnalysesAnalyses: : genegene expressionexpression profiling, profiling, linkagelinkage analysisanalysis,,

candidatecandidate genegene studiesstudies, GWAS (, GWAS (microarraysmicroarrays / / SNPsSNPs))

�� higherhigher concordanceconcordance ratesrates of AD of AD inin monozygoticmonozygotic twinstwins

�� familialfamilial clusteringclustering

�� frequencyfrequency of of riskrisk allelesalleles maymay varyvary byby regionsregions, , ethnicitiesethnicities

�� ssomeome polymorphisms are associated with multiple diseasespolymorphisms are associated with multiple diseases

�� ssomeome are diseaseare disease--specificspecific

�� inheritanceinheritance of of susceptibilitysusceptibility (MHC / (MHC / nonnon--MHCMHC genesgenes) )

**geneticgenetic polymorphismpolymorphism

**differentialdifferential genegene penetrancepenetrance inin F/MF/M

**geneticgenetic heterogeneityheterogeneity amongamong populationspopulations

**epistasisepistasis

Epigenetics

Definition: stable, heritable or acquired modifications of DNA without alterations in DNA sequence

Checkpoints:• DNA methylation• histone modifications• microRNA

Epigenetic changes can switch genes on/off and determine which

proteins are transcribed;

missing link between genomics and environment in determing

phenotype variability of autoimmune diseases

�� Fundamental problem: imbalance between immune Fundamental problem: imbalance between immune

activation and controlactivation and control

�� Nature of diseaseNature of diseasess is determined by the type of dominant is determined by the type of dominant

immune responseimmune response ((Th1, Th2, Th17Th1, Th2, Th17))

�� MMostost of of thethe diseases are chronic and selfdiseases are chronic and self--perpetuatingperpetuating

AD: factors of immune pathomechanism

Activationeffector T cells

Normal: reactionsagainst pathogens

Pathologic: reactions against self

Toleranceregulatory T cells

No response to selfControlled response

to pathogens

Balancing lymphocyte activation and control

Recognition of self antigens

active “NO”

“I see it but I do not react to it”

active “YES”

“I see it and I react to it”

immune tolerance autoimmune disease

Susceptibility genes Environmental triggers(e.g. infections,

tissue injury, etc.)

Failure ofself-tolerance

Activation ofself-reactive lymphocytes

Immune responses against self tissuesTarget organ: inflammation, irreversible damage

Persistence of functionalself-reactive lymphocytes

Activation of APCs

Epigenetic changes

Summary of AD pathomechanism

� Direct evidence of causality: an autoimmune response canbe shown to produce the disease by� transfer of autoantibody /autoreactive T cell from a patient to a

healthy recipient

� Indirect evidence

� availability of an appropriate animal model� reproduction of the disease in animals via immunization

with the appropriate autoantigen� naturally occurring disease in animals that resembles its

human counterpart

� Circumstantial evidence� presence of autoantibodies

�� levelslevels reflectreflect diseasedisease activityactivity

�� reductionreduction of of thethe autoimmuneautoimmune responseresponse leadsleads toto diseasediseaseimprovementimprovement

KochKoch--WitebskyWitebsky’’s criterias criteria

How to How to recognizerecognize autoimmune disease?autoimmune disease?

SymptomsSymptoms and and signssigns suggestivesuggestive forfor systemicsystemic

autoimmuneautoimmune diseasedisease

�� fatiguefatigue, , malaisemalaise, , weightweight lossloss, , lowlow--gradegrade feverfever

�� musclemuscle and/and/oror jointjoint painpain

�� musclemuscle weaknessweakness

�� swollenswollen glandsglands, , hepatohepato--splenomegalysplenomegaly

�� recurrentrecurrent rashesrashes oror hiveshives

�� RaynaudRaynaud’’ss phenomenonphenomenon

�� photosensitivityphotosensitivity

�� hairhair lossloss

�� drydry eyeseyes, , mouthmouth

�� recurrentrecurrent miscarriagesmiscarriages

�� nephritisnephritis, , nephrosisnephrosis

�� numbnessnumbness oror tinglingtingling inin thethe handshands oror feetfeet

�� anaemiaanaemia, , leukopenialeukopenia, , thrombocytopeniathrombocytopenia

�� increasedincreased ESR, ESR, highhigh CRP, CRP, polyclonalpolyclonal gammagamma--globulinemiaglobulinemia

