BOLI DE COLAGEN

SCLERODERMIA

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

SCLERODERMIA

• 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

SCLERODERMIA

• 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

Kelley’s textbook of rheumatologyKelley’s textbook of rheumatology

SCLERODERMIA

• Etiologie : necunoscuta• Factorii de risc :

– Factorii de mediu :• Infectiosi : CMV• Noninfectiosi : produse petroliere (toluen,

tricloretilen), clorura de polivinil , L-triptofan, silicon, medicamente ( bleomicina, pentazocina, cocaina, unele anorexigene

SCLERODERMIA

• 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

SCLERODERMIA

• Patogenie : mecanisme autoimune

– 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

SCLERODERMIA

• 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 (?)

SCLERODERMIA

• 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

SCLERODERMIA

• 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

SCLERODERMIA

• Patogenie : vasculopatia

– Ingustarea lumenului vascular :• Vasoconstrictie, ischemie de reperfuzie• Remodelare vasculara : proliferarea

intimei, fibroza adventicei• Tromboze intravasculare

– Obliterare vasculara si hipoxie tisulara

SCLERODERMIA

• Endotelina -1 eliberata de celulele endoteliale activate :– cel mai puternic vasoconstrictor– promoveaza adeziunea leucocitelor si

proliferarea celulelor musculaturii netede vasculare

– activarea fibroblastilor

SCLERODERMIA

• 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)

SCLERODERMIA

• 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

SCLERODERMIA

• Morfopatologie : 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

SCLERODERMIA

• Patogenie :– Manifestari ale vasculopatiei vaselor

mici :• Sindromul Raynau • Telangiectasia • Hipertensiunea arteriala pulmonara• Criza renala sclerodermica

SCLERODERMIA

• Patogenie :– Manifestari ale procesului de

fibroza :•Ingrosarea pielii•Boala pulmonara parenchimatoasa•Dismotilitatea tractului

gastrointestinal

SCLERODERMIA

• Clasificare :– Sclerodermia localizata

• Morpheea• Lineara • In “lovitura de sabie”

– Scleroza sistemica• Localizata : boala cutanata limitata (distal

de coate si /sau genunchi)• Difuza : boala cutanata difuza

SCLERODERMIA

• Manifestari clinice la debut :– 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)

SCLERODERMIA

• Manifestari clinice :– 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

SCLERODERMIA

• Manifestari clinice : 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

SCLERODERMIA• Manifestari clinice : 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

SCLERODERMIA

• Manifestari clinice pulmonare :

– 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

Scleroderma: Raynaud’s phenomenon, blanching of hands

Scleroderma: Raynaud’s phenomenon, cyanosis of the hands

Scleroderma: edematous changes, hands

Scleroderma: skin induration, hands

Scleroderma: acrosclerosis and terminal digit resorption

CREST syndrome: calcinosis cutis, fingers

Scleroderma: Mauskopf, facial changes

Scleroderma: Mauskopf, facial changes

Linear scleroderma: thigh and leg

Morphea: leg

Eosinophilic fasciitis: cutaneous lesions, arm

Scleroderma: acrolysis (radiographs)

Scleroderma: calcinosis and acrolysis (radiograph)

Scleroderma: pulmonary fibrosis (radiograph)

Isenberg DA, Renton P, Imaging in Rheumatology, 2003Isenberg DA, Renton P, Imaging in Rheumatology, 2003

FIBROZA PULMONARA FIBROZA PULMONARA >>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>

Isenberg DA, Renton P, Imaging in Rheumatology, 2003Isenberg DA, Renton P, Imaging in Rheumatology, 2003

Scleroderma: abnormal motility, esophagus (radiograph)

Isenberg DA, Renton P, Imaging in Rheumatology, 2003Isenberg DA, Renton P, Imaging in Rheumatology, 2003

Scleroderma: wide-mouthed diverticula, colon (radiograph)

• 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:

• 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 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 )