Transcript Psoriasis
Psoriasis Plus de 5 millions de patients souffrent de psoriasis aux USA Ils dépensent entre 1,6 et 3,2 milliards de dollars par an pour traiter leur maladie Entre 150000 et 260000 nouveaux cas sont diagnostiqués chaque année dont 20000 chez des enfants de moins de 10 ans Psoriasis Affection “ immunologique “ dont la manifestation principale est cutanée . La maladie débute en général chez des adultes jeunes et persiste toute la vie La forme la plus courante est le psoriasis en plaques qui se caractérise par le développement de plaques érythémateuses et squameuses qui peuvent atteindre n’importe quelle zone cutanée Impact sur la qualité de vie Important. Identique à celui de l’insuffisance cardiaque 25% des patients psoriasiques souffrent de dépression Traitements classiques Traitements locaux Kératolytiques Corticoïdes Goudron Dérivés de la vitamine D Rétinoïdes Traitements généraux Méthotrexate Cyclosporine Rétinoïdes Toxicité hépatique Toxicité rénale Tératogène Photothérapie PUVA UVB TLO1 Photovieillisement et Cancer cutané Biologic agents Recombinant proteins designed to -inhibit specific steps in T cell activation -block cytokine communication -induce immune deviation (modify the direction of the immune maturation) Delivery approach -monoclonal antibody( antibodies that identical because they were produced by one type of immune cell, all clones of a single parent cell). -Fusion proteins -Recombinant human cytokines ( not approved for clinical use) Monoclonal antibody Monoclonal antibody Immunoglobulin is composed of 4 polypeptide chains Each chain has constant and variable regions The standard procedure of producing monoclonal antibodies yield mouse antibodies significantly different of human antibodies. The human immune system recognizes mouse antibodies as foreign, rapidly removing them from circulation and causing inflammatory effects Monoclonal antibody Recombinant DNA technology has overcome this problem. -DNA that encodes the variable portion of a mouse monoclonal antibody is merged with a segment of human DNA producing the constant portion of the antibody. - Mammalian cell cultures is used to produce these half mouse and half human antibodies. -If only the constant region is replaced by the human form, it is termed chimeric(70% human). -If a part of the variable regions, is also substituted, it is termed humanized (95% human). Another approach involves phage display technique or mice genetically engineered to produce human antibodies Phage display technique Nomenclature Chimeric monoclonal antibody: ximab Humanized monoclonal antibody: zumab Fully human monoclonal antibody: umimab Fusion proteins Constant portion of a human IgG Binding site of a receptor • Fusion proteins are fully human constructs between the constant portion of an immunoglobulin molecule and the binding site of a receptor ( designated “cept”) Production en bioréacteurs (Abott) Centocor Biologic agents currently approved in the EU Two mechanism of action Cytokine blockade ( TNF alpha) Inhibition of T-cell activation Blocking TNF alpha Etanercept: -fusion protein comprised of two TNF alpha receptors linked to IgG -can bind only soluble TNF alpha and TNF beta Infliximab: -chimeric antibody to TNF alpha -neutralises soluble TNF alpha and blocks TNF alpha bound to cell membrane Adalumimab -human monoclonal antibody Blocking T cell activation Efaluzimab (1) -humanized monoclonal antibody - binds to LFA-1 on T cells and blocks T cell activation Alefacept (2) -fusion protein composed of LFA-3 linked to IgG -binds to CD2 and blocks T cell activation and also trigger memory T cell apoptosis 2 1 Biologic agents in EU Biologic agent ( brand name) Mechanism of Action Mode of delivery Infliximab (Remicade) Chimeric antibody to TNF alpha IV Infusion Adalumimab (Humira ) Human monoclonal antibody to TNF alpha SC Etanercept (Enbrel) Fusion protein of two TNF alpha receptors linked to IgG SC Efaluzimab (Raptiva) Humanized antibody to CD11a a component of LFA1 SC Dosage Infliximab 5mg/kg week 0,2,6,14 patients with a 75% PASI reduction Adverse effects 60% Tuberculosis activation Demyelinating disorder Infusion reactions Adalumima 40mg/ every b two weeks 67% Etanercept 25mg twice a week 44% Efaluzimab 1mg/kg once a week 44% Tuberculosis activation Local skin reaction Demyelinating disorder Tuberculosis activation Demyelinating disorder Local skin reaction Flu-like symptoms Thrombocytopenia Rebound flare Side effects of Anti-TNF Allergic reactions -skin reaction at the site of injection ( etanercept and adalumimab). -Infusion reaction (infliximab) : need for a slow intravenous infusion. Rarely potentially serious ( anaphylactic chock) -Vasculitis , erythema multiforme, lichenoid eruption Induction of antinuclear and anti-double stranded DNA antibodies. Rarely a clinical lupus can appear. Cardiovascular complications Demyelinating disorders Tuberculosis reactivation Squamous cell carcinoma (chronic phototherapy) Etanercept induced livedo Induction or aggravation of a pre-existing psoriasis (More than Forty published cases ) Psoriasis triggered by Remicade prescribed for Crohn disease Psoriasis triggered by Enbrel Prescribed for PCE Off-label Dermatologic uses of TNF alpha inhibitors Cutaneous sarcoidosis Hidradenitis Suppuritiva Behçet Disease Aphtous stomatitis Pytiriasis Rubra Pilaris Pyoderma gangrenosum Necrobiosis Lipoidica Scleroderma Reimbursement of etanercept and infliximab - - Second line treatment in EU (not in USA) No results to the following treatments Methotrexate : 15 mg/w for three months Ciclosporine : 2.5 mg/kg for two months Correctly used phototherapy Intolerance or counter-indications to the same three treatments PASI superior or equal to 10 or BSA of 10% or more Part PASI E I D Coverage Factor Results 1:less 10% 2: 10-30% 3: 30-50% X O.4 Legs 1-4 1-4 1-4 Torso 1-4 1-4 1-4 X 0.3 Arms 1-4 1-4 1-4 X O.2 Head 1-4 1-4 1-4 X O.1 Sum of Results is the PASI score Enbrel given for 24 weeks (2 X 25 mg/week) A retreatment is possible ( 24 weeks) when the PASI score is > 5O% to the last measurement Remicade 5mg/kg (100 mg/ ampoule) Week 0, 2,6, 14 Prolongation for 6 months (4 perfusions ) if PASI score is less than 50% of the score measured before the starting of the therapy Cost High : -Etanercept : 600 Euros/2 weeks -Adalumimab : 1200 Euros / 1 month -Infliximab : 1500 Euros/treatment -Efaluzimab : 272 Euros / week Combination regimens Use of etanercept and alfacept. Biologics and acitretin Infliximab and metothrexate Sequential therapy with infliximab and efaluzimab Choice of biologic therapy Efaluzimab is favorable in patients with high risk of latent tuberculosis or evidence of demyelinating disease Infliximab is adventageous where rapid disease control is required ( rapidly evolving erythroderma) Etanercept (Adalumimab) is the biologic of choice in stable psoriasis.