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Workshop 2014 Teil 1 Allgemeines, Neuigkeiten Teil 2 Therapie Topisch – Lichttherapie – Systemtherapie
Psoriasis Häufige polygen vererbte Krankheit
der Haut, Nägel, Schleimhaut und Gelenke mit Befall von besonderen Prädilektionsorten
Primäreffloreszenz: erythematosquamöse Plaque
Häufige vererbte Krankheit der Haut, Nägel, Schleimhaut und Gelenke
mit Befall von besonderen Prädilektionsorten
• 2% der Bevölkerung
• 150 000 Patienten in der Schweiz
Häufige vererbte Krankheit der Haut, Nägel, Schleimhaut und Gelenke
mit Befall von besonderen Prädilektionsorten
• Vererbungsmodus unklar aber familiäre Häufung
- 1 Elternteil betroffen Risiko 20%
- 2 Eltern betroffen Risiko 50 - 75%
Häufige vererbte Krankheit der Haut, Nägel, Schleimhaut und Gelenke
mit Befall von besonderen Prädilektionsorten
Workshop 2014 Teil 1 Neuigkeiten in der Therapie
Biologicals neue topische Anwendungen Betesil Pflaster Clarelux Schaum Daivobet Gel Onypso NL / Onyster NS
Nicht ansteckend !!
Therapie = Schweregrad
Jede Psoriasis muss gepflegt werden !
Psoriasis = Autoimmunerkrankung
• Calcipotriol • Anti-proliferativ, • anti-inflammatorisch • keine Tachyphylaxie • 1-2x täglich • auch intertriginös, Gesicht • Kombination mit Salicylsäure, Steroide, UVB
Vitamin D Analoga
topisch
Mild
Mittelschwere
Schwer Systemtherapie • Cyclosporin A • MTX • Neotigason • Fumarsäure Phototherapie • UVB 311nm, PUVA Lokaltherapie • Vitamin D Analoga • Steroide • Cignolin
Stadienabhängig
Psoriasis Therapie: Zusammenfassung
Concept from: Grabbe S, Schwarz T. Immunol Today. 1998;19:37-43.
Psoriasis = Autoimmunerkrankung
Embrel Remicaid
Nomenclature of biologic therapies
● Etanercept -cept = human receptor fusion protein
● Infliximab -ximab = chimaeric monoclonal antibody
● Adalimumab
● Ustekinumab -umab = fully human monoclonal antibody
Adapted from: Johnston SL. J Clin Pathol. 2007;60(1):8-17.
Ustekinumab1 Etanercept2 Infliximab3 Adalimumab4
Type of biologic Fully human
IgG1κ monoclonal antibody
Human TNFR2/p75 Fc fusion protein
Chimaeric human-murine IgG1 monoclonal
antibody
Recombinant human
monoclonal antibody
Target IL-12/23 p40 TNF-α
TNF-β (Lymphotoxin)
TNF-α# TNF-α#
Mode of action Blocks
IL-12 and IL-23 activity
Blocks TNF activity
Blocks TNF-α activity
Blocks TNF-α activity
Approved biologic therapies for plaque psoriasis Comparison of structure and function
1. Ustekinumab - European Summary of Product Characteristics. Date: March 2012. 2. Etanercept - European Summary of Product Characteristics. Date: March 2012.
3. Infliximab - European Summary of Product Characteristics. Date: December 2011. 4. Adalimumab - European Summary of Product Characteristics. Date: February 2012.
Adalimumab
Structure ● Fully human monoclonal antibody
Target ● TNF-α
Presumed mechanism of action ● Attenuates inflammatory action of TNF-α
by interfering with binding to cell-surface receptors
● Apoptosis of TNF-α-positive macrophages and T cells
Human anti-TNF-α#
Adalimumab - European Summary of Product Characteristics. Date: April 2010.
Adalimumab Mechanism of action
Adalimumab - European Summary of Product Characteristics. Date: April 2010.
Transmembrane-bound TNF-α#
Soluble TNF-α#
Receptor-bound TNF-α#
TNF receptor
Macrophage or activated T cell
Target cell
Etanercept
Structure ● Human fusion protein composed
of TNF receptor type II (TNF-R p75) and human IgG1 Fc fragment
Target ● TNF-α and TNF-β (lymphotoxin-α)
Presumed mechanism of action ● Attenuates inflammatory action
of TNF by interfering with binding to cell-surface receptors
Complement binding region
Fc
Human p75 TNF receptor
Etanercept - European Summary of Product Characteristics. Date: November 2009.
Etanercept Mechanism of action
Transmembrane-bound TNF#
Soluble TNF#
TNF receptor
Macrophage or activated T cell
Target cell
Etanercept - European Summary of Product Characteristics. Date: November 2009.
Infliximab
Structure ● Chimeric monoclonal antibody with
murine (mouse) variable region and human IgG1 region
Target ● TNF-α
Presumed mechanism of action ● Attenuates inflammatory action of TNF-α
by interfering with binding to cell-surface receptors
● Apoptosis of TNF-α-positive macrophages and T cells
Human IgG1 region
Anti-TNF-α#
Murine variable region
Infliximab - European Summary of Product Characteristics. Date: March 2010.
Infliximab Mechanism of action
Infliximab - European Summary of Product Characteristics. Date: March 2010.
