BOLI DE COLAGEN

SCLERODERMIA

Sinonime : scleroza sistemica (SS)

Definitie : boala generalizata a tesutului conjuctiv caracterizata clinic prin :
-Ingrosarea si fibroza pielii (SCLERODERMA: scleros = dur, derma =
piele)
-Afectarea organelor interne : inima, plaman, rinichi, tract gastro-intestinal
Epidemiologie :
 Incidenta : 18 – 20 pacienti /milion/an
 Prevalenta : 100000 cazuri in USA
 Varsta debutului : 30-50 ani, dar poate debuta la orice varsta
 F/B : 3-4/1
Etiologie : necunoscuta

Factorii de risc :
 Genetici :
-RR al rudelor de gradul I crescut pentru SS (RR =13) sau alte boli
autoimune (LES,PR)
-Asociere slaba cu genele HLA
 Factorii de mediu -Infectiosi : CMV
-Noninfectiosi : produse petroliere (toluen, tricloretilen),
clorura de polivinil , L-triptofan, silicon, medicamente ( bleomicina,
pentazocina, cocaina, unele anorexigene

Patogenie : trei procese patogenice esentiale:

(1) activarea SI prin inflamatie (prezenta in fazele precoce ale bolii) si
autoimunitate
(2) vasculopatia obliterativa
(3) fibroza progresiva viscerala si vasculara in multiple organe

Patogenie : mecanisme autoimmune:

 Susceptibilitate genetica : asocierea cu alte boli autoimune la acelasi
individ (sindrom overlap) sau la rudele sale
 Prezenta autoanticorpilor : anti-topoizomeraza (proteina implicata in
mitoza), anti- proteine centromerice, ANA (>95%)
 Asocierea autoanticorpilor cu moleculele HLA-DQ sintetizate de gene
ale raspunsului imun

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Patogenie : inflamatie si autoimunitate:
 Afectarea /lezarea endoteliului vascular este momentul initial in
patogeneza SS
 Factorii trigger posibili : factori serici citotoxici (radicalii de oxigen?),
enzime proteolitice (?), autoanticorpi anti celula endoteliala (?),virusuri
vasculotrope (?), citokinele inflamatorii (?), factorii de mediu (?)
Patogenie : activarea sistemului imun
 Limfocitele T: infiltrate limfocitare perivasculare in fazele precoce ale
bolii (CD4 in piele, CD8 in plaman)->Prezenta infiltratelor cu celule T cu
profil secretor de tip TH2 si actiune profibrotica: IL4, IL5 , IL13, IL6
 Activarea monocitelo/macrofagelor cu secretia de citokine
proinflamatorii (IL1,TNFalfa) si profibrotice ( IL6, TGF-beta)
 Limfocitele B :Productie de autoanticorpi, IL6
Patogenie : vasculopatia proliferativ/obliterativa
 Cresterea reactivitatii vasculare prin injuria endoteliului vascular cu
dereglarea productiei de substante vasodilatatoare (prostaciclina, oxidul
nitric) si vasoconstrictoare (endotelina-1)
 Agregare plachetara : tromboze intravasculare , eliberare de substante
vasoconstrictoare (tromboxan)
 Remodelare vasculara : proliferarea intimei si a mediei, fibroza
adventicei
Patogenie : vasculopatia:
 Ingustarea lumenului vascular :
-Vasoconstrictie, ischemie de reperfuzie
-Remodelare vasculara : proliferarea intimei, fibroza adventicei
-Tromboze intravasculare
 Obliterare vasculara si hipoxie tisulara

Endotelina -1 eliberata de celulele endoteliale activate :

 cel mai puternic vasoconstrictor
 promoveaza adeziunea leucocitelor si proliferarea celulelor
musculaturii netede vasculare
 activarea fibroblastilor
Patogenie :Fibroza : rezultatul final al inflamatiei cronice, autoimunitatii,
afectarii vasculare si a hipoxiei. Este caracterizata prin :
 Inlocuirea tesutului normal cu tesut conjuctiv dens
 Activarea si proliferarea unui fenotip anormal de fibroblasti (“fenotip
sclerodermic”), caracterizat prin cresterea persistenta a sintezei de colagen
si a matricei extracelulare, secretia de citokine profibrotice si rezistenta la
semnale inhibitorii (ex. ITF gama)

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Morfopatologie : -leziunile morfopatologice sunt prezente in:
 Piele
 Tractul GI : gura, esofag, stomac, intestin
 Plaman
 Rinichi
 Inima
 Alte organe :sinoviala, tecile tendoanelor, muschi, glanda tiroida,
glandele salivare

-leziunile morfopatologice caracteristice sunt :

