BOLI DE COLAGENSCLERODERMIA

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-intestinalEpidemiologie : Incidenta : 18 – 20 pacienti /milion/an Prevalenta : 100000 cazuri in USA Varsta debutului : 30-50 ani, dar poate debuta la orice varsta F/B : 3-4/1Etiologie : 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, IL6Patogenie : 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 adventiceiPatogenie : 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 fibroblastilorPatogenie :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 sclerodermicaPatogenie :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 )

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