SystemicSystemic autoimmuneautoimmune diseasesdiseases

„„immuneimmune--mediated inflammatory diseasesmediated inflammatory diseases””

„„autoimmuneautoimmune rheumaticrheumatic diseasesdiseases””

„„connectiveconnective tissuetissue diseasesdiseases””

�� ubiquiterubiquiter autoantigensautoantigens

�� severalseveral affectedaffected organsorgans

�� acuteacute //subacutesubacute inflammationinflammation

�� destructiondestruction of of thethe targettarget organorgan

�� variablevariable clinicalclinical manifestationsmanifestations

�� diseasedisease coursecourse: : relapsingrelapsing / / remittingremitting

�� „„markermarker”” autoantibodiesautoantibodies

Hepatobiliary

Main Main ttypesypes of of systemicsystemic autoimmuneautoimmune diseasesdiseases

�� systemicsystemic lupuslupus erythematosuserythematosus (SLE)(SLE)

�� rheumatoidrheumatoid arthritisarthritis (RA)(RA)

�� SjSjöögrengren’’ss syndromesyndrome (SS) (SS)

�� ((progressiveprogressive) ) systemicsystemic sclerosis (PSS)sclerosis (PSS)

�� inflammatoryinflammatory myopathiesmyopathies ((polypoly//dermatomyositisdermatomyositis, PM/DM), PM/DM)

�� mixed mixed connectiveconnective tissuetissue diseasedisease (MCTD)(MCTD)

�� systemicsystemic ((necrotizingnecrotizing) ) vasculitidesvasculitides

�� antiphospholipidantiphospholipid syndromesyndrome (APS)(APS)

�� seronegativeseronegative spondylarthritidesspondylarthritides (SNSA)(SNSA)

�� relapsingrelapsing polychondritispolychondritis

�� undifferentiatedundifferentiated autoimmuneautoimmune syndromessyndromes

�� overlap overlap syndromessyndromes

SLE: SLE: „„THE GREAT IMITATORTHE GREAT IMITATOR””

�� SLE/SLE/DefinitionDefinition: *: *idiopathicidiopathic, *, *multifactorialmultifactorial, *, *chronicchronic, ,

**inflammatoryinflammatory,, *multi*multisystemicsystemic,,

**intermittentintermittent ((flaresflares / / remissionsremissions))�� T / T / BB /DC /DC cell cell overoveractivationactivation, , characteristiccharacteristic autoantibodiesautoantibodies

�� iimmunemmune complexcomplex pprroductionoduction, , depositiondeposition

�� HeterogenousHeterogenous�� vvariableariable onsetonset, , clinical clinical expressionsexpressions

�� several clinical subsetsseveral clinical subsets

�� vvariablariablee diseasedisease coursecourse and and prognosisprognosis

�� EpidemiologyEpidemiology ((adultsadults))

�� prevalanceprevalance: 20: 20--150 150 casescases //100.000 100.000

�� iincidncidenceence raterate: 1: 1--2525/100/100..000000//yyrr

�� familialfamilial aggregationaggregation

�� geographicgeographic//racialracial distributiondistribution: : AsiansAsians, , Afric.Afric.--AmericansAmericans>>CaucasiansCaucasians

�� urbanurban > > ruralrural areasareas

�� gendergender: F / M ~ 9: F / M ~ 9--10 / 110 / 1

�� ageage of of onsetonset: : 1616--55 55 yrsyrs. (65 %), < 16 . (65 %), < 16 yrsyrs (20 %), > 55 (20 %), > 55 yrsyrs. (15 %). (15 %)

SLE: SLE: multifactorialmultifactorial etioetiologylogy

�� GeneticsGenetics

�� EnvironmentalEnvironmental factorsfactors�� infectionsinfections (EBV !)(EBV !)

�� UVB UVB lightlight

�� smokingsmoking

�� dietarydietary factorsfactors

�� vitamin Dvitamin D

�� silicasilica dustdust

�� drugsdrugs, , chemicalschemicals

�� HormonalHormonal factorsfactors

�� OOE (E (contraceptivescontraceptives / HRT/ HRT) )

�� PRLPRL

�� FailureFailure of of immunimmunee regulationregulation

�� EpigeneticsEpigenetics

SLE: chromosome loci and associated genes

TsokosTsokos GC. N GC. N EnglEngl J Med 201J Med 20122

6.: MHC-II: HLA-DR2 (DRB1*1501)HLA-DR3 (DRB1*0301)

