Lupusul EritematosSistemic (LES)

Sef Lucrari Dr. Codrina ANCUTA

Reumatologie & Recuperare

Bolile tesutului conjunctiv(colagenoze, conectivite)

Clasificare Lupus Eritematos Sistemic (LES) Sclerodermie Sistemica (SSc) Polimiozita/Dermatomiozita (PM/DM) Boala Mixta de Tesut Conjunctiv (boala Sharp)

(BMTC)

sindroame overlap: PR-SSc, PR-LES, PM-SSc, etc

+ poliartrita reumatoida

Plan de studiu

DefinitieMecanisme imuno-patogeniceManifestari cliniceExplorareTerapie

Definitie si Clasificare LES

boala inflamatorie cronica a tesutului conjunctiv, de cauza autoimuna, cu determinari

multisistemice & articulare

Subtipuri

Lupus eritematos sistemic (LES); Lupus cutanat cronic (discoid); Lupus cutanat subacut; Lupus drog-indus; Lupus neonatal; Sindroame overlap

Lupus Eritematos Sistemic (LES)

Boala autoimuna inflamatorie cronica a tesutului conjunctiv, cu determinari articulare

& multi-sistemice

Trei caracteristici majore inflamatie cronica sinteza autoanticorpi depunere tisulara de complexe imunefixatoare de complement

Caracteristici generale

etiologie obscura, boala multi-factoriala afectare articulara, cutanata & mucoase,

renala, sistem nervos (central, periferic), cardio-vasculara & respiratorie

prezenta auto-anticorpi (> 100!)

simptomatologie polimorfa, cu mare variabilitate

evolutie cronica cu pusee la intervale variabile

Epidemiologie

boala rara, subdiagnosticata prevalenta: 40-50/100.000 cazuri incidenta: 2-7 /100.000 cazuri/an

varsta de debut: femei etapa fertila (20-40ani)

femei vs. barbati = 9-10 vs 1

Plan de studiu

DefinitieMecanisme imuno-patogeniceManifestari cliniceExplorareManagement

Etiologie

LES

Factor genetic

Hormo-

nal

Psiho-emotional

Factoride

mediu

Etiologie

istoric familialrude grad 1 = 1%; gemeni monozigoti = 50%

susceptibilitate genetica: complex poligenicGene HLA: DR2,DR3, DQ1, DQ2; DR4-DIL,

DR5-APS

Gene non-HL: fractiuni ale complementului & receptori, receptori fractiune Fc, CRP, citokine, gene apoptoza (FAS)

Etiologie Factori de mediu ultraviolete (UV-B): alterarea structurala derm &

apoptoza keratinocitelor

infectii virale & bacteriene (hiperreactivitate imuna)medicamente: clasice (procainamida, isoniazida,

methildopa, contraceptive orale; hidralazina; D-penicilnamine, peniciline; sulfonamide) & moderne(blocanti TNF)

Substante chimice - pesticide, solventi, metale grele, expunere siliciu

Factori hormonali estrogenii sunt permisivi pt autoimunitate; androgenii au rol protectiv

Factori psiho-emotionali

Patogenie

Anomalii reglare imuna

- Prezentare patologica antigenica

- Cresterea expresiei HLA

- Accentuarea co-stimularii

- -Dezechilibru citokinic (Th1/Th2)

- Scadere T reglatorii

- Anomalii ale apoptozei

- Activare policlonala B - hipersinteza autoanticorpi

- Alterarea clearancecomplexe imune

- Depozite tisulare de complexe imune

- Activare cascada complement

Mecanisme patogenice

Predispozitie genetica(HLA, non-HLA)

Factori trigger

(ultraviolete, infectii, medicatie)

Status hormonal (estrogeni)

Anomalii imune

Activare policlonala celule B

Hiperproductie anticorpi

Clearance defectuos & depozite tisulare de complexe imune & activare complement

Anomalii apoptoza

Damage de organ

Predispozitie genetica (gene HLA & non-HLA)Factori trigger (UV, medicatie, infectii)

