Download Psoriasis

Psoriasis
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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
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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
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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)
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Monoclonal antibody
Monoclonal antibody
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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
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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
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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
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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
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Blocking T cell activation
Efaluzimab (1)
-humanized monoclonal
antibody
- binds to LFA-1 on T cells
and blocks T cell
activation
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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
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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)
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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
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Cutaneous sarcoidosis
Hidradenitis Suppuritiva
Behçet Disease
Aphtous stomatitis
Pytiriasis Rubra Pilaris
Pyoderma gangrenosum
Necrobiosis Lipoidica
Scleroderma
Reimbursement of
etanercept and infliximab
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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
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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
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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
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Combination regimens
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Use of etanercept and alfacept.
Biologics and acitretin
Infliximab and metothrexate
Sequential therapy with infliximab and
efaluzimab
Choice of biologic therapy
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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.