MHC-III: C4, C2

1.: C1q

SLE: SLE: identiidentiffiedied eepigeneticpigenetic alterationsalterations

MechanismMechanism TargetTarget Cell TypeCell Type AlterationAlteration ConsequenceConsequence

DNA DNA methylationmethylation

ITGAL (CD11a)ITGAL (CD11a)

CD70 (TNFSF7)CD70 (TNFSF7)

CD154 (CD40L)CD154 (CD40L)

PerforinPerforin

KIR familyKIR family

CD4 T cellsCD4 T cells

CD4 T cellsCD4 T cells

CD4 T cellsCD4 T cells

CD4 T cellsCD4 T cells

CD4 T cellsCD4 T cells

HypomethylationHypomethylation

HypomethylationHypomethylation

HypomethylationHypomethylation

HypomethylationHypomethylation

HypomethylationHypomethylation

Increased CD11a expressionIncreased CD11a expression

Increased CD70 expression and BIncreased CD70 expression and B--cell cell

costimulationcostimulation

Increased BIncreased B--cell cell costimulationcostimulation

Increased Increased perforinperforin expressionexpression

Increased KIR expressionIncreased KIR expression

RUNX3RUNX3 CD4 T cellsCD4 T cells HypermethylationHypermethylationDysregulationDysregulation of ITGAL (CD11a) of ITGAL (CD11a)

expressionexpression

MMP9MMP9 CD4 T cellsCD4 T cells HypomethylationHypomethylation Cellular basement membrane breakdownCellular basement membrane breakdown

CD9CD9 CD4 T cellsCD4 T cells HypomethylationHypomethylation TT--cell activationcell activation

HistoneHistone

modificationmodificationHistoneHistone H4H4 MonocytesMonocytes

Increased Increased

acetylationacetylationIncreased expression of Increased expression of proinflammatoryproinflammatory

cytokinescytokines

MicroRNAMicroRNA miRmiR--146a146a PBMCsPBMCs UnderexpressionUnderexpression Type I IFN overproductionType I IFN overproduction

miRmiR--2121 CD4 T cellsCD4 T cells OverexpressionOverexpressionDownregulationDownregulation of DNMT1 (indirect) of DNMT1 (indirect)

and thus decreased DNA and thus decreased DNA methylationmethylation

miRmiR--148a148a CD4 T cellsCD4 T cells OverexpressionOverexpressionDownregulationDownregulation of DNMT1 (direct) and of DNMT1 (direct) and

decreased DNA decreased DNA methylationmethylation

miRmiR--125a125a PBMCsPBMCs UnderexpresssionUnderexpresssionIncreased KLF expression and thus Increased KLF expression and thus

RANTES overproductionRANTES overproduction

miRmiR--126126 CD4 T cellsCD4 T cells overexpressionoverexpressionDownregulationDownregulation of DNMT1 and of DNMT1 and

decreased DNA decreased DNA methylationmethylation

Crampton S P et al. Dis. Model. Mech. 2014

SLE: players involved in systemic autoimmunity

pDendritic cell

Apoptosis-related nucleic acids

SLE: SLE: stagesstages inin pathogenesispathogenesis

Co-morbidites

autoantibodies inflammation

early / late

initiating amplifying

autoimmunity

EpigeneticsEnvironment

SLE: cSLE: clinicallinical ffeatureseatures

�� cconstitutionalonstitutional symptomssymptoms (90(90--95 %) 95 %)

�� mmucocutaneousucocutaneous (80(80--90 %)90 %)

�� mmusculoskeletalusculoskeletal (80(80--9090 %)%)

�� rrenalenal (40(40--60 %)60 %)

�� neuropsychiatricneuropsychiatric (40(40--60 %)60 %)

�� ophthalmologicophthalmologic (50(50--70 %) 70 %)

�� ccardioardiovascularvascular / / pulmonary pulmonary (50(50--60 %)60 %)

�� hhematologicematologic (20(20--30 %)30 %)

�� digestivedigestive tracttract (25(25--40 %)40 %)

�� lymphadenopathylymphadenopathy, , splenomegalysplenomegaly (20(20--30 %) 30 %)

MucocutaneousMucocutaneous mmanifestationsanifestations

�� 8080--90 90 %%

�� mmalaralar rashrash**

�� ddiscoidiscoid lesionslesions**

�� pphotosensitivityhotosensitivity

�� ooralral/ nasal ulcer/ nasal ulcerss

�� RaynaudRaynaud’’s phenomenons phenomenon

�� aalopecialopecia

�� vvasculitisasculitis

�� uurticariarticaria ((hiveshives))