 Vasculopatie obliterativa a arterelor mici si a arteriolelor caracterizata
prin proliferarea intimei si ingustarea lumenului: inima, plamanul, rinichii,
tractul intestinal
 Fibroza interstitiala a organelor tinta : piele, plaman, tract
gastrointestinal, inima, teaca tendoanelor, tesutul perifascicular al muschilor
scheletici, unele organe endocrine (tiroida) care are drept consecinta
->Inlocuirea parenchimului cu un tesut conjuctiv omogen, distrugerea
arhitecturii, disfunctiionalitate, insuficienta de organ

Patogenie :Manifestari ale vasculopatiei vaselor mici :

 Sindromul Raynau
 Telangiectasia
 Hipertensiunea arteriala pulmonara
 Criza renala sclerodermica
Patogenie :Manifestari ale procesului de fibroza :
 Ingrosarea pielii
 Boala pulmonara parenchimatoasa
 Dismotilitatea tractului gastrointestinal

Clasificare :
1.Sclerodermia localizata
 Morpheea
 Lineara
 In “lovitura de sabie”
2.Scleroza sistemica
 Localizata : boala cutanata limitata (distal de coate si /sau genunchi)
 Difuza : boala cutanata difuza

Manifestari clinice la debut :

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 Sindromul Raynaud (mai ales in formele cutanate limitate)
 Tumefierea difuza a mainilor, ingrosarea tegumentelor sau artrita in
formele de boala cu afectare difuza
 Ocazional , afectarea viscerala : simptome esofagiene (disfagie,
pirozis) sau pulmonare (dispnee)
 Sindromul Raynaud secundar SS :
-Vasculopatie obliterativa a vaselor mici ale membrelor +
vasospasm indus de frig
-Principala forma de debut in SS localizata (poate precede celelalte
simptome/semne cu luni sau ani)
-Evolutie fazica : paloare (vasospasm), cianoza (staza venoasa),
roseata (hiperemia si revenirea fluxului sanguin)
-Leziuni ireversibile : ulcere digitale, suprafetele de extensie a IPP,
MCP, stiloida ulnara, cot (ischemie + microtrumatism), gangrena (nu sunt
prezente in sindromul Raynaud primar)
-Poate precede alte manifestari clinice cu luni sau ani
 Modificari ale pielii ( ingrosarea tegumentelor)
-edeme cu sau fara godeu ale degetelor, mainilor, antebratelor,
fetei, gambe, picioare (faza edematoasa)
-piele ingrosata si dura la degete, maini, fata +/- antebrate, brate,
piept, membre inferioare, abdomen (faza indurativa)
-telangiectazii (dilatatia vaselor din derm)
-calcinoza (calcificari cutanate sau subcutanate din hidroxiapatita)
-cicatrici ale pulpei degetelor, ulceratii, gangrene, mumificare,
amputare
 Tractul gastrointestinal (prin dismotilitate determinata de atrofia si
fibroza musculaturii netede sau vasculopatie/GAVE : gastric antral vascular
ectasia)
-Gura : ingrosarea tegumentului perioral, reducerea aperturii orale, carii
dentare xerostomia
-Esofag : reflux, stricturi, metaplazia Barrett
-Stomac : gastropareza (satietate precoce), gastrita, ectazii vasculare antrale
-Intestinul subtire : hipomotilitate (borborigme, flatulenta),
staza, suprapopulare bacteriana (diaree, malabsorbtie), pseudo-obstructie,
pneumomatoza
-Colonul : hipomotilitate, pseudo-obstructie, pseudo-diverticuli
-Anus si rect : incompetenta sfincteriana
-Ficat : ciroza biliara primitiva
 Manifestari clinice pulmonare :

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-Fibroza pulmonara : dispnee, tuse seaca, modificari Rx, disfunctie
ventilatorie restrictiva, HRCT(85% din pacientii cu SS), DLCO, lavajul
bronhoalveolar
-Hipertensiunea pulmonara:DLCO (scadere izolata), ECO, cateterismul
cordului drept prin afectare:
>pulmonara : fibroza, vasculopatie sclerodermica
>cardiaca : disfunctie diastolica, boala valvulara, ICC

 Manifestari
-Anti Topoisomerase-I : SS difuza, fibroza pulmonara, afectarea cardiaca,
criza renala sclerodermica
-Anti proteine ale centromerului :SS localizata, ischemia degetelor,
calcinoza, HTP izolata
-U3-RNP : dcSScPAH, ILD, scleroderma renal crisis, myositis
-Th/T0 : lcSScILD, PAH
-PM/Scl : lcSScCalcinosis, myositis
-U1-RNP : MCTD, PAH
-RNA polymerase III : dcSScExtensive skin, scleroderm

