TERAPIA BIOLOGICA

TERAPIA BIOLOGICA SEF LUCRARI DR. ELENA REZUS

Terapia biologica 

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consta in administrarea de proteine recombinate care au drept tinta molecule specifice implicate in procesul imunoinflamator poate utiliza un singur agent sau combinatii ale acestora indicatii: boli autoimune, neoplazice, cardiovasculare

Terapia biologica-clasificare 

Anti-citokine:   

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Anti-celulara:  

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Ly T: anti CD4, anti R IL2 Ly B: anti CD20: Rituximab

Anti-molecule costimulatoare: 

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cnti TNFα: Infliximab, Adalimumab, Etanercept anti IL1: Anakinra anti IL6, IL12, IL18, IL15

CTLA4 Ig: Abatacept anti CD40, anti CD40L

Anti-molecule de adeziune: anti- VEGF, -ICAM1, -integrine , anti CD11a: Efalizumab, LFA3 Ig G1 – Alefacept Anti-chemokine: anti MIP1 Anti-angiogeneza: trombospondin, endostatin, angiostatin

ABATACEPT

Citokine “pivot”

Citokine “pivot” TNF-α

IL 1 efect pro-inflamator

↑TNF-α ↑ activarea OC ↑Angiogeneza

efect pro-inflamator

↑COX-2 ↑PGE2 ↑NO ↑ MA ↑Chemokine

↑IL-1 ↑apoptoza

↑Colagenaza ↑IL-6

COX-2 = cyclo-oxygenase type 2; PGE2 = prostaglandin-E2; NO = nitric oxide

TNF α

Key actions of anti-TNF-alpha  pro-inflammatory cytokines Increased Macrophages inflammation  chemokines Endothelium  Adhesion molecules

Increased cell infiltration

TNF- α  Acute phase response Synoviocytes

Increased CRP in serum

 metalloproteinase synthesis  collagen synthesis Articular cartilage degradation

Epithelium

 keratinocyte  hyperproliferation

Skin plaques

INHIBITORII TNF α Anticorpi monoclonali chimerici – INFLIXIMAB  Anticorpi monoclonali umanizati – ADALIMUMAB  Receptori solubili ai TNFα – ETANERCEPT (proteina de fuziune receptor TNF p75 – Ig G1) 

INFLIXIMAB (REMICADE) 

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Anticorp monoclonal chimeric Alcatuit din regiunea constanta a Ig G1 umane si regiunea variabila a unei Ig murine Leaga moleculele de TNFα libere si fixate de celule

INFLIXIMAB (REMICADE)  

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Se adm in combinatie cu MTX Doze: 3 mg/kgc in piv la momentul initial, la 2 sapt, la 6 sapt si apoi din 8 in 8 saptamani Raspuns insuficient: se creste doza pana la 10 mg/kgc sau se poate micsora intervalul dintre administrari la 4-6 sapt

INFLIXIMAB (REMICADE) -reactii adverse        

Reactii adverse acute ale piv : febra, frisoane, cefalee, prurit, urticarie, hipotensiune, dispnee Infectii – reactivarea tuberculozei Hipersensibilitate de tip intarziat: mialgii, artralgii, eritem, edeme Fen autoimune : anticorpi antimolecula chimerica (HACA), ANA, Ac anti ADNdc, fen lupus like Fen CV : agravarea insuf cardiace, aritmii Fen digestive: greata , diaree, dureri Fen neurologice : sdr demielinizante Fen hematologice : leucopenie, anemie, trombocitopenie Neoplazii : limfoame

ADALIMUMAB (HUMIRA) 

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Anticorp monoclonal complet umanizat Doza: 40 mg la 2 sapt, sc Adm in monoterapie sau combinat cu MTX Fara rct alergice si aparitia Ac ( rar – anticorp “umani-antiumani”

ETANERCEPT (ENBREL) 

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Molecula himerica alcatuita din 2 reg extracelulare de legare ale R p75 al TNFα legate de portiunea Fc a unei Ig G1 umane Doza: 25mg x 2/sapt, sc In monoterapie sau in combinatie cu MTX Rct adverse: asemanatoare INF

Which patient with RA should ideally receive TNF inhibitors? 