TypesTypes of cof cutaneousutaneous llupusupus

AcuteAcute / / subacutesubacute**�� mmalaralar rashrash ((localizedlocalized –– generalizedgeneralized))

�� pphotosensitivehotosensitive

�� mmaculopapularaculopapular

�� annularannular**

�� papulosqamouspapulosqamous ((psoriapsoriassiformiform))**

ChronicChronic

�� ddiscoidiscoid rashrash ((localizedlocalized –– generalizedgeneralized))

�� hhypertrophicypertrophic ((verrucousverrucous) )

�� llupusupus panniculitispanniculitis ((profundusprofundus))

�� cchilblainshilblains lupuslupus

�� mmucosalucosal lupuslupus

facial eruption: malar rash (butterfly erythema)

photosensitive erythema

photosensitive rash

erythematous maculopapular rash

oral ulcers

discoid lupus lesions

subacute cutaneous lupus

diffuse alopecia

Raynaud’s phenomenon

vasculitis

Musculoskeletal Musculoskeletal ddiseaseisease

�� 8080--90 %90 %

�� aarthralgiasrthralgias / a/ arthritisrthritis ((painpain + + stiffnessstiffness))

�� nnonon--erosiveerosive, , nonnon--defdeforormingming, , symmetricsymmetric

�� small joints of handssmall joints of hands, , wristswrists, , kneesknees

�� migratory, lasting 24migratory, lasting 24--48 h48 hrrss

�� mmyalgiasyalgias/ muscle / muscle tendernesstenderness, , weaknessweakness

�� myositismyositis: u: usuallysually proximalproximal

� avascular bone necrosis

arthritis

RenalRenal ddiseaseisease(40(40--60 %)60 %)

�� gglomerulonephritislomerulonephritis ((lupuslupus nephritisnephritis))

�� mmicrohematuriaicrohematuria

�� pproteinuriaroteinuria of of variousvarious levelslevels

�� hhypertensionypertension

�� ddecreasedecreased GFRGFR

�� rrenalenal failure failure

�� tubulointerstitialtubulointerstitial nephritisnephritis

�� vascularvascular diseasedisease ((thromboticthrombotic microangiopathymicroangiopathy) )

20020033 ISN/RPS Consensus ISN/RPS Consensus cconferenceonference on on

the the cclassificationlassification of of llupusupus nnephritisephritis

�� Class I. Class I. Minimal Minimal mesangialmesangial lupus nephritis (LN)lupus nephritis (LN)

�� Class II. Class II. MesangialMesangial proliferative LNproliferative LN

�� Class III. Class III. Focal LN Focal LN (involving < 50 % of (involving < 50 % of glomeruliglomeruli) )

((activeactive, , proliferativeproliferative and/and/oror chronicchronic, , sclerosingsclerosing))

�� Class IV.Class IV. Diffuse LN Diffuse LN (involving 50% or > (involving 50% or > of of glomeruliglomeruli))

((activeactive and/and/oror chronicchronic; ; segmentalsegmental oror globalglobal))

�� Class V. Class V. Membranous LNMembranous LN ((globalglobal oror segmentalsegmental););(mixed w/III. (mixed w/III. oror IV.)IV.)

�� Class VI.Class VI. Advanced sclerotic LN Advanced sclerotic LN (>90% (>90% of of sclerotic sclerotic glomeruliglomeruli))

International Society of International Society of NephrologyNephrology (ISN)(ISN) //RenalRenal PathologyPathology Society Society (RPS)(RPS)

�� cognitivecognitive dysfunctiondysfunction

�� stroke (stroke (cerebrovascularcerebrovascular diseasedisease))

�� seizuresseizures

�� headacheheadache� demyelinating syndrome („lupoid sclerosis”)

�� peripheralperipheral neuropathneuropathiesies

�� psychosispsychosis, , deliriumdelirium

�� opticoptic neuritisneuritis

�� cranialcranial neuropathiesneuropathies

�� transversetransverse myelitismyelitis

�� asepticaseptic meningitismeningitis

Neuropsychiatric Neuropsychiatric mmanifestatioanifestationsns(40(40--60 %)60 %)

Ophthalmologic manifestations(50-70 %)

� keratoconjunctivitis sicca

� retinal vasculitis

� episcleritis or scleritis

� anterior uveitis (iritis, iridocyclitis)

