1. Biological Therapies for Psoriasis Carle Paul, Dermatology, Purpan Hospital, Toulouse International Psoriasis Day, October 2006

2. "After I was born, it took six months for my psoriasis to appear: proof of my infamy and my difference; in one word, a scab... I scratched myself completely, and I can say here that anyone who has not known what it is like to itch without cease knows very little of hell. Oh, this awful thing which kept me from speech for so long, a stranger to the world, this thing that kept me a virgin for so many years.” Lorette Nobécourt. The Itch, Sortilèges 1994

3. Local therapies: insufficient when psoriasis covers more than 10% of the body surface

4. Patients' perception of therapy 78% 32% 0102030405060708090100 Percentage of patients Disappointed by therapy Therapy not aggressive enough N A T I O N A L P S O R I A S I S F O U N D A T I O N P A T I E N T S U R V E Y Krueger G, et al. Arch Dermatol. 2001;137:280-284.

5. Impact of psoriasis on quality of life  Profound impact, similar to that of major illnesses  Depression  Stigmatisation  Loss of self esteem  Imperfect correlation with severity  Often inadequately assessed by the dermatologist 1 1 Br J Dermatol 2005; 152:1256, and 153:997

6. Biological Agents: Mechanism of Action  TNF alpha inhibition: an important cytokine, which plays a role in: - T lymphocyte activation and secretion of proinflammatory cytokines - Activation and migration of Langerhans cells - Expression of endothelial adhesion molecules - Keratinocyte proliferation  LFA-1(CD11a) inhibition: adhesion and cutaneous migration of activated T lymphocytes (through the interaction of LFA-1 and ICAM-1)

7. Molecules available in dermatology Enbrel (Etanercept) : a chimeric fusion protein composed of the Fc fragment of human IgG and the extracellular portion of the human TNF alpha receptor. Blocks soluble TNF alpha, weak immunogenicity Remicade (Infliximab) : anti-TNF alpha chimeric monoclonal antibody (human Fc and murine Fab) Blocks soluble TNF alpha and its receptor, strong immunogenicity Raptiva (Efalizumab): anti-LFA-1 chimeric monoclonal antibody Humira (Adalimumab): anti-TNF antibody humanised in development

8. Therapeutic indication (Enbrel, Remicade, Raptiva) Plaque psoriasis which is "moderate to severe" (European license), "serious" (Transparency Commission of the French Ministry of Health) and which has “failed” to be treated by at least two systemic therapies from among: - Phototherapy - Methotrexate - Cyclosporin Severe psoriasis: at least 30% of body surface or significant psychological and social impact Initial and six monthly in-hospital prescription, performed by a specialist Failure: intolerance, inefficacy, side effects, contraindications

9. Comparative efficacy of psoriasis treatments (% of patients with a 75% improvement of their PASI)

10. Week 10 At Baseline

11. Improvement in depression score with psoriasis therapy (etanercept) Tyring S et al. Lancet 2006: 379:29-35

12. Contraindications to biological agents - Sensitivity to product - Tuberculosis and other severe infections (septicaemia) - Active infection - Moderate or severe congestive heart failure (infliximab) - Immunodeficiency

13. Most common side effects  "Allergic" reactions, urticaria, injection site reaction, flu- like symptoms, occasionally anaphylaxia  Other effects: Anti-TNF alphas  Antinuclear antibodies (50% Remicade, 10% Enbrel)  Anti infliximab antibodies (28% in psoriasis)  transaminases  Cutaneous vasculitis Efalizumab  Rebound effect (3-5%)  Lymphocytosis  Thrombocytopenia (0.3%)  transaminases

14. Side effects rare but serious  Excess immunosuppression  Severe systemic infections: tuberculosis, septicaemia  Lymphoproliferative syndrome  Other types of cancer Anti-TNFs  Demyelinating neurological disorders: multiple sclerosis, optic neuritis (0.01 to 0.1%)  Aggravation of cardiac failure  Hepatotoxicity and drug-induced SLE