FDA: 

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RA patients with moderate to severe disease activity after failing MTX and/or another DMARD(s)

Romania: 

Active RA after failing at least 2 DMARD s in maxim um doses  Activ e  ≥ 5 “active” joints +  2 from 3:  Morning stiffness > 60 minute s  ESR > 28mm/h  CRP > 2 0 mg/l  Failing at least 2 DMARD s , from which one had to be MTX, after min 12 weeks of maximal dosage

TNF Antagonists: Other Indications and Clinical Investigations 

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Confirmed in Trials Crohn’s disease Spondyloarthropathies  Psoriatic arthritis   

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Psoriasis Ankylosing spondylitis Reactive arthritis

Juvenile RA Adult Still’s disease

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Cush J. Rheumatology. 2003. In press.

Under Investigation Vasculitis: Wegener’s disease, giant cell arteritis Scleroderma Graft-versus-host disease Inflammatory myositis Interstitial lung disease Sjogren’s syndrome Inflammatory eye and ear disease Asthma Hepatitis Sarcoidosis Behcet’s disease Pyoderma gangrenosum

TNF Antagonists: Relative Contraindications 

Systemic lupus erythematosus

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Multiple sclerosis, optic neuritis

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Current active serious infections

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Chronic/recurrent infections

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History of TB or positive PPD test

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Congestive heart failure

IL1

IL-1 – rol central IL-1 Activare monocite/ macrofage

INFLAMATIE

Induce proliferare fibroblast

FORMARE PANUS SINOVIAL

Activare condrocite

Activare osteoclaste

DISTRUCTIE RESORBTIE OSOASA CARTILAJ

ANAKINRA (KINERET)    

Anatagonist neglicozilat al R pentru IL1 Doza: 100mg/zi, sc Posibil asociere cu MTX Reactii adverse: infectii, neutropenie, reactii la locul injectiei

BLOCANTE ALE COSTIMULARII

ABATACEPT 

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Proteina de fuziune dintre antigenul 4 asociat LyTc (CTLA4) si Ig G1 CTLA4 se leaga de CD80 si de CD86 de pe CPA blocand activarea LyT prin CD28 Doza: 2mg/kgc sau 10 mg/kgc

Ac monoclonali anti CD20

RITUXIMAB 

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1. 2. 3.

CD20 = antigen fosfoproteic de suprafata care se pierde inainte de transformarea Ly B in plasmocit. Ac anti CD20 contine o reg constanta Ig G1 Fc si regiuni mici variabile ale Ig murin Are 3 modalitati prin care produce depletia Ly B: Citotoxicitate celulara Ac dependenta Citotoxicitate dependenta de complement Promovarea apoptozei Ly B CD20

RITUXIMAB 

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doza: 300 mg piv in ziua 2, apoi 600 mg piv in zilele 8, 15, 22 sau in 2 piv la 14 zile. Reactii adverse;febra, frisoane, greata, cefalee, hipotensiune tranzitorie

TERAPIA BIOLOGICA  

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inaintea tratamentului este obligatoriu: excluderea infectiei – in special TBC (IDR la tuberculina si Rg toracica) si markeri virali (Ag HBs si Ac anti HVC) excluderea neoplaziei excluderea fen autoimune asociate – Ac anti ADN dc

TERAPIA BIOLOGICA IN SPONDILITA ANCHILOZANTA  -

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Indicatii: Boala activa de cel putin 4 sapt (scor BASDAI>4) si fara raspuns la cel putin 2 AINS adm timp de 3 luni fiecare, la dozele maxime indicate sau in conditiile in care AINS a fost intrerupt din cauza intolerantei sau contraindicatiilor Lipsa de raspuns la dozele standard de SSZ in formele periferice de SA dupa cel putin 4 luni de tratament ETANERCEPT 50 mg/sapt sc mg/kgc piv la 6-8 sapt dupa incarcare

sau INFLIXIMAB 5 faza initiala de

TERAPIA BIOLOGICA IN ARTRITA PSORIAZICA   

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ETANERCEPT INFLIXIMAB ALEFACEPT – molecula de fuziune intre LFA3 si portiunea Fc a Ig G1 EFALIZUMAB – Ac monoclonal umanizat anti CD11a