Cardiovascular Cardiovascular featuresfeatures

((5050--60 %)60 %)

�� ppericarditisericarditis

�� mymyocarditisocarditis

�� heartheart failurefailure, a, arrhythmiasrrhythmias

�� valvularvalvular diseasedisease(s(sterileterile valvularvalvular vegetatiovegetationsns: : LibmanLibman-- SacksSacks endocarditisendocarditis) )

�� vvasculitisasculitis ((coronarycoronary heartheart diseasedisease))

�� prematurepremature aatherosclerostherosclerosisis

Pulmonary Pulmonary manifestationsmanifestations((5050--60 %)60 %)

�� ppleurileurisysy

�� ppleuralleural effusioneffusion

�� ppneumonitisneumonitis

�� alveolaralveolar hemorrhagehemorrhage

�� interstitialinterstitial lung diseaselung disease

�� ppulmonaryulmonary hypertensionhypertension

DigestiveDigestive tracttract involvementinvolvement((2525--40 %)40 %)

�� dysphagiadysphagia ((esophagealesophageal hypomotilityhypomotility, reflux), reflux)

�� abdominalabdominal painpain

�� mmesentericesenteric vasculitisvasculitis / / infarctioninfarction

�� pproteinrotein--losing losing enteropathyenteropathy

�� ppancreatitisancreatitis

�� peritonitisperitonitis

�� eexxssudativeudative ascitesascites

mesenterial vasculitis (lupus enteritis)

Hematologic Hematologic abnormalitiesabnormalities(20(20--30 %)30 %)

�� lleukopeniaeukopenia (WBC < (WBC < 4.000/uL)

�� ccomommonmon

�� especially especially lymphopenialymphopenia ( < 1.500/( < 1.500/uLuL))

�� aanemianemia

�� ccommonommon ((mainlymainly duedue toto chronic chronic inflammationinflammation))

�� autoimmuneautoimmune hemolytichemolytic ((Coombs +)Coombs +)

�� tthrombocytopeniahrombocytopenia (< 100.000 (< 100.000 uLuL))

�� ITPITP

�� antianti--CLCL

�� aplasticaplastic anemiaanemia: : very rarevery rare

CoagulopathyCoagulopathy

�� HypocoagulableHypocoagulable statesstates ::

�� aantinti--platelet antibodiesplatelet antibodies

�� aantinti--clotting factor antibodiesclotting factor antibodies

�� HypercoagulableHypercoagulable statesstates ((thrombophiliathrombophilia))::

�� aantiphospholipidntiphospholipid aantibodyntibody ssyndromeyndrome (APS)(APS)

�� pproteinrotein C and S deficienciesC and S deficiencies

�� Thrombotic thrombocytopenic Thrombotic thrombocytopenic purpurapurpura

SLE: dSLE: diagnosticiagnostic workupworkup

�� nno o „„goldgold--standardstandard”” testtest/s/s

�� no no diagnosticdiagnostic criteriacriteria

�� dg.: dg.: basedbased onon cclinicallinical judgmentjudgment !!patientpatient’’ss **historyhistory,, symptomssymptoms

**reviewreview of of systemssystems**physicalphysical examinationexamination**laboratorylaboratory testtesting,ing, **imagingimaging

�� cclassificationlassification criteriacriteria

�� exclusionexclusion of of alternativealternative diagnosesdiagnoses

Classification criteria for SLEClassification criteria for SLE

American College of Rheumatology (ACR) American College of Rheumatology (ACR)