15. Reactivation of tuberculosis and biological agents The importance of screening and monitoring Cases recorded (EU) for 1,000 patients exposed to infliximab Feb 2000 – Aug 2005 TB: Educational approach begun in June 01

16. Tuberculosis screening: clinical guidelines Afssaps 2005 Before beginning anti-TNFs Screening for a history of TB exposure + tuberculin skin test (tubertest* 5 Ul) + chest x-ray IDR ≤ 5mm and Normal chest x-ray Begin anti-TNF IDR > 5mm (BCG > 10 years) or calcification > 1 cm Anti-TB therapy: INH + RIF 3 months orINH 9 months Begin anti-TNF at least 3 weeks later

17. Risk of cancer and anti-TNF antibodies: probably similar to other immunosuppressants Meta-analysis of PR clinical trials All doses versus placebo Low doses versus placebo High doses versus placebo

18. Place of biological therapies in moderate to severe psoriasis: a modulated vision First line: Phototherapy Second line: Photochemotherapy Retinoids Re-PUVA Methotrexate Cyclosporin Third line: Biological therapies In practice, flexibility should be exercised, depending on the context and discussion of the course of treatment with the patient

19. Biological agents in practice Enbrel 25 mg x 2 / week SC Max 24 weeks Skin and joints PASI 75: 30% after 12 weeks Time without relapse 12 weeks Clinical monitoring Remicade 5 mg/kg in perfusion, weeks 0,2,6 then every 8 weeks Skin and joints 80% after 10 weeks 20 weeks Clinical monitoring Raptiva 0.7mg/kg then 1 mg/kg/week, SC Skin 29% after 12 weeks 10 weeks Clinical monitoring FBC with special reference to platelets/month

20. Biological agents: Cost MoleculeDoseMonthly cost Enbrel 25 mg x 2 / week 50 mg x 2 / week 1140 Euros 2280 Euros Remicade 5mg/kg (<60 kg) 5mg/kg (>60 kg) Day 0, Week 2, Week 6 then Every 8 weeks 1122 Euros* 1496 Euros* *+ cost of day hospitalisation Raptiva1 mg/kg/week1087 Euros

21. Biological agents: Cost MoleculeDoseMonthly costCost/success Enbrel 25 mg x 2 / week 50 mg x 2 / week 1140 Euros 2280 Euros 3800 Euros 4560 Euros Remicade 5mg/kg (<60 kg) 5mg/kg (>60 kg) Day 0, Week 2, Week 6 then Every 8 weeks 1122 Euros* 1496 Euros* *+ cost of day hospitalisation 1402 Euros 1870 Euros Raptiva1 mg/kg/week1087 Euros3623 Euros

22. Pre-therapy assessment: day hospitalisation History and examination: cancer, tuberculosis, multiple sclerosis, severe infection, heart failure, live vaccine administration, intention to become pregnant  Assessment of the impact of psoriasis: severity, quality of life, depression  Additional tests: full blood count; serum electrophoresis; liver function tests; HIV, HBV and HCV serology; ANA titres, tuberculosis skin test 5U (<5 mm = normal), chest x-ray  Raptiva, Enbrel: in-hospital prescription, monitoring by an office-based dermatologist, hospital assessment every six months as an outpatient  Remicade: monthly monitoring, in-hospital perfusion every 8 weeks

23. Biological therapies: questions  When should they be used in practice?  Does early treatment alter disease progression?  Feasibility of integration of treatment into a therapeutic education programme  Long term efficacy?  Long term safety?

24. Biological therapies: a confirmed hope  Demonstrated efficacy : - Reduction in severity - Improvement in quality of life - Improvement in depression score  Satisfactory tolerance and straightforward administration if patient well informed and rigorous monitoring  A triple opportunity for doctors : - To better manage the condition - To develop listening skills and individualised care - To make better use of systemic therapies (methotrexate and cyclosporin)