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SwatiKaushik
Definition:
Rheumatologic(orRheumatic)Disease:
diseasescharacterizedbypainandinflammation
injointsandconnectivetissues,oftenreferredto
ascollagenvasculardiseases.
IntroductiontoRheumatology:HistoricalPerspective
ThePaintersFamily
JacobJordaens(15931678)
Evidenceof:
RheumatoidArthritis
TheVirginwithCanonvan
DerPaele,1436
JanvanEyck(13851440)
Evidenceof:
Temporal(GiantCell)
Arteritis
ImportanceandImpactofRheumatologicDisease
Prevalence(per100,000)
RheumatoidArthritis
AnkylosingSpondylitis
Gout
SLE
Scleroderma
Osteoarthritis
Male
Female
440
1,100
197
73
980
230
7
32
15
3,470
5,870
AllMusculoskeletalconditions15,510
20,720
TheNormalJoint
PathogenesisofRheumatoidArthritis
Choy, E. H.S. et al. N Engl J Med 2001;344:907-916
Inflammedsynovialtissue(synovitis)
Villoushyperplasia
Intimalcellproliferation
Inflammatorycellinfiltration
Tcells,Bcells,macrophagesand
plasmacells
Productionofcytokinesandproteases
Increasedvascularity
Selfamplifyingprocess
MultipleCellTypesandCytokineSignalingPathwaysInvolved
inChronicInflammatoryArthritis
Modified from Choy, E. H.S. et al. N Engl J Med 2001;344:907-916
Nave T cell
KeycytokinesinChronic
InflammatoryArthritis:
TNF
IL1
IFN
IL6
OPGL(RANKligand)
IL17
MultipleTcellSubsetsContributetotheDevelopmentofArthritis
adaptedfromMcInnesandSchett,Nat.Rev.Immunol.,7:429442,2007
CD4
CD28
KeyFactorsthatRegulateOsteoclastDifferentiation
inArthritis
Th17CellsContributetoCartilageDistruction
inAdditionalWays
ProgressiveChronicInflammationCanLeadtoJointDestruction
Chronicinflammation
inthejointleadsto
bonedestruction
evidentaserosions
Prolongedsevere
chronicarthritis
leadstodeformityand
disability.
EarlyArthritissofttissueswelling,
especiallyaroundthePIPjoints
WhatistheImmuneResponseDirectedAgainst?
VeryDiverseAutoantigens
LymeDisease:
ResidualOrganisms
Crossreactiveantigens
RheumatoidArthritis:
TypeIIcollagen
IgG(rheumatoidfactor)
Citrullinatedproteins(arginineresiduesmodified)
SystemicLupusErythematosus(intraandextracellularantigens):
Nuclearantigens:
Ribonuclearproteins
Histones
dsDNA
Leukocytecellsurfaceantigens
Cardiolipin
RheumatoidFactors:AnAutoantibodytoSelfIgGFc
MultipleNuclearAntigensCanbeDetectedbyAutoantibodies
inSeraofPatientswithRheumaticDiseases
Homogeneous
ANA
Speckled
ANA
Nucleolar
ANA
Centriolar
ANA
Whydoestolerancefail?
Whydopeopledevelopautoimmune
rheumatologicdiseases?
GeneticBasisofRheumaticDiseases:
Genotypecontributestorheumaticdiseasesusceptibility
________TwinStudies____________
Monozygotic
Dizygotic GeneticComponent
DiseaseConcordance(%)Concordance(%)ExplainedbyHLA(%)
RheumatoidArthritis
1534
0635
SLE
2557
03
AnkylosingSpondylitis
5075
131837
______________________________________________________________________________
Mostoftenrheumaticdiseasesarepolygenic.Acertain
genotypepredisposesanindividualtoadisease,butdoes
notmakediseasedevelopmentacertainty.
PTPN22 is #2 hit
Odds ratio < 2
II.EnvironmentalFactors
A.Viralinfections(hepatitisB,hepatitisC,others)
B.Bacterialinfections(Shigella,Salmonella,
gpAstrep.,etc.)
