med2 20101203 ct diseases

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Connective Tissue Diseases

Emmanuel C. Perez, M.D., MPH, FPCP, FPRA

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Connective Tissue Diseases

Systemic lupus Erytematosus

Reumatoi! Artritis

Polymyositis / Dermatomyositis

Systemic Sclerosis

Sjogrens Syndrome Mixed Connective Tissue Disease

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Polymyositis "

Dermatomyositis

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Polymyositis "

Dermatomyositis #n$lammatory !isease o$ striate!

s%eletal muscle, some times &itcaracteristic s%in ras

'ccurs (et&een te )tto *t!eca!e o$

li$e &it a $emale prepon!erance

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Classification of Myositis

Dermatomyositis

Polymyositis

Myositis associate! &it CTD Myositis associate! &it mali+nancy

#nclusion (o!y myositis

Myositis !ue to in$ectious a+ents Dru+ an! To-inin!uce! myositis

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Pato+enesis

A((erations in te immune system tat +ives

rise to an increase! suscepti(ility to in$ectious

a+ents viruses an to-oplasma +on!ii/, an! tomo!i$ications o$ cellular immunity tat lea! to

te !evelopment o$ mononuclear cells

capa(le o$ in0urin+ muscle

Complement may play a role in tissue in0uryin !ermatomyositis

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Histopatolo+y

Inflammatory cellular infiltrate&it

associate! degeneration and necrosiso$

muscle $i(ers Regenerationo$ $i(ers an! perivascular

in$lammatory in$iltrate lea!in+ to interstitial

$i(rosis later on Calcinosis may(e seen especially in te

cil!oo! $orm

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Histopatolo+y

#n$iltrates in PM an! #1M contain mainly C23

Tlympocytes an! macropa+es, &ile 1

cells are more common in DM 4asculopaty may(e seen in te small

arteries o$ te muscle, s%in an! te

+astrointestinal tract

Eosinopilic inclusions in te sarcoplasm an

nucleus may(e seen in inclusion (o!y

myositis

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Dia+nostic Criteria $or PM" DM

Symmetric pro-imal muscle &ea%ness withor without dysphagia or respiratory muscle involvement/

Elevation o$ serum muscle enzymes creatinekinase, aldolase, LHD, AST/

Typical EM5 tria! Sort!uration, smallamplitu!e, polypasic motor unit

potentials

Pseu!omyotonic i+$re6uency pattern

Spontaneous $i(rillation an! 3/ sarp &aves sa& tootpattern/ in restin+ muscle

Typical istolo+y in muscle specimens

Caracteristic s%in ras o$ !ermatomyositis

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S%in Rases o$ Dermatomyositis

7ilac !iscoloration o$ te upper eyeli!s&it perior(ital e!ema Heliotrope ras/

Erytematous or atropic scalin+,

patcy or linear ras involvin+ tee-tensor sur$aces o$ te 0oints 5ottron8sras/, $ace, nec% an! (ac% Sa&l si+n/,

or te cest in a 4sape! pattern 4nec% si+n/

Erytematous scalin+ 5ottron8spapules/ over te MCP an P#P 0oints

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Clinical Features o$ #MDFeatures DM PM Myositis

&" CTD

Ras 9:; (-) :; :; >=; =:;

#nterstitial pneumonitis,cariomyopaty, eart

(loc%s

rare rare

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'ter Myositis

Myositis associate! &it mali+nancy? DM i+er association &it mali+nancy@ el!erly PMDM

patients )- li%ely to ave cancer

? Myositis prece!es mali+nancy (y an avera+e o$ > to :

years

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CREST Syn!rome

Telangiectasia

Calcinosis

&aynauds

phenomenon

*sophageal

dysmotility

Sclerodactyly

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Possi(le causes o$ Sclero!erma

