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Biological Therapies for Psoriasis
Carle Paul,
Dermatology, Purpan Hospital, Toulouse
International Psoriasis Day, October 2006
"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
Local therapies: insufficient when psoriasis
covers more than 10% of the body surface
Patients' perception of therapy
78%
32%
0 10 20 30 40 50 60 70 80 90 100
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.
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)
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
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
Comparative efficacy of psoriasis treatments (% of patients with a 75% improvement of their PASI)
80
6860 60
49 4940
3430 29
21
0
10
20
30
40
50
60
70
80
90
Rem
icade
(5m
g/kg
)
CsA
(5m
g/kg
/d)
Met
hotre
xate
PUVA
CsA
(2.5
mg/
kg/d
)
Enbr
el25
mgx
2
UVB
TL01
Enbr
el25
mgx
2
Acitr
etin
e(5
0mg)
Rapt
iva(1
mg/
kg)
Alef
acep
t(IM
)
Week 10At Baseline
Improvement in depression score with psoriasis therapy (etanercept)
Tyring S et al. Lancet 2006: 379:29-35
Contraindications to biological agents
- Sensitivity to product
- Tuberculosis and other severe infections (septicaemia)
- Active infection
- Moderate or severe congestive heart failure (infliximab)
- Immunodeficiency
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
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
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
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 ≤ 5mmand
Normal chest x-ray
Begin anti-TNF
IDR > 5mm (BCG > 10 years)or calcification > 1 cm
Anti-TB therapy: INH + RIF 3 monthsor INH 9 months
Begin anti-TNF at least 3 weeks later
Risk of cancer and anti-TNF antibodies: probably similar to other immunosuppressants
Meta-analysis of PR clinical trials
All doses versus placebo
Low dosesversus placebo
High dosesversus placebo
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
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
Biological agents: Cost
Molecule
Dose Monthly 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
Raptiva 1 mg/kg/week 1087 Euros
Biological agents: Cost
Molecule
Dose Monthly cost Cost/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
Raptiva 1 mg/kg/week 1087 Euros 3623 Euros
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
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?
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)
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