Status hormonal

Anomalii imune

Clearance defectiv Scaderea activitatii celulelor T

ADN,

Celule apoptotice

Celule prezentatoare de Ag

Celule TCresterea activitatii CD4+

Celule B autoreactiveCK, co-

stimulare

Hiperprodictie

autoAC

Acumularecomplexe imune

Distructie tisulara

Tinte antigenice

Antigene nucleare: DNA nativ, DNA dublucatenar, histone, Sm, RNP, etc

Antigene citoplasmatice: SS-A, SS-B, proteina P ribozomala, ANCA

Antigene de suprafata celulara: celuleendoteliale, eritrocite, neutrofile, limfocite, plachete

Alte antigene & factori plasmatici: -2 glicoproteina I, fosfolipide, imunoglobuline, etc

Plan de studiu

DefinitieMecanisme imuno-patogeniceManifestari cliniceExplorareManagement

Manifestari clinice

Cutanate (specifice, non-specificice; butterfly, lupus discoid; fotosensibilitate; ulceratii orale)

Musculo-scheletale (artrite PR-like, non-erozive)Cardio-vasculare (pericardita, miocardita, endocardita

Liebmann-Sachs, ATS precoce accelerata)

Renale (nefrita lupica 6 clase OMS)Respiratorii (pleurezie, alveolita, pneumonita, embolii,

etc)

Neurologice (neuro-lupus; neuropatii periferice)

Criteriile de diagnostic ACR 1997 Factori de prognostic negativ

Tablou clinic: simptome generale

AstenieFatigabilitate Febra/ subfebrilitate Scadere ponderalaAlopecie areata/ difuza Limfadenopatie

1. Afectare cutanata

Leziuni specificeA. Lupus acute rash malar in fluture,

butterfly lupus generalizat fotosensibilitateB. Lupus subacut lupus anular Leziuni psoriaziformeC. Lupus cronic Leziuni discoide clasice Lupus hipertrofic Paniculita lupicaUlceratii mucoaseAlte leziuni (L.tumidus,

lichenoid)

Leziuni non -specificeA. Leziuni cutaneo-

vasculare Vasculita Vasculopatie Fen Raynaud Livedo reticularisB. Alopecie difuza non-

cicatricialaC. UrticariaD. Eritem multiform

Leziuni cutanate specifice

Vespertiliobutterfly (rash malar)

Lupus acut cutanat

Web site

Web site

Leziuni cutanate specifice

Lupus discoid Leziuni psoriaziformeWeb site

Leziuni non-specifice

vasculita

Fen Raynaud

Web-site

2. Afectare musculo-scheletala

Poliartrita simetrica non erosiva artic miciale membrelor

Rupus = artropatie eroziva!Artropatie JaccoudNecroza aseptica (cap femural)OsteoporozaMiozita

Web-site

3. Poliserozita

PleuritaPericarditaPeritonita

pleurita pericarditaWeb site

4. Afectare respiratorie

PleuritaAlveolita obliteranta Fibroza pulmonaraHipertensiune pulmonaraEmbolism pulmonar

Web-site

5. Afectare cardio-vasculara

Pericardita Miocardita Cardiomiopatie Endocardita - non-infectioasa verucoasa Liebman-

Sacks - infectioasa subacute Valvulopatie Ateroscleroza precoce acelerata artere

coronare

6. Afectare neurologica

Sistem nervoscentral

Meningita aseptica Leziune cerebrovasculara Sdr. demielinizant cefalee Coree Mielopatie Convulsii Psihoza Status confuzional acut Disfunctie cognitiva