5enetic $actors #n$ectious a+ents

? viral, e.+. CM4

? Imolecular mimicryJ

onin$ectious

environmental $actors? silica !ust

? petroleum(ase! solvents

? vinyl clori!e

? contaminate! rapesee! oil

? 7tryptopan

Dru+s? (leomycin

? pentazocin

? cocaine

Microcimerism no. o$ immunolo+ic

stem cell o$ $etal ori+in in

&omen &it sclero!erma

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Pato+enesis

patolo+ic allmar% pro+ressive$i(rosis o$ te s%in an! various internal

or+ans lun+s, eart, 5#T/ !isruption o$ te normal arcitecture o$

te a$$ecte! or+ans lea!in+ to teir!ys$unction an! $ailure

upre+ulation o$ colla+en +enee-pression in SSc $i(ro(lasts

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#mmunopato+enesis

S+SC*PT$%)* ,OST

E-o+enous tri++ers

1cell activation T-C*)) .CT$.T$O0 Activation o$ nonspeci$ic in$lammatory cells

Autoanti(o!ies, #+ #n$lammatory in$iltrates

Solu(le me!iators, cytoto-icity

F#1R'17ASTS ED'THE7#A7 CE77S

Activation, in0ury

#$%&OS$S $SC,*M$C .SC+)OP.T,1

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Difuse cutaneous SScLimited cutaneous SSc

Anti-DNA topoisomerase l

Pulmonary fbrosis

Peripheral vasculopathy

Anti-RNA polymerase l, ll , lllScleroderma kidney

Pulmonary fbrosis

NONE SKIN THICKNESS MAXIMUM

Anticentromere

calcinosis

telaniectasias

Pulmonary fbrosis

Antinuclear anti(o!ies in Sclero!erma

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Autoanti(o!ies

anti-topoisomerase-$ 'Scl-23(? speci$ic

? !i$$use sclero!erma

? interstitial lun+ $i(rosis? Kprotection8 $rom isolate! pulmonary

ypertension

? !i+ital pittin+ scars an! ma-imum s%in

tic%ness score? lcSSc more $re6uent an! more severe

0oint, s%in, an! lun+ involvement

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Autoanti(o!ies

anti-&0. polymerase $4 $$$? !i$$use sclero!erma

? more o$ten male an! ol!er at onset? i+er $re6uency o$ renal an! car!iac

!isease

anti-+5&0P 'fi6rillarin(? nonspeci$ic

? poor outcome in (lac% male patients &it!cSSc an! visceral involvement

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Autoanti(o!ies

anticentromere anti6odies? limite! sclero!erma

? increase! esopa+eal !isease

? possi(le increase! isolate! pulmonaryypertension

? Kprotection8 $rom pulmonary $i(rosis an!renal !isease

PM-Scl? sclero!ermapolymyositis overlap syn!rome

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5enetic mar%er

,).-D&78a

? interstitial lun+ $i(rosis

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Sclero!erma Facies

$ace is stretce!, an!

Imas%li%eJ or

Ie-pressionlessJ

pince! nose tin lips &it

!iminise! oral

aperture

ra!ial $issurin+ aroun!

te mout Imouseli%eJ $ace

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Cutaneous mani$estations

S%in involvement? inflammatory

edematous phase

pu$$iness, s&ellin+,

s%in $le-i(ility

? indurative phase

s%in tic%enin+, pu$$y

$in+ers, loss o$ normal(o!y creases an! s%in

appen!a+es

? atrophic phase

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&aynauds phenomenon

- closure of digital arteries inresponse to cold

- 5 color phases9 whitenessor pallor !ue to

vasoconstriction

cyanosis!ue to stasis an!

removal o$ o-y+en $rom te(loo!

redness!ue to vaso!ilatation

an! reactive yperemia

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periun+al telan+iectasia a(normal nail$ol!

capillary patterns

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ulcerations

telan+iectasias

calcinosis cutis 9;/

? calcium hydro(yapatite deposits

pi+mentary a(normalities

? )salt and pepper* pattern

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Muscle A(normalities

nonspeci$ic

muscle enzymes normal to >::L EM5 a(normalities

s%eletal muscle involvement ris% $or

si+ni$icant myocar!ial !ys$unction

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5astrointestinal Mani$estations

*sophagus

a(normal motility+astroesopa+eal re$lu-

1arrett8s esopa+us

a!enocarcinoma

in$ectious esopa+itis

pillin!uce! esopa+itis

Stomach

+astroparesis

telan+iectasias

Small intestine

pseu!oo(struction

(acterial over+ro&t

telan+iectasias

pneumatosis cystoi!es intestinalis

small (o&el !iverticula

Colon

&i!emout !iverticulacolonic inertia

$ecal"(arium impaction

me+acolon

per$oration

telan+iectasias.norectum

impaire! internal spincterrela-ation

anal spincter restin+ pressure

rectal compliancerectal prolapse

,epatic

primary (iliary cirrosis

!ru+in!uce! epatitis

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Pulmonary Mani$estations

#nterstitial in$lammation

an! $i(rosis

Pulmonary vascular

!isease

1ronciolectasis cysts/

Spontaneous

pneumotora- Pleural !isease

Aspiration pneumonia

Calcinosis

Mali+nancy Pneumoconiosis

silica/

Di$$use alveolar

emorra+e

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#nterstitial 7un+ Fi(rosis

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Ma0or Pulmonary Mani$estationsClinical Features Pulmonary

