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7/25/2019 Agentii Anti-TNF ReactivareaTB Ancuta
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SWITCHINGSWITCHING--ULUL ININ TERAPIATERAPIA
BIOLOGICABIOLOGICA
Codrina Ancuta,MD, PhD, sef lucrari
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SWITCHING AGENTI ANTI-TNF
RASPUNS
INADECVAT
ESEC LA TERAPIA ANTI -TNF
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CONDITIISWITCHING
Esecul la terapia biologica anti-TNF = TNF-failure raspuns terapeutic inadecvat (65%) non-responsivitate primara = absenta raspunsului terapeutic non-responsivitate partiala = ameliorare initiala, cu
persistenta la nivel redus a simptomatologiei clinice /biologice
non-responsivitate secundara (pierderea raspunsului) =ameliorare initiala & recurenta activitatii bolii
toxicitate imediata (reactii alergice) pe termen lung (anomalii imune cel mai frecvent)
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INTRE AGENTII ANTI-TNF
INFLIXIMAB
ETANERCEPTADALIMUMAB
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CU UN ALT BIOLOGIC
RASPUNS
TRATANTI -TNF
-INHIBITORI
& TOXICITATE RITUXIMAB
Anti-IL6 (TCZ),golimumab...
COSTIMULARE
CTLA4
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TERAPIA ANTI-TN F si
TUBERCULOZA
Co rina Ancuta,MD, PhD, sef lucrari
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PROFIL TOXICITATE TERAPIA BIOLOGICA ANTIPROFIL TOXICITATE TERAPIA BIOLOGICA ANTI --TNFTNF
INFECTII (nespecifice & specifice): TB &oportunistice (histoplasmoza, aspergiloza,candidioza, listerioza)
NEOPLAZII
,ADNdublu catenar, ac anti-inhibitorTNF)
PATOLOGIE C-V ACTIVARE- hepatita B, C, HIV
Blocarea / modularea efectelor fiziologice aleTNF
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ROLURI FIZIOLOGICE TNF
CK pro-inflamatorie exprimata de Mf*, T*, B* forme transmembranare si solubile (tmTNF sTNF prin clivare TACE) cuplare cuTNF-R
;mentinerea granulomTB tip II (p75) preferential tmTNF
efecte biologice multiple
raspuns inflamator-imun la infectie/ sepsis activitate anti-tumorala apararea antivirala, etc
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TNF IN PR
Interventie prinactivare celulara (Mf, T, B)apoptoza si/sau distructie celulara
inducere de alte CK proinflamatoriirecrutare celule la locul inflamatiei
Inflamatie & damage
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Risc crescut deTB sub terapia anti-TNF ? rolul TNF in raspunsul imun la infectia cu
Mycobacterium tuberculosis (mTb) interventia anti-TNF in reactivarea TB
Particularitati ale TB in contextul terapiei anti-TNF ?
eren e n re agen an - n reac varea mAb (INF, ADA)versus sTNF -R (ETN)
Recomandari screening, profilaxie, management ILTBin contextul terapiei anti-TNF
? Center for Disease Control and Prevention British Thoracic Society Romania ?
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rolulTNF in raspunsul imun la infectia cuMycobacterium tuberculosis (mTb) interventia anti-TNF in generareaTB
Risccrescut de TB sub terapia anti-TNF ?
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TB activa 10%
1/3 populatie infectata(2 bilioane)
Mycobacterium Tuberculosis Website: www.tb
Infectie latenta>90%
munosupresa
Reactivare
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RI inascut versus RI specific
TNF solubil ESENTIAL PT OBTINEREA & MENTINEREALATENTEI INFECTIEI TB
we s e
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TNF SI INFECTIA TB
website
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Particularitati ale TB in contextul terapiei anti-TNF ?
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PATTERN-UL TB SUB TERAPIE BIOLOGICA
Frecventa4-5xRAexperienta postmarketing
Mecanismreactivarea ILTB screening obligatoriuinainte de initiereterapie
TB atipicaExtrapulmonara (56-65%) vs 15%diseminata (24% vs 1%)mortalitate (5-11%)
-
Risc diferit infectiemAb vs sTNF-R
interval mediu aparitierapid (3-6 L)INFversuslent (20 L) ETN
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Diferente intre agentii anti-TNF in reactivareaILTB?
