Agentii Anti-TNF ReactivareaTB Ancuta

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)

BTS = British Thoracic Society (2005)PDF created with pdfFactory trial version www.pdffactory.com


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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

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Agentii Anti-TNF ReactivareaTB Ancuta