Hypertension

#nterstitial

Pulmonary Fi(rosisClinical su(set lcSSc lcSSc or !cSSc

Symptoms !yspnea, syncope !yspnea, cou+

Si+ns lou! P< crac%les, !i+italpittin+

PFT isolate! D7C' F4C, FE4>,D7C', FE4>"F4C,

T7CAA associations 3/ ACA, (ut notpre!ictive

3/ Scl:

=year survival N>:; $rom !ia+nosis )=; $rom initialPFTs

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Car!iac #nvolvement

myocar!ial $i(rosis? allmar% o$ car!iac involvement

? patcy

? systolic an!"or !iastolic !ys$unction

myositis

myocar!ial in$arction

con!uction a(normalities an! arrytmias pericar!ial !isease

valvular !isease

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Sclero!erma Renal Crisis

ne& onset o$ accelerate! arterialypertension an!"or rapi!ly pro+ressiveoli+uric renal $ailure !urin+ te course o$

systemic sclerosis primary process en!otelial cell in0ury

in >:; o$ all patients at +reatest ris% are

tose &it !i$$use sclero!erma

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ervous System #nvolvement

Central nervous system mo!i$ication o$ EE5

activity

psyciatricsymptomatolo+y

(ul(ar palsy

Peripheral nervous system

optic neuritis

tri+eminal neuropaty

(ul(ar palsy

t, 2t, 9t,>

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Mana+ement Strate+ies

4ascular terapy

#mmunomo!ulation

Anti$i(rotic !ru+s

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Raynau!8s penomenon

$on#pharmacologic therapy

stop smo%in+, avoi!ance o$ a++ravatin+

!ru+s e.+. (loc%ers/ central an! periperal &armt (o!y

&armers, mu$$s, +loves, etc./

even, am(ient temperature pysical e-ercises &irlin+ o$ te arms,

(io$ee!(ac% tecni6ues/

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Raynau!8s penomenon

Parmacolo+ic terapy Calcium cannel (loc%ers

? lon+ actin+ ni$e!ipine, nicar!ipine

Alpa (loc%ers? prazosin

ACE ini(itors

A+ents &ic a$$ect serotonin

? =y!ro-ytryptamine, %etanserin, SSR#s $luo-etine/ Topical terapy

? trans!ermal nitro+lycerin patces, topicalnitro+lycerin

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Raynau!8s penomenon

parenteral vaso!ilators? car(oprostacyclin #loprost/

+igley - et al., Ann Intern -ed /0012 /345/00

+reater re!uction in te no. o$ &ee%ly attac%s B9 vs.

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Raynau!8s penomenon

Sur+ical proce!ures

lum(ar sympatectomy ra!ical arteriolysis !i+ital sympatectomy/

!e(ri!ement, !i+ital amputation

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#mmunomo!ulation

Cyclopospami!e? uncertain

? primary role in com(ination &itcorticosteroi!s $or patients &it $i(rosin+

alveolitis &o !o not yet ave a!vance!$i(rosis

Corticosteroi!s

? restricte! to patients &it myositis, active$i(rosin+ alveolitis, symptomatic serositis,te early e!ematous pase o$ te s%in!isease, an! re$ractory artritis an!tenosynovitis

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#mmunomo!ulation

Cyclosporine? suppresses CM# an! re!uces colla+en

syntesis

? !iminise! s%in tic%enin+ (ut no can+e in

car!iac or pulmonary !isease? neproto-ic

Metotre-ate

? improve! s%in scores an! sense o$ &ell (ein+? o$ +reater (ene$it in localize! sclero!erma

immunoistocemical parameters/ Seyer !! et al", # $athol 2001

A%r& 193'():511-1*

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Anti$i(rotic Terapy

Dpenicillamine? a$$ects colla+en (iosyntesis an! te immune

system

? improve! cumulative $ive year survival 2:;/an! a lo&er rate o$ ne& visceral involvement