classificationclassification

19711971 Criteria Criteria developeddeveloped for SLE classification for SLE classification

19821982 Revised classificationRevised classification

19971997 ReRe--rrevisedevised senssens.: 8.: 83 % % specspec.: .: 996 %%

20122012 SLICCSLICC ccriteriariteria forfor SLE 9SLE 97 % % 84 %

SLICC: Systemic Lupus International Collaborating Clinics

20122012 -- SLICC classification criteriaSLICC classification criteria

Clinical Clinical

11 Acute Acute ccutaneousutaneous llupupuuss

22 Chronic Chronic ccutaneousutaneous llupusupus

33 Oral or nasal ulcersOral or nasal ulcers

44 NonNon--scarring alopeciascarring alopecia

55 ArthritisArthritis

66 SerositisSerositis

77 Renal Renal ddisorderisorder

88 Neurologic Neurologic ddisorderisorder

99 Hemolytic anemiaHemolytic anemia

1010 LeukoLeuko--/ / llymphopeniaymphopenia

1111 ThrombocytopeniaThrombocytopenia

20122012 -- SLICC classification criteriaSLICC classification criteria

ImmunologicImmunologic

11 ANAANA

22 AntiAnti--DNADNA

33 AntiAnti--SSmm

44 AntiAnti--phospholipidphospholipid antibodiesantibodies

Lupus anticoagulantLupus anticoagulant

AnticardiolipinAnticardiolipin , , IgAIgA, , IgGIgG or or IgMIgM

AntiAnti--B2B2--glycoprotein I ,glycoprotein I ,IgAIgA, , IgGIgG or or IgMIgM

55 Low complements (C3,Low complements (C3, C4 or CH 50)C4 or CH 50)

66 Direct Coombs test ( in absence of hemolytic anemia)Direct Coombs test ( in absence of hemolytic anemia)

20122012 –– SLICCSLICC classification criteriaclassification criteria

((definitedefinite)) SLE = SLE = presence of 4 criteria:

aat least 1 clinical t least 1 clinical + + 11 immunologicimmunologic

OROR

bbiopsyiopsy--provenproven lupuslupus nephritisnephritis

with ANA or antiwith ANA or anti--dsDNAdsDNA antibodies antibodies

(Arthritis Rheum, 2012)

� Probable SLE: 2-3 of SLICC criteria+

at least 1 of major organ involvement:

*optic neuritis, aseptic meningitis

*glomerular hematuria

*pneumonitis, ILD, alveolar hemorrhage

*verrucous endocarditis

*mesenterial vasculitis

� Possible SLE: 1 of SLICC criteria + at least 2 of organ

involvement

� UCTD: < 4 of SLICC criteria (only)

SLE: SLE: autoantibodiesautoantibodies

AntigenicAntigenic targettarget AntibodyAntibody

nucleusnucleus//chromatinchromatin ANAANA

antianti--nucleosomenucleosome (85 %)(85 %)

antianti--dsDNSdsDNS (80 %)(80 %)

antianti--histonehistone/s (70 %)/s (70 %)

ribonucleoproteinsribonucleoproteins antianti--ENAENA

antianti--SmSm (30 %)(30 %)

antianti--U1RNP (30 %)U1RNP (30 %)

antianti--RoRo/SSA/SSA (35 %)(35 %)

antianti--LaLa /SSB/SSB (15 %)(15 %)

otherother targetstargets: : phospholipidsphospholipids,,

leukocyteleukocyte // RBC / THRRBC / THR

*homogeneous pattern; target: chromatin

*peripheral / rim: nuclear targets

*speckled: ribonucleoproteins

*Indirect immunofluorescence test for ANA

DIF: lupus band test (IC at DEJ)

SLE: SLE: differentialdifferential diagnosisdiagnosis

�� otherother autoimmuneautoimmune diseasesdiseases�� „„rhupusrhupus”” / RA/ RA

�� MCTDMCTD

�� SjSjöögrengren’’ss

�� APSAPS

�� UCTDUCTD

�� systemicsystemic vasculitisvasculitis

�� adultadult StillStill’’ss diseasedisease

�� infectionsinfections

�� malignanciesmalignancies�� NHLNHL

�� MDSMDS

DrugDrug--inducedinduced lupuslupus (DIL)(DIL)

�� aantiarrhythmicsntiarrhythmics **10.00010.000--30.000 30.000 casescases//yryr

�� pprocainamiderocainamide *F:M = 1: 1*F:M = 1: 1

�� qquinidineuinidine **feverfever, , arthritisarthritis, , rashrash ~~SCLE,SCLE,

�� AntihypertensivesAntihypertensives pulmonary involvement,

�� hhydralazineydralazine hepatohepato--splenomegalysplenomegaly,,

�� mmethyldopaethyldopa anemiaanemia, , leukopenialeukopenia

�� ccaptoprilaptopril *ANA, *ANA, antianti--histonehistone positivitypositivity

�� AnticonvulsantsAnticonvulsants

�� carbamazepinecarbamazepine

�� hydantoinhydantoin

�� antianti--infectivesinfectives: : isoniazidisoniazid

�� othersothers: : DD--penicillaminepenicillamine, , sulfasalazinesulfasalazine; ; propylthiouracilpropylthiouracil