mAb (INF & ADA)versus sTNF-R (ETN)
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FrecventaTB pt INF >> ETN , ADANU studii head to head
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mAb versus sTNFRmAb: INF sTNF-R: ET
Structura - Ab chimeric monoclonal sTNF-R2 (p75)PK (t &biologic)
- 8-9.5 zile; 2 luni 3 zile; max 3 zile
Mecanism deactiune
s-TNF & tm-TNF & r-TNF(reverse, bi-directional
sTNF-R2 + tm TNF(4x
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mAb: INF sTNF-R: ETComplex
TNF-anti-TNF
stabil, durabilireversibilneutralizare completabioactivitatea TNF este
NeutralizareinstabilaReversibilaTNF disociat
legarea in complex primele 10 min)Impact
granulomgramulomul NU se refaceintre administrari INF
diseminare MTb
Se reface intreadministrari
NUdiseminareaMTb
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mAb: INF sTNF-R: ETNEfecte
indirecteapoptoza cel producatoareTNF (Mo/Mf, TCD4, CD8) prinlegare tmTNF (mec caspaza-dependent)
anti-apoptotic(depletie sTNF NU
pe tmTNF)
citotoxicitate C, Ac liza Mf granulomactivare deficitaraTh1inhibare secretieTh1
actiune sinergistica alteDMARDs (MTX)
sTNF pt formare granulom (ILTB)tmTNF controlul infectiei active
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DIFERENTE ANTI-TNF IN RISCUL REACTIVARE ILTB
Modularea activitatii TNF Medierea apoptozei celulare (T activate cu
memorie, monocite periferice si sinoviale)
Riscul de reactivare a ILTBBiodisponibilitatea TNF la nivelul granulom
&rata ILTB in populatie (origine, status socio-econimic)
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Center for Disease Control and PreventionBritish Thoracic Society Romania ?
Recomandari screening, profilaxie &management ILTB in contextulanti-TNF?
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SCREENING TB INAINTE DE INITIEREATERAPIEI ANTI-TN
- Factori de riscTBanamneza & examen fizic
- InfectiaTB
ExcludereaTBactiva
Tratarea ILTB
moderne (IGRA - QFT)- ILTBversus TB activaRadiografie toracica
Stratificareariscului infectiei
TB
CDC = Center for Disease Control and Prevention(2003)
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NU EXISTA GOLD STANDARD PENTRU
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FACTORI DE RISC TB
Provenienta din zona endemicaTB
contact TBIDR la PPD pozitiv/ tratament pt TB activaTB incorect tratata (netratata/partialtratata)secheleTB pe Rg toracica (infectie TBanterioara)imunosupresie: DMARDs, CS
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2. IDR PPDMasoara hipersensibilitatea
intirziata la inocularea tuberculina> 200 proteine mTb
Dependenta de: functia T normala IDRfals ne ativa in IMID
vaccinarea BCG prevalenta TB
Specificitate scazutaIDR 2U PPDCitire la 48- 72 ore pana la 7 ziledaca +Apreciere INDURATIE NU eritemReactia = mm , NU sau +
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VALORI PRAG
< 5 mm negativa
>5 mm pozitiva in IMID
>10 mm pozitiva
< 15 mm si >15 mm - BTS
CDC
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IDR PPD
vaccinare BCG valori < 15 mm consideratnormal - BTS) / expuneremicobacterii mediu
FALSPOZITIVA
IMID boala (RA: incapacitate de a
dezvolta un raspuns imunadecvat la tuberculina)
terapie (IS, CS)
FALSNEGATIVA
nerg e 37
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Marimea induratiei & Factori de risc
VALORI PRAG IDR (CDC/ AST/ AAP)
> 5 mm > 10 mm > 15 mmn Imunocompromisi
(BIMI, IS, CT;transplant)
n Personal laboratormicrobiologie
n Provenienta din arie
Fara factoririsc
n Contact recent TBactiva
n Sechele fibrotice Rg= TB
n Co-infectie HIV
endemica crescuta
n Pacientri afectiuni cronicen Drogatin Copii & adolescenti in
contact cu adulti risc crescutn Copii
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RECOMANDARI CDCversus BTSCenter for Disease Control and
Prevention Status imunocompromis
IDR < 5 mm, negativaSUSPECTA, NU exclude TBmonitorizare clinica
Statusimunocompromis(IMID, DMARDs, CS)