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 DISEASE CLASSIFICATION — Five major diffuse connective
tissue diseases (DCTD) exist according to current classification schema:
systemic lupus erythematosus (SLE); scleroderma (Scl); polymyositis (PM);
dermatomyositis (DM); and rheumatoid arthritis (RA). A sixth disorder,
Sjögren's syndrome, is commonly associated with each of these diseases, but
is called primary Sjögren's syndrome when it occurs alone.
 The classical clinical descriptions of these disorders are well known
and most patients with well-differentiated disease are easily recognized.
However, experienced physicians often note that one DCTD seems to evolve
into another over the course of several years [5-10] . This occurs in about 25
percent of patients, who are then said to have an overlap syndrome [6] . (See
"Undifferentiated systemic rheumatic (connective tissue) diseases and
overlap syndromes").
 (Definition and diagnosis of mixed connective tissue disease )

 Is MCTD a specific disease? — If a distinct illness requires both

unique clinical features and consistent pathology, then none of the DCTDs
can be defined as a specific illness. Each DCTD contains subsets of patients
with clinical and pathologic characteristics which differ from other patients
with the same diagnosis.
 In the early stages most patients destined to develop MCTD cannot be
differentiated from the other classical DCTDs. The early simultaneous
presence of overlap features usually seen in SLE, Scl and PM is seldom
seen. More commonly the overlapping features occur sequentially over
several years. Prominent early symptoms are: easy fatiguability poorly
defined myalgias, arthralgias and Raynaud phenomenon. The common
diagnostic considerations at this juncture are usually RA, SLE or
undifferentiated connective tissue disease (UCTD) [7,8] . A patient with
swollen hands and/or puffy fingers in association with a high titer speckled
ANA should be carefully followed for the evolution of overlap features. A
high titer of anti-RNP antibodies in such a patient is a powerful predictor of
a later evolution into MCTD [9,10] . Other, less common, early features
include: a severe inflammatory myopathy, acute arthritis, aseptic
meningitis, digital gangrene, high fever, acute abdomen and trigeminal
neuropathy.

 The major reason to consider MCTD a distinct clinical entity is that

the presence of high titers of anti-U1 RNP antibodies is associated with
several distinctive clinical characteristics; for example:

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 Patients with U1 RNP antibodies seldom develop diffuse proliferative
glomerulonephritis, psychosis, or seizures; these abnormalities are a major
source of morbidity and mortality in SLE [11,12] .
 Patients with U1 RNP antibodies nearly always have an early
development of Raynaud phenomenon [1,2] and a nailfold capillary pattern
that is the same as in Scl but different from classical SLE [13] . The
Raynaud phenomenon only occurs in about 25 percent of patients with
classical SLE.
 Patients with U1 RNP antibodies are more likely to develop
pulmonary hypertension than patients with classical SLE or Scl. Pulmonary
hypertension is the major cause of death in MCTD [14,15] .
 Patients with U1 RNP antibodies are more likely than SLE patients to
be rheumatoid factor positive [2] and develop an erosive arthritis [3,16] .
 Thus, the concept of MCTD is useful in defining a subgroup of
patients with unique clinical features, treatment profile, and prognosis.
Whether MCTD is a unique subset of SLE or Scl or is a distinct clinical
entity is not clinically so important.

 The criteria utilized by Alarcon-Segovia had a sensitivity and

specificity of 63 and 86 percent and is the most widely used.
 These classification criteria are as follows [19] :
 Serologic criteria — Anti-RNP antibodies at a hemagglutination titer
> 1:1600
 Clinical criteria — Swollen hands, synovitis, biologically or
histologically proven myositis, Raynaud phenomenon, and acrosclerosis
with or without proximal systemic sclerosis
 If serologic criteria and at least three of the five clinical criteria are
present then a diagnosis of MCTD can be made.
 However, a patient with sufficiently elevated anti-RNP titers in
combination with swollen hands, Raynaud phenomenon, and acrosclerosis
with or without proximal systemic sclerosis, must also have either synovitis
or myositis to meet the criteria for diagnosis

 CLINICAL MANIFESTATIONS — The early clinical features of

MCTD are nonspecific and may consist of general malaise, arthralgias,
myalgias, and low-grade fever [2,5] . A specific clue that these symptoms
are caused by a connective tissue disease is the discovery of a positive
antinuclear antibody (ANA) in association with Raynaud's phenomenon [6] .
 As will be described below, almost any organ system can be involved
in MCTD. There are, however, four clinical features that suggest the

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presence of MCTD rather than another connective tissue disorder such as
SLE or Scl:
 Raynaud's phenomenon and swollen hands or puffy fingers [7,8]
 The absence of severe renal and central nervous system (CNS) disease
[2,9,10]
 More severe arthritis and the insidious onset of pulmonary
hypertension (not related to lung fibrosis) differentiate MCTD from both
SLE and Scl [11,12]
 Autoantibodies whose fine specificity is anti-U1 RNP, especially
antibodies to the 68 Kd protein [13] ( Clinical manifestations of mixed
connective tissue disease )