B patients on Dpenicillamine vs. )= patients on place(o

Steen + et al", Ann ntern !ed 1982& 9.:*52

=; improvement in s%in sclerosis in *9 patients treate!&it penicillamine $or * monts

#imene/ SA, et al", # Rheumatol 1991& 18:1(9*

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Anti$i(rotic Terapy

#nter$erons

? ini(it colla+en syntesis

? inter$eron more potent tan inter$eron Colcicine

? ini(its colla+en pro!uction (y !isruptin+

microtu(ule $ormation in $i(ro(lastcytos%eleton

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'ter a+ents

antitymocyte an! antilympocyte +lo(ulin? improvement o$ autoimmune emolytic

anemia, +lomerulonepritis, lun+ $i(rosis, s%in

an! 0oint involvements? in cases o$ severe autoimmune !iseases

unresponsive to re+ular immunosuppressive

treatment Scand 6 Rheumatol /00

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'ter a+ents

e-tracorporeal potoperesis? e$$ective treatment mo!ality in severe

sclero!erma particularly &en starte! early,

&it sta(ilization o$ te !isease course an!partial remission o$ te cutaneous $in!in+s,&ereas visceral involvement may rarelyimprove

>rasagakis > et al., Dermatology /008 /0=

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'ter a+ents

P4A potocemoterapy? $or localize! sclero!erma

Araane et al", # Cutan !ed Sur 2001!ar-A%r& 5'2):135-9

antitymocyte +lo(ulin 3 mycopenolate

mo$etil? $or recent onset !i$$use sclero!erma Stratton R# et al", Rheumatoloy 'ord) 2001

#an&(0'1): 8(-8

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e& Potential Terapies

#mmune

? Rapamycin (loc%s cyto%ine action in Tcell activation"proli$eration

? Mycopenolate mo$etil ini(its lympocyte proli$eration

? Stem cell terapy

? 'ral tolerance in!uces re+ulatory suppression o$ speci$ic immune

response trou+ oral a!ministration o$ smallamounts o$ anti+en

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e& Potential Terapies

Anti$i(rotic

? anticentromere anti(o!ies

(loc% me!iators o$ $i(ro(last activation

? enzyme anta+onists

lysyl an! prolyl y!ro-ylase ini(itors

? pretranslational ini(ition

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'r+an(ase! Terapy

S%in Disease Pruritus

? antiistamines

?lu(ricatin+ creams

Calcinosis? sur+ical removal

? anti(iotics i$ in$ecte!

? pro(eneci!, colcicine, &ar$arin not proven/

? !iltiazem

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'r+an(ase! Terapy

Musculos%eletal Symptoms

.rthritis? acetaminopen,

? SA#Ds

? lo& !ose steroi!s

Myopathy? muscle stren+tenin+ e-ercises 3 SA#Ds

? pysical terapy to limit contractures

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'r+an(ase! Terapy

Renal Disease .C* inhi6itors

? mainstay o$ treatment

? increase! antiypertensive e$$icacy

? associate! &it improve! survival

? (etter preservation o$ renal $unction

? +reater inci!ence o$ renal $unctional recovery Steen + et al", Arthritis Rheum 1998& (1:1*13

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'r+an(ase! Terapy

Renal Disease

Calcium channel 6loc"ers? a!!e! i$ response to ACE ini(itor is ina!e6uate

$ntravenous prostacyclin? at te onset

? anec!otal reports

? elp in te microvascular lesion

#ish oils? teoretically (ene$icial emo!ynamic an! antiplateletproperties

? e$$icacy unproven

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'r+an(ase! Terapy

Pulmonary Disease

0o evidence of lung disease? Reevaluate patient every * monts to permit early

!ia+nosis since :; o$ patients eventually !evelop

lun+ !isease

Symptoms e.+. !yspnea/

Pulmonary $unction tests inclu!in+ D7co

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Fi(rosin+ Alveolitis an!

#nterstitial 7un+ Disease :round glass opacification on ,&CT

? imme!iate terapy in!icate! since tis pattern almost

al&ays respon!s &it an improvement in lun+ $unctionan!"or te appearance on CT scan

? 7o& !ose pre!nisolone

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Fi(rosin+ Alveolitis an!

#nterstitial 7un+ Disease Predominantly reticular

pattern on ,&CT

? Fast clearance o$ isotope onDTPA scannin+ treat as

+roun! +lass +roup

? ormal DTPA clearance

monitor &itout speci$icterapy

P l 4 l Di !