C.Drugs(procainamide,dilantin,others)
D.Toxins(heavymetals,others)
E.UVlight(i.e.,inSLE)
IV.StatusofTargetOrgan/Tissue
A.Visibilityofautoantigen(privilegedsites,
intravsextracellular,etc)
B.Expressionlevelofautoantigen
C.ExpressionlevelofMHC
D.Costimulatorymolecules
E.Ongoinginflammation
MultipleFactorsContributetotheDevelopmentofArthritis
ClinicalFeatures
AcutevsChronicInflammatoryArthritis
AcuteArthritis
Rapidonset(hoursordays)
Severesymptoms
Mediatedbycomponentsofinnateimmuneresponse,
especiallyneutrophils(proteases,leukotrienes,prostaglandins,etc.)
Canresultinrapidjointdestruction
Canalsoevolveintochronicdisease
Examples:GoutandInfectiousArthritis
ChronicArthritis
Moregradualonset(daystoweeks)
Symptomsaremoremoderate,AMstiffnessisaprominentsymptom
Mediatedbytheadaptiveimmuneresponse,especiallyTcells
andmacrophagesaTh1disease
Cytokinesandchronicinflammationleadtojointremodelingand
destructionviaerosions
Examples:RheumatoidArthritis,AnkylosingSpondylitis,SLE,
LymeDisease
PatternofJointInvolvementisDistinctinDifferentDiseases
MonoarticularvsPolyarticular
Mono
Gout
Infection
Reactive
Poly
RA
SLE
Jointdistribution
PIPsandMCPs: RA,SLE
DIPs:
Osteoarthritis,Psoriatic
MTP:
Gout
SymmetricalvsAsymmetrical
Symmetrical:
Asymmetrical:
RA,SLE
Psoriatic,Reactive
RheumaticDiseaseAreSystemicInflammatoryDiseaseswith
anUnderlyingImmuneorInflammatoryPathogenesis
Disease
OrganSystemInvolvement
RheumatoidArthritis
Joints(arthritis)
Vessels(vasculitis)
Eyes(scleritisandepiscleritis)
Hematologic(anemia,thrombocytosis)
Pulmonary(plueritis,alveolitis,etc,)
SystemicLupusErythematosus(SLE)
Joints(arthritis)
Skin(photosensitiverash)
Serosa(pericardium&pleura)
Hematology(anemia,thrombocytopenia)
Kidneys(glomerulonephritis)
Lungs(interstitialdisease,alveolitis,etc.)
CNS(cognitivedysfunction,seizures,etc.)
LymeDisease
Joints(arthritis)
Skin(Erythemachronicummigrans)
Heart(carditis)
CNS(meningoencephalitis)
RheumatoidArthritisisSystemic
InflammatoryDisease
SLEisaSystemicInflammatoryDisease
TherapeuticStrategies
Reagentsthatbluntinflammationbutdonthaveeffectsondiseaseprogression:
Aspirin
Nonsteroidalantiinflammatorydrugs(NSAIDs)
NonselectiveandselectiveCOX2antagonists
Steroids(prednisone)
DiseaseModifyingAntiRheumaticDrugs(DMARDs):
BroadActing:
Methotrexate
Hydroxychloroquin
Azathoprine
Cyclophosphamide
Cyclosporin
Moreselectivebiologics:
TNFantagonists
IL6Rantagonists
IL1Rantagonists
antiBcell(CD20)therapy
costimulatoryinhibitors(CTLA4Ig)
IntravenousImmunoglobulin(ivIg)
MethodsofBlockingtheActivityofanInflammatoryCytokine
Choy, E. H.S. et al. N Engl J Med 2001;344:907-916
BlockingCD28dependentCostimulation
From:Moreland
http://www.medscape.com/viewprogram/3415_pnt
AbataceptisafusionoftheextracellulardomainofCTLA4(similartoCD28butwithhigheraffinityforCD80
andCD86)withtheFcfragmentofIgG1(foreffectorfunctionandtoprolonghalflife)
BiologicalTherapeutics
Targets,Rationale,Status