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Challenges in Managing Psoriasis – Opinion on Biologic Therapies
antagonists are the monoclonal CD11a antibody efalizumab Figure 1: Disease Duration of Major Disorders
(Raptiva
®
, also approved by the FDA) and the lymphocyte function
antigen-3 (LFA-3)–immunoglobulin G (IgG)–Fc fusion protein alefacept
Type 1 diabetes
(Amevive
®
). They interfere with T-cell recruitment, activation and
expansion and may induce natural killer (NK)-cell-mediated T-cell
Cardiovascular
depletion (alefacept).
6,7
The TNF-α antagonists (all also FDA-approved) diseases
include the chimaeric monoclonal antibody infliximab (Remicade
®
),
Cancer
the human monoclonal antibody adalimumab (Humira
®
) and
Depression
etanercept (Enbrel
®
). Etanercept is a genetically engineered fusion
protein composed of a dimer of the extracellular portions of the Psoriasis
human TNF receptor (TNFR2) fused to the Fc portion of human IgG1.
Arthritis
TNF-α antagonists bind to TNF-α, rendering it functionally inactive and
blocking its pro-inflammatory effects.
5,8
While the bivalent antibodies
0 10 20304050607080
may bind two TNF-α trimers, etanercept binds only one TNF-α trimer.
Main age of disease onset (years)
Finally, the IL-12/IL23 p40 agonist ustekinumab (Stelara
®
) is a
monoclonal antibody that binds to the p40 protein subunit shared by
Psoriasis causes lifelong suffering and impairment.
both IL-12 and IL-23, which are cytokines with fundamental roles in
inflammation and immunity.
9
Another p40 antibody, ABT 874, is Figure 2: Induction of Remission in Clinical Trials of
currently being tested in clinical trials.
Biologic Agents
Treatment Challenges for Psoriasis Vulgaris
T-cell antagonist Cytokine antagonists
Since psoriasis requires lifelong treatment, therapeutic approaches 100 100 100
need to address various factors. They should:
80
80 80
68
80
67
• be able to induce remission;
60 60
57
49
60
42
• show long-term safety and efficacy;
37
a
tients (%) 40 40 40
• improve QoL;
P
27
21
• reduce or prevent co-morbidities;
20 20 20
4
• allow treatment according to needs; 0 0 0
• show safe responses to treatment discontinuation;
Efalizumab
a
Etanercept
b
Infliximab
c
Adalimumab
d
Ustekinumab
e
1mg/kg 50mg 5mg/kg 40mg/kg 45 mg/kg
• address different life phases and the need for flexibility during
‘life events’ such as infections, vaccination and surgery; and
PASI 75 PASI 90 TNF-
IL-12/IL-23
α antagonists
p40 antagonist
• be efficacious in treating and/or preventing PsA.
a. Leonardi, 2004;
11
b. Papp et al.,. 2005;
12
c. Reich et al., 2005;
13
d. Menter et al., 2008;
14
e. Leonardi et al., 2008;
9
f. EMEA.
26
This article aims to assess the extent to which biologic agents meet
Comparison of Psoriasis Area and Severity Index (PASI) 75 and PASI 90 responder rates in the
pivotal clinical studies for efalizumab,
f
etanercept,
b
infliximab
c
and adalimumab.
d
Infliximab =
these therapeutic challenges. week 10 data; efalizumab, etanercept, adalimumab and ustekinumab = week 12 data.
IL = interleukin; TNF = tumour necrosis factor.
Assessment of Biologic Agents in Terms of
Meeting Treatment Challenges syndrome, neurological disorders, demyelinating disease,
Induction of Remission hepatotoxicity and haematological changes; TB used to be a risk,
Therapeutic outcomes in psoriasis are defined according to the but screening prior to treatment has almost eliminated this. It
Psoriasis Area and Severity Index (PASI). Typically, a good clinical should be noted that most safety data on TNF-α antagonists refer
response is defined as PASI 75, i.e. an improvement of 75% within to their use in rheumatoid arthritis (RA) and Crohn’s disease, and
10–24 weeks.
10
Key clinical trials involving the major biologics showed further investigation is needed for their use in psoriasis.
16,17
Biologic
PASI 75 rates ranging from 27 to 80% and PASI 90 rates from 4 to 57% therapies should not be used in pregnancy: infliximab, adalimumab
of patients. The highest rates were achieved with infliximab; and entanercept are pregnancy category B, while efalizumab is
adalimumab and ustekinumab had slightly lower rates; depending on pregnancy category C.
16
the dose, etanercept achieved a PASI 75 rate between 38 and 50% at
week 24; and efalizumab had the lowest rate (see Figure 2).
9,11–14
More A meta-analysis evaluating and comparing the efficacy and safety of
recent data for etanercept show that, depending on dosing, up to 71% biological agents in psoriasis treatment evaluated safety by the
of patients may achieve PASI 75 with etanercept over 24 weeks.
15
incidence of one or more adverse event (AE) and serious AE (SAE)
during 10–30 weeks of treatment. The safety data revealed an
Long-term Safety and Efficacy increased risk of AEs for efalizumab and infliximab (see Table 1).
18
Safety Infliximab may lead to infusion reactions during and after infusion.
Given the long duration of psoriasis treatment, safety and long-term These reactions occur in 3–22% of patients with psoriasis treated
efficacy are vital when assessing treatment options. The greatest with infliximab. Most of these reactions are mild or moderate, and
amount of clinical data is available for TNF-α antagonists, which only a few are severe.
19
have been used for over 12 years in different indications on more
than 1.5 million patients. The following safety issues are associated Since TNF-α plays a crucial role in the inflammatory response, which
with treatment: infection, tuberculosis (TB), lymphoma, lupus-like helps provide protection from infectious organisms, there is a risk
EUROPEAN DERMATOLOGY 3
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