Transmembrane-bound TNF-α#
Soluble TNF-α#
Receptor-bound TNF-α#
TNF receptor
Macrophage or activated T cell
Target cell
Stelara Ustekinumab Mechanism of action
Infliximab - European Summary of Product Characteristics. Date: March 2010.
Stelara Ustekinumab Usage
Infliximab - European Summary of Product Characteristics. Date: March 2010.
Approved biologic therapies for plaque psoriasis Comparison of dosing and administration
Ustekinumab1 Etanercept2 Infliximab3 Adalimumab4
Method of administration Subcutaneous Subcutaneous Intravenous
infusion Subcutaneous
Induction dose 45/90 mg at weeks 0 and 4 NO 5 mg/kg at
weeks 0, 2, 6 80 mg at
wk 0
Maintenance dose
45/90 mg every
12 weeks
25/50 mg once or twice
weekly (up to 24 weeks)
5 mg/kg every
8 weeks
40 mg every
other week
Self-administered YES YES NO YES
Weight-based dosing YES NO YES NO
1. Ustekinumab - European Summary of Product Characteristics. Date: March 2012. 2. Etanercept - European Summary of Product Characteristics. Date: March 2012.
3. Infliximab - European Summary of Product Characteristics. Date: December 2011. 4. Adalimumab - European Summary of Product Characteristics. Date: February 2012.
Biologic therapies Comparison of tolerability and safety*
Ustekinumab1 Etanercept2 Infliximab3 Adalimumab4
Infusion/injection/ allergic reactions YES YES YES YES Malignancies/ lymphoma/HSTCL !, - , - !, !, - !, !, !† !, !, !†
Anti-drug antibodies‡ 5% 7% 28% 8%
Neurological events - ! ! ! Haematologic reactions - ! ! !
HBV reactivation - ! ! ! Hepatobiliary events/jaundice - !
1. Ustekinumab - European Summary of Product Characteristics. Date: March 2012. 2. Etanercept - European Summary of Product Characteristics. Date: March 2012.
3. Infliximab - European Summary of Product Characteristics. Date: December 2011. 4. Adalimumab - European Summary of Product Characteristics. Date: February 2012.
*Based on Contraindications (section 4.3) and Warnings and Precautions (section 4.4) of the SmPCs. † HSTCL with infliximab or adalimumab was reported only in patients with Crohn’s disease or ulcerative colitis. ‡ In patients enrolled in clinical studies of plaque psoriasis.
Ustekinumab1 Upper respiratory tract infection, nasopharyngitis
Etanercept2 Infections (including upper respiratory tract infections, bronchitis, cystitis, skin infections), injection site reactions (including bleeding, reddening, itching, pain, swelling)
Infliximab3 Viral infection (including influenza, herpes virus infection), headache, upper respiratory tract infection, sinusitis, abdominal pain, nausea, infusion-related reaction, pain
Adalimumab4
Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral), leucopaenia (including neutropenia and agranulocytosis), anaemia, lipids increased, headache, abdominal pain, nausea and vomiting, elevated liver enzymes, rash (including exfoliative rash), musculoskeletal pain, injection site reaction (including injection site erythema)
1. Ustekinumab - European Summary of Product Characteristics. Date: March 2012. 2. Etanercept - European Summary of Product Characteristics. Date: March 2012.
3. Infliximab - European Summary of Product Characteristics. Date: December 2011. 4. Adalimumab - European Summary of Product Characteristics. Date: February 2012.
*Very common (≥1/10)
Biologic therapies Very common adverse events*
FDA 2012.
Psoriasis treatment in pregnancy FDA categorisation of drug risk to the foetus
Treatment FDA foetal risk category
Adalimumab B
Etanercept B
Infliximab B
Ustekinumab B
Methotrexate X
Ciclosporin C
Acitretin X
Note: non-biologics included for comparison
Biologics in pregnancy FDA categorisation of drug risk to the foetus
● The FDA categorizes medicines according potential risk to the foetus ‒ The categories are from "Category A" (safest) to "Category X" (known
danger – do not use) ● Adalimumab, etanercept, infliximab and ustekinumab are all
category B medicines ‒ Either animal-reproduction studies have not demonstrated a foetal risk but
there are no controlled studies in pregnant women, or ‒ Animal-reproduction studies have shown an adverse effect (other than a
decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters)
FDA 2012.
PASI 75 and PASI 90 responses for infliximab (week 10 data), etanercept, ustekinumab (week 12 data) and adalimumab (week 16 data)
Patie
nts
(%)
34
11
Etanercept1 25 mg
100
80
40
0
20
60
Etanercept1 50 mg
49
21
100
80
40
0
20
60
Infliximab2 5 mg/kg
80
57
100
80
40
0
20
60
Adalimumab3 40 mg
71
45
100
80
40
0
20
60
Ustekinumab4 45 mg
67
42
100
80
40
0
20
60
Ustekinumab4 90 mg
76
51
100
80
40
0
20
60
Approved biologic therapies for plaque psoriasis PASI 75 and PASI 90 responses
1. Papp KA, et al. Br J Dermatol. 2005; 152:1304-12. 2. Reich K, et al. Lancet. 2005; 366:1367-1374. 3. Menter A, et al. J Am Acad Dermatol. 2008; 58:106-115. 4. Papp K, et al. Lancet. 2008;371:1675-84.
Note: Not head-to-head comparisons. PASI 75 PASI 90