1. Biologic therapy Spyridon Gkalpakiotis,MD,PhD Dermatovenereology department Third faculty of medicine,Charles University,Prague

2. Biologic therapy Biologics are formed in the human body Formed by: -recombinant DNA technology -hybridoms -blood -from human cells Biologics are - Large molecules - Applied usually by injection Less side effects than traditional systemic therapeutics

3. Therapy of psoriasis and psoriatic arthritis with biologics Humira® (adali- mumab)‏ Enbrel® (etanerce pt)‏ Stelara® (Ustekinu mab)‏ Remicade ® (infliximab )‏ Psoriasis Psoriasis- Arthritis

4. Humira® (adali- mumab)‏ Enbrel® (etanerce pt)‏ Stelara® (Ustekinu mab)‏ Remicade ® (infliximab )‏ Mechanis m anti TNF-a proti IL12/23 Aplication s.c anti TNF-a s.ci.v

5. Role of TNF in psoriasis Creation of tumor necrosis factor (TNF) is increased in psoriasis Elevated serum TNF Increased concentrations of TNF in psoriatic lesion TNF levels correlate with scores of the Psoriasis Area and Severity Index (PASI) Decreased TNF correlates with clinical manifestations

6. Efektorová aktivita zprostředkovaná TNF-  TNF-  se neváže na svůj receptor: nevytváří se signál TNF-  receptor Prozánětlivýcytokin TNF-  Y Solubilníreceptor MonoklonálníProtilátka Anti–TNF-  No antagonist of TNF with antagonist of TNF Prozánětlivé signály Prozánětlivé signály TNF-  receptor Choy ES, Panayi GS. N Engl J Med. 2001;334:907-916.

7. Infliximab Mouse Fv )‏ (binding site for TNF)‏ Human (IgG1)‏ Human kappa Chimeric human - mouse monoclonal antibody anti-TNF Chimeric human - mouse monoclonal antibody anti-TNF

8. Infliximab Aplication i.v ( 5mg/kg) – 0,2,6 and then every 8 weeks Aplication i.v ( 5mg/kg) – 0,2,6 and then every 8 weeks Side effects – headache, elevaion of liver enzymes, infections Side effects – headache, elevaion of liver enzymes, infections Infusion Infusion reactions !! PASI 75 až u 80% pacientů PASI 75 až u 80% pacientů References: 1. Gottlieb, A.B, et al., Poster, 61st Annual AAD Meeting, 2003 2. Centocor, Inc. Summary of Product Characteristics. 1999.

9. Etanercept ■ Etanercept is a fusion protein ■ Composition of the ligand, which binds to the receptor for TNF attached to the Fc portion of human IgG1 ■ Approved for childhood psoriasis ■ Application: 25mg 2x a week sc or 50 mg 1x a week event. 50mg 2x a week (12weeks)

10. Adalimumab Complete human monooclonal antibody anti–TNF-a Aplication: s.c baseline 80mg, 40mg after a week and then 40mg every 2 weeks VHVH Light chain CLCL CH1CH1 CH3CH3 CH2CH2 Fc Fab Heavy chain VLVL Bain B, Brazil M. Nat Rev Drug Discov. 2003;2:693-694. Lidský peptid S-S

11. New biologic therapy - Block subinit of p40, which is part of IL-12 a IL-23 IL-23 IL-12 TNF-  IFN-  TNF-  IL- 17 IL-22 T cell Je utlumena diferenciace a klonální pomnožení subsetů Th1 a Th17 Protilákta váže na podjednotku p40 IL-12 a IL-23, zabraňuje navázání na její buněčné receptory 1. Gately MK, et al. Annu Rev Immunol. 1998;16:495-521. 2. Wilson NJ, et al. Nat Immunol. 2007;8(9):950-7. 3. Nickoloff BJ, Nestle FO. J Clin Invest. 2004;113(12):1664-75. 4. Nestle FO et al. J Invest Dermatol. 2004; 123:xiv-xxv. Th1 Th17 Snížení hladiny zánětlivých cytokinů

12. Ustekinumab The complete human antibody against the IL- 12/IL-23 Applications s.c Baseline, 4 weeks and then 1 every 12 weeks Dose: 1 to 100 kg inj. 45mg, 2inj over 100 kg

13. Pappu R.J Clin Immunol (2010) 30:185–195

14. N Engl J Med 2012;366:1181-9.

15. Pappu R.J Clin Immunol (2010) 30:185–195 Brodalumab

19. N Engl J Med 2012;366:1190-9.

23. Which biologic? Individual According speed of effect According way of administration European S3-Guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol. 2009, vol.23(2) British Association of Dermatologists' guidelines for biologic interventions for psoriasis 2009. Br J Dermatol. 2009 Nov;161(5):987-1019

24. Why biologic therapy High effect Less adverse events Long-term therapy

25. Future