Lupusul Eritematos

Sistemic (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
Definitie
Mecanisme imuno-patogenice
Manifestari clinice
Explorare
Terapie
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 imune
fixatoare 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 (20-40
ani)
femei vs. barbati = 9-10 vs 1
Plan de studiu
Definitie
Mecanisme imuno-patogenice
Manifestari clinice
Explorare
Management
Etiologie
LES
Factor
genetic
Hormo-
nal
Psiho-
emotional
Factori
de
mediu
Etiologie
istoric familial
rude grad 1 = 1%; gemeni monozigoti = 50%
susceptibilitate genetica: complex poligenic
Gene 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)
- ScadereT reglatorii
- Anomalii ale apoptozei
- Activare policlonala B
- hipersinteza
autoanticorpi
- Alterarea clearance
complexe 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
CeluleT
Cresterea activitatii CD4+
Celule B
autoreactive
CK, co-
stimulare
Hiperprodictie
autoAC
Acumulare
complexe imune
Distructie tisulara
Tinte antigenice
Antigene nucleare: DNA nativ, DNA dublu
catenar, histone, Sm, RNP, etc
Antigene citoplasmatice: SS-A, SS-B, proteina P
ribozomala, ANCA
Antigene de suprafata celulara: celule
endoteliale, eritrocite, neutrofile, limfocite,
plachete
Alte antigene & factori plasmatici: -2
glicoproteina I, fosfolipide, imunoglobuline, etc
Plan de studiu
Definitie
Mecanisme imuno-patogenice
Manifestari clinice
Explorare
Management
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
Astenie
Fatigabilitate
Febra/ subfebrilitate
Scadere ponderala
Alopecie areata/ difuza
Limfadenopatie
1. Afectare cutanata
Leziuni specifice
A. Lupus acute
rash malar in fluture,
butterfly
lupus generalizat
fotosensibilitate
B. Lupus subacut
lupus anular
Leziuni psoriaziforme
C. Lupus cronic
Leziuni discoide clasice
Lupus hipertrofic
Paniculita lupica
Ulceratii mucoase
Alte leziuni (L.tumidus,
lichenoid)
Leziuni non -specifice
A. Leziuni cutaneo-
vasculare
Vasculita
Vasculopatie
Fen Raynaud
Livedo reticularis
B. Alopecie difuza non-
cicatriciala
C. Urticaria
D. Eritem multiform
Leziuni cutanate specifice
Vespertilio
butterfly (rash malar)
Lupus acut cutanat
Web site
Web site
Leziuni cutanate specifice
Lupus discoid Leziuni psoriaziforme
Web site
Leziuni non-specifice
vasculita
Fen Raynaud
Web-site
2. Afectare musculo-scheletala
Poliartrita simetrica non erosiva artic mici
ale membrelor
Rupus = artropatie eroziva!
Artropatie Jaccoud
Necroza aseptica (cap femural)
Osteoporoza
Miozita
Web-site
3. Poliserozita
Pleurita
Pericardita
Peritonita
pleurita
pericardita Web site
4. Afectare respiratorie
Pleurita
Alveolita obliteranta
Fibroza pulmonara
Hipertensiune pulmonara
Embolism 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 nervos
central
Meningita aseptica
Leziune cerebrovasculara
Sdr. demielinizant
cefalee
Coree
Mielopatie
Convulsii
Psihoza
Status confuzional acut
Disfunctie cognitiva
Sistem nervos
periferic
Sdr acute Guillain-Barr
Anomalii sistem nervos
autonomic
Mononeurita
simplex/multiplex
Miastenia gravis-like
Leziuni nervi cranieni
Polineuropatie
7. Nefrita lupica
Minimal mesangial nephritis (CLASS I)
Mesangial proliferative nephritis (CLASS II)
Focal lupus nephritis (<50%glomeruli) (CLASS III)
A. Active lesions: focal proliferative GN
A/C. Active and chronic lesions: focal proliferativ &sclerosing GN
C. Chronic inactive lesions & glomerular scarring (focal sclerosing
GN
Diffuse 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
affected
Membranous lupus nephritis (CLASSV)
May associate with findings characterised in class III/IV
Sclerosing glomerulonephritis (90%glomeruli) (CLASS IV)
8. Alte manifestari
Hematologice
Citopenii: anemie, leucopenia + limfopenie,
trombocitopenie, pancitopenie
Altele
Vasculita
Pancreatita & hepatita lupica
Ulcer peptic + singerare gastrointestinala
Tromboza / vasculita mezenterica
Tromboza artera/ vene centrala retina
Nevrita optica
Corioretinita
Sindrom sicca
Plan de studiu
Definitie
Mecanisme imuno-patogenice
Manifestari clinice
Explorare
Management
Explorare
Sindrominflamator (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-epiderm
decelabile in IF), renala (stadializare nefrita lupica),
musculara, etc
Criterii diagnostic ACR 1997
nr 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 sindromantifosfolipidic
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
Definitie
Mecanisme imuno-patogenice
Manifestari clinice
Explorare
Management
Management-ul LES
Corticoterapie cronica (iv, po): doza stabilita in
functie de visceralizari
Imunosupresive (metotrexat, azatioprina,
ciclofosfamida, ciclosporina, micofenolat
mofetil) & 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 zile
consecutive, apoi adminstrare
orala, 0.5-1 mg/kg/zi, cu scadere
ulterioara la doza minima
eficace
Management: Imunosupresoare
Methotrexat
10-20 mg /sapt, doza unica, treatmentul afectarii
articulare, vasculare
Efecte adverse: toxicitate hepatica, medulara, pulmonara
Azathioprina (Imuran)
2-4 mg/kg/zi, afectare multiorganica
efecte 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 CFM
nefrita lupica, alveolita, vasculita, afectare SNC
efecte adverse: idem
Management
Ciclosporina A (Sandimmun Neoral)
Afectare hematologica, nefropatie lupica
membranoasa
doza: 3 mg/kg/zi
Micofenolat mofetil (Cellcept/Myfortic)
Nefropatia lupica max. 3 gr/zi
Tinte potentiale
Terapia biologica
BENLYSTA (belimumab) = inhibitor specific BLyS, anticorp
monoclonal 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