RheumatologicDisease

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?

Factors that Predispose an Individual

to Rheumatologic Diseases
I. Susceptibility Genes
A. MHC class I (i.e., HLA-B27 in
spondyloarthropathies)
B. MHC class II (i.e. HLA-DR4 in RA)
C. Complement deficiency states (i.e., C2 or C4
deficiency in SLE)
D. Fc Receptor Polymorphisms (i.e., FcR
deficiency in SLE)
E. PTPN22, a tyrosine phosphatase, polymorphism
associated with rheumatoid arthritis, SLE, others
F. Gender (female:male cases of SLE are 9:1)
G. Others (48 susceptibility loci for SLE in the
genome)

GeneticBasisofRheumaticDiseases:
Genotypecontributestorheumaticdiseasesusceptibility

________TwinStudies____________
Monozygotic
Dizygotic GeneticComponent
DiseaseConcordance(%)Concordance(%)ExplainedbyHLA(%)
RheumatoidArthritis

1534

0635

SLE

2557

03

AnkylosingSpondylitis
5075
131837
______________________________________________________________________________

Mostoftenrheumaticdiseasesarepolygenic.Acertain
genotypepredisposesanindividualtoadisease,butdoes
notmakediseasedevelopmentacertainty.

Genome Wide Scan of SNPs Associated with RA

A common polymorphism in PTPN22 confers susceptibility to
multiple autoimmune diseases
- RA, Lupus, T1 diabetes, Hashimotos Thyroiditis
Whole genome scan for RA

PTPN22 is #2 hit
Odds ratio < 2

Plenge et al. NEJM. 357:1199 (2007)

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)

III. Status of the Immune System

A. Relative state of activation

B. Relative balance of Th1 and Th2
C. History of previous responses

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