�� biologicsbiologics: : TNFTNF--blockersblockers

SLESLE:: ddiseaseisease assessmentassessment

Disease DamageIndex

Disease ActivityIndex

●Intermittent disease flares

●Chronically active disease●Quiescent disease

SLE: SLE: diseasedisease activityactivity indindexex

SLEDAI: mild < 5; moderate: 6-12; severe: > 13

SLE: SLE: chronicitychronicity and and damagedamage indindexex (SLICC/ACR)(SLICC/ACR)

ItemItem ScoreScore

OcularOcular

��Any cataract ever Any cataract ever

��Retinal change Retinal change or or optic atrophy optic atrophy 0,10,1

0,10,1

Neuropsychiatric Neuropsychiatric

��Cognitive impairment/ major psychosis Cognitive impairment/ major psychosis

��Seizures requiring therapy for 6 months Seizures requiring therapy for 6 months

��CVA ever (score 2 if >1) CVA ever (score 2 if >1)

��Cranial or peripheral neuropathy Cranial or peripheral neuropathy

��Transverse Transverse myelitismyelitis

0,10,1

0,10,1

0,10,1

0,10,1

0,10,1

Renal Renal

��Estimated GFR <50% Estimated GFR <50%

��ProteinuriaProteinuria >3.5 gm/24 h >3.5 gm/24 h 0,10,1

0,10,1

PulmonaryPulmonary

��Pulmonary hypertensionPulmonary hypertension

�� Pulmonary fibrosis and radiograph) Pulmonary fibrosis and radiograph)

��Shrinking lung (radiograph) Shrinking lung (radiograph)

��Pleural fibrosis (radiograph) Pleural fibrosis (radiograph)

��Pulmonary infarction (radiograph)Pulmonary infarction (radiograph)

0,10,1

0,10,1

0,10,1

0,10,1

0,10,1

CardiovascularCardiovascular

��Angina Angina oror coronary artery bypasscoronary artery bypass

��Myocardial infarction ever (score 2 if > 1)Myocardial infarction ever (score 2 if > 1)

�� CardiomyopathyCardiomyopathy (ventricular dysfunction) (ventricular dysfunction)

��ValvularValvular disease (murmur >3/6)disease (murmur >3/6)

�� PericarditisPericarditis for 6 months, for 6 months, oror pericardiectomypericardiectomy

0,10,1

0,1,20,1,2

0,10,1

0,10,1

0,10,1

ItemItem ScoreScore

Peripheral vascular Peripheral vascular

��ClaudicationClaudication for 6 months for 6 months

��Minor tissue loss (pulp space)Minor tissue loss (pulp space)

��Significant tissue loss ever ( loss of digit) (score 2 if >1 Significant tissue loss ever ( loss of digit) (score 2 if >1

site)site)

�� Venous thrombosis, swelling, ulceration, Venous thrombosis, swelling, ulceration, oror venous stasisvenous stasis

0,10,1

0,1,20,1,2

0,10,1

0,10,1

Gastrointestinal Gastrointestinal

��Infarction or resection of bowel below duodenum spleen, Infarction or resection of bowel below duodenum spleen,

liver, or gall bladder ever, for cause any (score 2 if > 1 site)liver, or gall bladder ever, for cause any (score 2 if > 1 site)

��Mesenteric insufficiencyMesenteric insufficiency

��Chronic peritonitisChronic peritonitis

��Stricture Stricture oror upper gastrointestinal tract surgery everupper gastrointestinal tract surgery ever

0,10,1

0,1,20,1,2

0,10,1

0,10,1

Musculoskeletal Musculoskeletal

��Muscle atrophy or weaknessMuscle atrophy or weakness

��Deforming or erosive arthritis Deforming or erosive arthritis

��Osteoporosis with fracture or vertebral collapse Osteoporosis with fracture or vertebral collapse

��AvascularAvascular necrosis (score 2 if >1)necrosis (score 2 if >1)

��OsteomyelitisOsteomyelitis

��Tendon RuptureTendon Rupture

0,10,1

0,10,1

0,10,1

0,1,20,1,2

0,10,1

0,10,1

SkinSkin

��Scarring chronic alopeciaScarring chronic alopecia

��Extensive scarring other than scalp and pulp spaceExtensive scarring other than scalp and pulp space

��Skin ulceration (excluding thrombosis) for >6 monthsSkin ulceration (excluding thrombosis) for >6 months

0,10,1

0,10,1

0,10,1

Premature Premature gonadalgonadal failurefailure 0,10,1

Diabetes Diabetes (regardless of treatment)(regardless of treatment) 0,10,1

MalignancyMalignancy (exclude dysplasia) (score 2 if > 1 site)(exclude dysplasia) (score 2 if > 1 site) 0,1,20,1,2

SLE: SLE: principlesprinciples of of treatmenttreatment

�� GGeneraleneral:: SLE SLE couldcould be be lifelife--threateningthreatening !!

