1 Piergiorgio Neri, BMedSc, MD(Hons), PhD Head: Ocular Immunology Unit The Eye Clinic-Ospedali Riuniti di Ancona Anti-TNF-α α therapy in uveitis The The Eye Eye Clinic Clinic Polytechnic Polytechnic University of Marche University of Marche Head: Prof Alfonso Head: Prof Alfonso Giovannini Giovannini Gold salts Sulfasalazine Hydroxychloro- quine Glucocor- ticoids Methotrexate (MTX) NSAIDs Penicillamine 1930-40 1950 1950 1960 1988 1995 1998+ 1998+ Combo therapy Anti-TNF Anti-TNF Therapeutic breakthroughs Therapeutic breakthroughs Biologics Biologics The Copernican Revolution in Pharmacology Biologics Biologics: drugs created by biologic processes, rather than being chemically synthesized. Different types: Monoclonal Antibodies Fusion Proteins Other (i.e.: Interferon)
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Anti-TNF- therapy in uveitis Hydroxychloro- - · PDF fileScarce control of uveitis Selected case 2-HLA-27+ spondylitis associated uveitis Golimumab . 11 Biologics Immunesuppressives
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Posarelli C, Arapi I, Michele Figus M, Neri P 2011
Tumor Necrosis Factor-αTumor necrosis factor (TNF, cachexin orcachectin and formally known as tumornecrosis factor-alpha) is a cytokine (tumornecrosis factors) involved in systemicinflammation and is a member of a groupof cytokines that all stimulate the acutephase reactionTNF causes apoptotic cell death, cellularproliferation, differentiation, inflammation,tumorigenesis, and viral replicationTNF's primary role is in the regulation ofimmune cells
Murphy CC, et al. Br J Ophthalmol 2004;88:412–416
T cell activation and TNF production in intermediate uveitis
33
EAU in TNF p55 receptordeficient miceddeeffiicciieenntt mmiiccee
Development of Human Antibodies UsingHuman Antibody Transgenic Mice
Normal mouse Human antibodytransgenic mouse
Mouse Ig genes deleted
Human Ig genes insertedHu
Immunize with antigen
Immunize with antigen
Mouse antibody Human antibodyLonberg et al. Nature Biotech 2005; 23(9): 1117
http://www.medarex.com/Development/Evolution.htm
For clarity, several intermediate steps are not shown.
IFXchimeric
ADAhuman
44
HELP!!!!!!
55
UveitisNon-responderSevereSteroid dependant Traditional immunesuppressives not effective
When anti-TNF-αIdentikit
Financial Issues
Day HospitalD H i l
+
+Domiciliary Care
=
=
Intravenous
Sub-cutaneous
Difficulty to attendhospital for the i.v.
infusions
Difficulty to attendhospital for the i.v.
infusions
Motivation fortreatment change
3ys
2ys
Follow-up
Humira
Humira
Currenttreatment
i.v. and oral steroid,ciclosporin,
methotrexate,azathioprine,
mycophenolatemofetil, and i.v.
cyclophosphamide
i.v. and oral steroids,CSA, AZA, MTX,CYP,Infliximab
i.v. and oral steroids,CSA, MTX,
CYP,Infliximab
Previoustreatment
6/9
6/18
LE
After treatmentBefore treatment
Case3
Case2
Case1
HM6/9HM
6/96/186/9
RELERE
Difficulty to attendhospital for the i.v.
infusions CF 6/36 1/60 6/36 Humira 3ys
Mushtaq B et Al. Eye 2007
66
Clin Exp Rheumatol. 2011 Jul-Aug;29(4 Suppl 67):S93.Efficacy of switching to adalimumab in a patientwith refractory uveitis of Behçet's disease toinfliximab. Leccese P, Latanza L, D'Angelo S, PadulaA, Olivieri I.
Clin Exp Rheumatol. 2011 Jul-Aug;29(4 Suppl 67):S54-7. Efficacy of adalimumab in patients with Behçet'sdisease unsuccessfully treated with infliximab.Olivieri I, Leccese P, D'Angelo S, Padula A, Nigro A,Palazzi C, Coniglio G, Latanza L.
6/7 Humira
Dhingra N et Al. Eye 2009 Neri P et Al. MEAJO 2010
Review
Summary•Effective•Safe (?)•Promising
77
Baseline 1 3 6 12Months
Refractory Non-infectious Uveitis with CMO
n=10
Data on file 2009-2013 Neri P et Al. Clin Exp Rheumetol 2013
Neri P et Al. Clin Exp Rheumetol 2013
Selected case 1-Adalimumab
Male16-yrAll tests negativeBilateral panuveitis with haemorrhagic retinal
vasculitisSevere CMO
88
Selected case 1-Adalimumab
0.4 0.2
Selected case 1-Adalimumab
Would you inject Sub-TTA?
0.8 0.4
1.0 (2-mts) 0.5
Selected case 1-Adalimumab Selected case 1-Adalimumab