Sistem nervosperiferic

Sdr acute Guillain-Barr Anomalii sistem nervos

autonomic Mononeurita

simplex/multiplex Miastenia gravis-like Leziuni nervi cranieni Polineuropatie

7. Nefrita lupicaMinimal mesangial nephritis (CLASS I)Mesangial proliferative nephritis (CLASS II)Focal lupus nephritis (50% glomeruli) (CLASS IV) - diffuse segmental (IV-S) type, when only a part of the involved

glomeruli are affected - diffuse global GN (IV-G), when the entire glomeruli are

affectedMembranous lupus nephritis (CLASS V) May associate with findings characterised in class III/IVSclerosing glomerulonephritis (90% glomeruli) (CLASS IV)

8. Alte manifestariHematologice

Citopenii: anemie, leucopenia + limfopenie, trombocitopenie, pancitopenie

Altele Vasculita Pancreatita & hepatita lupicaUlcer peptic + singerare gastrointestinala Tromboza / vasculita mezenterica Tromboza artera/ vene centrala retinaNevrita optica Corioretinita Sindrom sicca

Plan de studiu

DefinitieMecanisme imuno-patogeniceManifestari cliniceExplorareManagement

Explorare

Sindrom inflamator (VSH accelerat dar CRP normal)Anomalii imune (ANA totali, anticorpi anti-ADNdc, -Sm, -

Ro, -La, -fosfolipidici, complement total si fractiuni C3, C4, etc)

Bilant hematologic (citopenii)Bilant renal (inclusiv Addis & proteinurie; punctie biopsie

renala)

Bilant pulmonar, cardio-vascular, neurologic, muscular Osteodensitometrie DXA (tratament cronic corticoizi!)

Activitate LES versus distructie tisulara(Indici: SLEDAI, BILAG)

Raspuns terapeutic

Explorare

Rg toracica, CT + hsCT, spirometrie Ecografie abdomino-pelvina ECG, echocardio Examen neurologic: EEG, ENG, EMG, CT, MRI, LCR Biopsie: cutanata (testul benzii lupice = depozite

compleze immune la jonctiunea derm-epidermdecelabile in IF), renala (stadializare nefrita lupica), musculara, etc

Criterii diagnostic ACR 1997nr criteriu

1 Rash malar in fluture

2 Lupus discoid

3 Fotosensibilitate

4 Ulceratii orale, nazale

5 Poliartrita non-eroziva

6 Serozite

7 Afectare renala: proteinuria >0.5; cilindri celulari

8 Afectare neuropsihiatrica: convulsii, psihoza

9 Afectare hematologica: anemie hemolitica, leucopenie, limfopenie, trombocitopenie

10 Anomalii immune: ADNdc sau anti-Sm sau anti-CL

11 ANA pozitiv

LES daca minimum 4 criterii

Indicele de activitate a LES (SLEDAI)

Convulsii 8 Psihoza 8 Organic brain syndrome 8 Afectare oftalmologica

(retinopatei) 8

Afectare nervi cranieni 8 Cefalee 8 Stroke 8 Artrita 4 Miozita 4

Cilindri celulari 4 Hematurie 4 Proteinurie 4 Piurie 4 Rash 2 Alopecia 2 Ulceratii orale 2 Pleurita 2 Pericardita 2 scadere complement 2 Cresterea DNAdc 2 Febra 1 Trombopenia 1 Leucopenia 1

Subtipuri de lupus

lupus cutanat subacut lupus neonatal lupus indus medicamentos lupus la varstnic lupus cu sindrom antifosfolipidic

Lupusul neonatal Frecventa: rara

Cauze: pasajul transplacentar al autoAc materni

Clinic: eruptie cutanata generalizata

hepato-splenomegalie

trombocitopenie pasagera

AHAI

bloc cardiac congenital

Laborator: ac anti-SSA/aSSB

ANA

anti DNAdc titru inalt

tratament: Corticosteroizi + HIVIG + pace maker

Lupusul la varstnic

Debut > 60 ani

Frecventa - 10%, cu afectare ambele sexe

Severitate medie

Clinic

Afectare musculo-skeletala

serozita

Afectae pulmonara - fibroza

Rash

Sdr. sicca

Excludere patologie neoplazica!!!!!!!

