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)