�� rrapidapid diagnosisdiagnosis

�� ccorrectorrect assessment of disease assessment of disease extentextent, , activityactivity and and severityseverity

�� regularregular clinicalclinical monitoring monitoring

�� PPharmacotherapyharmacotherapy: : notnot curativecurative !!

main main goalsgoals: : diseasedisease activityactivity controlcontrol, , longlong--termterm survivalsurvival

�� iinductionnduction of remissionof remission (stop (stop / / reversereverse ongoingongoing organorgan inflammationinflammation))

�� ppreventionrevention oror limitationlimitation of relapseof relapses (s (irreversirreversibleible organorgan damagedamage))

�� mmanagementanagement of drugof drug--toxicitytoxicity

SLE: SLE: traditional treatment traditional treatment optionsoptions

�� ApprovedApproved drugsdrugs

�� corticosteroidscorticosteroids

�� hydroxychloroquinehydroxychloroquine

�� lowlow dosedose aspirinaspirin

�� „„OffOff--labellabel”” butbut standard of standard of carecare

�� azathioprineazathioprine

�� cyclophosphamidecyclophosphamide

�� NSAIDsNSAIDs

�� ImmunosuppressivesImmunosuppressives developeddeveloped forfor otherother diseasesdiseases

�� methotrexatemethotrexate

�� cyclosporinecyclosporine, , tacrolimustacrolimus ((calcineurincalcineurin inhibitorsinhibitors))

�� mycofenolatemycofenolate mofetilmofetil

�� biologicsbiologics: : rituximabrituximab

BelimumabBelimumab // BenlystaBenlysta®®

• monoclonal anti-sBAFF / BLyS

• the first biologic for SLE

• FDA approval: March, 2011

• the first new drug for SLE in over 50 yrs (!)

Adapted from Gregersen, J. W. et al., Nat. Rev. Nephrol. (2012)

Abetimus

Blisibimod

blocking IFNα: Sifalimumab

Rontalizumab

Algorithm for the treatment of SLE

Nature Rev. Rheumatol., 2014

SLE: SLE: poorpoor prognosticprognostic factorsfactors forfor

survivalsurvival

�� renalrenal diseasedisease ((especiallyespecially diffusediffuse proliferativeproliferative LLN)N)

�� hypertensionhypertension

�� youngyoung ageage

�� poorpoor socioeconomicsocioeconomic statusstatus

�� blackblack racerace

�� presencepresence of of antiphospholipidantiphospholipid antibodiesantibodies

�� highhigh overall overall diseasedisease activityactivity

SLE: leading causes of death

�� aactivective lupuslupus ((renalrenal, CNS) (21 , CNS) (21 -- 2266 %)%)

�� infectioninfections (s (bacteribacteriaal > l > viralviral / / fungalfungal)) (18 (18 -- 225 %)5 %)

�� ccardiovascularardiovascular diseasedisease ( ~ ( ~ 25 %)25 %)

�� llateate lupuslupus complicationscomplications ( ~ ( ~ 220 %)0 %)

SLE: co-morbid conditions

**aacceleratedccelerated atherosclerosisatherosclerosis

**oosteopeniasteopenia / / ostosteeoporosisoporosis

**mmalignancyalignancy (NHL)(NHL)

SLE:SLE: a a threefoldthreefold increasedincreased riskrisk of of mmortalityortality

SLE: SLE: prognosisprognosis

1950-1954

Corticosteroids

5-year-survival: 50 %

1970-1990s

Methotrexate

Organ transplantation

Plasmapheresis

Cyclosporine

10-year-survival: >80%

2011

Belimumab

1940-1950

Antimalarials

1960-1970s

Cyclophosphamide

Azathioprine

10-year-survival: >60%

2000-2010s

Mycophenolate mofetil

Biologics, Rituximab

Improvement in antibiotic,antihypertensive, and

antithrombotic

therapiesAdapted from Manzi S, ACR 2012

10-year-survival: ~90%

ThankThank youyou forfor thethe attentionattention !!

May 10: World Lupus Day