Tratament: GC doza joasa & AINS

Lupus indus medicamentos

Caracteristici clinice Mai frecvent la varstnic Reversibil Severitate medie Afectare renala si SNC rara Afectare pulmonara frecventa

Laborator

Acetilatori lenti

asociere HLA DR4

Histone H2A, H2B histone = tinta antigenca

Therapie

Intreruperea medicatiei + corticosteroizi

Factori de prognostic negativ

Sexul masculin

Varsta < 20 ani sau > 50 ani

Nefropatie proliferativa difuza

Manifestari SNC

Prezenta anticorpilor anti-fosfolipidici

Endocardita

Plan de studiu

DefinitieMecanisme imuno-patogeniceManifestari clinice ExplorareManagement

Management-ul LES

Corticoterapie cronica (iv, po): doza stabilita in functie de visceralizari

Imunosupresive (metotrexat, azatioprina,ciclofosfamida, ciclosporina, micofenolatmofetil) & imunomodulatorii (antimalarice de sinteza)

Terapia biologica: inhibitori BLyS(belimumab), anti-CD20 (rituximab, ocrelizumab)

Management

Recomandari generale

evitarea expunerii la raze UV crme ecran fotoprotector (SPF>50%) intrerupere medicatie potential inductoare atentie la contraceptive orale ?!? terapie AB adecvata infectii intercurente

-

Management

Antimalarice de sinteza: hidroxicloroquin, cloroquin

Artralgii/ artrite, afectarea cutanata, serozite, sdr. antifosfolipidic

Doze: 400 mg/zi, seara (doza atac), 3-max 6 luni 200 mg/zi (intretinere)

Efecte adverse: oftamologice (diplopie, depozite retiniene) control

oftalmologic pre, si apoi la interval de 6 luni Pigmentare mb inferioare

Management: glucocorticoizi

Trat de electie, doza raportata la tipul devisceralizare 0.5-1mg/kg/zi

Pulseterapie metilprednisolon 1000 mg/zi, iv, 3 zileconsecutive, apoi adminstrareorala, 0.5-1 mg/kg/zi, cu scadereulterioara la doza minima eficace

Management: Imunosupresoare

Methotrexat 10-20 mg /sapt, doza unica, treatmentul afectarii

articulare, vasculareEfecte adverse: toxicitate hepatica, medulara, pulmonara

Azathioprina (Imuran)2-4 mg/kg/zi, afectare multiorganicaefecte adverse: toxicitate hepatica si medulara

Ciclofosfamida (Endoxan)pulse- terapie 500-1000 mg/m2/luna, 6 luni, apoi piv la interval de 3 luni, 1.5 ani (EUROLUPUS); 6-10 g CFMnefrita lupica, alveolita, vasculita, afectare SNCefecte adverse: idem

Management

Ciclosporina A (Sandimmun Neoral)Afectare hematologica, nefropatie lupicamembranoasa

doza: 3 mg/kg/zi

Micofenolat mofetil (Cellcept/Myfortic)Nefropatia lupica max. 3 gr/zi

Tinte potentiale

Terapia biologica

BENLYSTA (belimumab) = inhibitor specific BLyS, anticorpmonoclonal uman care se leaga de BLyS (soluble B lymphocyte stimulator) favorizeaza apoptoza B, inclusive a celulelor B autoreactive, redice diferentierea B in plasomocite

Tratament LES- forme active autoanticorpi positive, nonresponsive la terapia standard

Limite: LES cu nefropatie active severa sau afectare SNC active

NU se administreaza in asociere cu CFM iv

Doza: 120 mg/ 1 f=5 ml; 400 mg in f = 20 ml, adm iv