NU se recomanda
British Thoracic Society
,infectieTB TB activa versus ILTB NU two-step / booster IDR
(creste sensibilitatea, scad
specificitatea pt ILTB!) Repetare screening? Daca expunere potentiala
de rutina IDR PPD
Imunocompetenti Test pozitiv >15mm,
in vaccinarea BCG
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T cells IFN" release assay (IGRA)
Alternativa imunodiagnostic Teste ex vivo Antigene specifice, NU in
ELISpot (T-SPOT) NumarT ag-specifice
izolate din PMBC cesecreta IFN "
ELISA (QFN)
ESAT6 - early secretoryantigen target-6
CFP10 - culture filtrate protein-10
Specificitate ILTB Sensibilitate posibil > IDR
sensibilizate QuantiFERON-TB
Gold (QFT-G) ESAT6, CFP10
QuantiFERON-TB intube (QFT-IT) &TB7.7
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QFN versus IDR In vitro/ ex vivo Antigene specifice mTb Control intern raspuns IFN "
la mitogen (PHA) NU efect booster 1 vizit & rezultate 1 zi
In vivo Antigene comune mTB
Efect booster 2 vizite Citire la 48-72 h Variabilitate inter-cititor
Variabilitate inter-cititor min
website
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PERFORMANTA CLINICA QFT IN IMID
IDR vs QFN corelatie slaba % ! IDR + magnitudine raspuns celule T !! comparativ normal
Discordanta IDR QFNIDR+ & QFN -= ex unere anterioara la BCG
IDR- & QFN+= utilizare CT Corelatie
QFN factori risc ILTB
IDR vaccinarea BCG IMID sub anti-TNF QFN indeterminabil (?)
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3. RG TORACICA
NU pt screening ILTB, ci pt depistarea TB activa Indicatii: IDR PPD > 5 mm (pozitiv) IDR PPD
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ALGORITM SCREENING CDCALGORITM SCREENING CDC
Evaluare pacient (istoric & ex obiectiv
IDR PPDPPD Pozitiva PPD
Negativa
Rg toracica
IDR PPD +#5 mm
Centers for Disease Control and Prevention. MMWR. 2004American Thoracic Society. Am J Respir Crit Care Med.2000
TB activa Normal radiografic
chimioterapie Chimioprofilaxie(ILTB)
Initiere blocant TNFRomania
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ALGORITM BTS
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PROTOCOL SCREENINGTBPRE TERAPIA ANTI-TNF IN
ROMANIA?
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TENDINTE ACTUAL E
ExcludereTB activa Excludere ILTB
TB activa Chimioterapie clasica Trat anti-TNF ? Oricum dupa
finalizarea tratamentInfectie latenta TB
QFN Rg toracica
m opro ax e protocol Start terapie anti-TNF
dupa 3 sapt-2 luni HIN + anti-TNF pana la
9 luni Control vindecare ?
Berna, 2006
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CHIMIOPROFILAXIE LTBI
Medicatie Doza Frecv Durata
Izoniazida(HIN)5 mg/kg
300 mg Zilnic 9 luni
Izoniazida5 mg/kg
900 mg Bi-sapt 6-9 luni
Izoniazida5 mg/kg
300 mg zilnic 6 luni
Rifampicina10mg/kg
+ HIN5 mg/kg
600 mg zilnic 4 luniprofilaxie corecta ILTB: HIN =minimum 270 doze/ 12 luni
Monitorizare hepatica lunara
Initierea a-TNF dupa 1 luna (3 s -2 l) de profilaxie activa
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MANAGEMENT TB ACTIVA IN CURSULTERAPIEI ANTI-TNF
SuspiciuneTB Sdr febril prelungit aparent fara cauza Spt respiratorii
Initierea tuberculostatice - 4 terapie (clasic) Intreruperea anti-TNF?
DA
Re-administrare? Continuarea DMARDs, CS - posibila
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CONCLUZII
Risc crescut de reactivare a ILTB sub terapia anti-TNF
Screening ILTB si tratamentul inainte de initierea
tera iei anti-TNF = OBLIGATORIU si reduce riscul complicatiilor ATENTIE la spt respiratorii/ constitutionale/ febra
in cursul terapiei anti-TNF TB activa atipica
De raportat ca ef advers postmarketing
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CONCLUZII
Directii de cercetare: clarificarea diferentelor intre riscul de reactivare ILTB
sub agenti anti-TNFinfluenta terapiei anti-TNF asupra trat ILTB / TB activaspecificitatea si sensibilitatea IGRA pt ILTB la pacienticu boala autoimuna in perspectiva/ aflati sub terapiebiologica