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Pulmonary 4ascular Disease an!

Pulmonary Hypertension

0ifedipine? no !e$initive stu!ies &ic so& an improvement in survival

Chronic anticoagulation ;ith ;arfarin

? still unproven (ut may so& similar (ene$it to tose &it primarypulmonary ypertension #R

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'r+an(ase! Terapy

Car!iac Disease

pericar!itis SA#Ds, corticosteroi!s

pericar!ial

e$$usion

pericar!iocentesis,

pericar!iotomymyocar!ial $i(rosis none

myocar!itis corticosteroi!s

arrytmias o$ten no treatmentre6uire!

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'r+an(ase! Terapy

5astrointestinal Disease

:*&D? pro%inetic !ru+s, omeprazole, sur+ery

$ntestinal pseudoo6struction? pro%inetic !ru+s an! !ietary mo!i$ication $or te

early pase

? rotatin+ anti(iotics $or (acterial over+ro&t

Malnutrition? parenteral nutrition

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Summary

Pro+ressive $i(rosis o$ te s%in an! variousinternal or+ans is te patolo+ic allmar% o$sclero!erma.

E-cessive colla+en !eposition in a$$ecte! tissuesis responsi(le $or most o$ its clinicalmani$estations.

Oile supportive terapy is man!ate!,

parmacolo+ic manipulation o$ te multiple stepsinvolve! in te comple- pat&ay lea!in+ toe-a++erate! $i(ro+enesis o$$ers a potentiallysuccess$ul approac to treatment.

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S0o+ren8s Syn!rome

Cronic in$lammatory !isease

associate! &it lympocyte in$iltration

o$ e-ocrine +lan!s Classi$ication

? Primary

? Secon!ary &it associate! connectivetissue !isease/

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S0o+ren8s Syn!rome

De$ine! as te presence o$ t&o o$ te

$ollo&in+ $in!in+s

? eratocon0uctivitis sicca !ry eyes/? Lerostomia !ry mout/

?Any o$ CTD syn!romes

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S0o+ren8s Syn!rome

More common amon+ mi!!le a+e!

&omen ): years an! a(ove 9:;/

Se- ratio 9> #mmuno+enetic stu!ies !emostrate

H7A12, DRB an! DR&=:;/

? Sclero!erma =2;/

? Polymyositis

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Pato+enesis o$

S0o+ren8s Syn!rome

Caracterize! (y lympocytic Telper

"in!ucer/ in$iltation o$ e-ocrine +lan!s

an! 1lympocyte yperreactivity. Autoanti(o!ies !irecte! to

immuno+lo(ulins rheumatoid a4tor/

an! nuclear" cytoplasmic anti+ensRoSS-A, 6a SS-7/

A ti( ! A i ti i

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Anti(o!y Associations in

S0o+ren8s Syn!rome Earlier !isease onset

7on+er !isease !uration

Salivary +lan! enlar+ement Severe lympocytic in$iltration o$ minor

salivary +lan!s

E-tra+lan!ular mani$estations? lympa!enopaty

? purpura

? vasculitis

Clinical Mani$estations o$

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Clinical Mani$estations o$

S0o+ren8s Syn!rome

Lerostomia &it !ry, erytematous, stic%y oralmucosa

Decrease! lacrimal an! salivary +lan! $unctions

? Dyspa+ia &it (urnin+ sensation in te mout

? #na(ility to spea% continously

? #ncrease! !ental caries

? Paroti! +lan! enlar+ement

? Dry eyes &it san!y or +ritty sensation lea!in+ to eyeirritation, re!ness, itcin+ an! corneal ulcerations

E-tra+lan!ular Mani$estations

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E-tra+lan!ular Mani$estations

in S0o+ren8s Syn!rome

Artral+ias" onerosive artritis

Raynau!8s penomenon

7ympa!enopaty

7un+, i!ney, an! liver involvement

4asculitis

7ympoma

Splenome+aly Periperal neuropaty

Myositis

T t t

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Treatment

Symptomatic relie$ an! limit !ama+e o$-erostomia an! CS

Flui! replacement i.e. arti$icial tears

Avoi!ance o$ te $ollo&in+ me!ications

? Diuretics?Antiypertensives

?Anti!epressants

'ter me!ications

? Pilocarpine, (rome-ine

? Hyro-ycloro6uine

? steroi!s

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THA '

$or your %in! attention

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med2 20101203 ct diseases

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