DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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Epidermis
Non-lesional skin
Antigen APC Re-activation
Lesional psoriatic skin
Cytokine secretion
Lymphocytic
infiltrate
Migration
through afferent
lymphatics
Cytokine
secretion
Clonal expansion
Keratinocyte
activation
Migration
Chemokine
secretion
Epidermis
Dermis
Antigen
presentation
CD45RA +
CLA – Lymph node
CD45RO +
CLA +
CD45RO +
CLA +
Blood
Dermis
SECTION IX
Figure 65–4. Immunopathogenesis of psoriasis. Psoriasis is a prototypical inflammatory skin disorder in which specific T-cell populations
are stimulated by as-yet undefined antigen(s) presented by antigen-presenting cells. The T cells release pro-inflammatory
cytokines, such as tumor necrosis factor- (TNF-) and interferon- (IFN-), that induce keratinocyte and endothelial cell proliferation.
APC, antigen-presenting cell; CLA, cutaneous lymphocyte-associated antigen.
SPECIAL SYSTEMS PHARMACOLOGY
and serum of patients with active psoriasis. This
cytokine is central to the T H
1 response in active psoriasis,
inducing further inflammatory cytokines, upregulating
intracellular adhesion molecules, inhibiting
EFALIZUMAB
ICAM-1 LF3A
ALEFACEPT
CD80/CD86
LFA1
CD2 CD28CD4
T cell
TCR
CD3
Langerhans cell
MHC
Ag
CD45RO +
Figure 65–5. Mechanisms of action of selected biological agents
in psoriasis. Newer biological agents can interfere with one or
more steps in the pathogenesis of psoriasis, resulting in clinical
improvement. See text for details. ICAM-1, intercellular adhesion
molecule 1; LFA, lymphocyte function–associated antigen; MHC,
major histocompatibility complex; TCR, T-cell receptor.
apoptosis of keratinocytes, and inducing keratinocyte
proliferation. Therefore, blockade of TNF- with biologicals
reduces inflammation, decreases keratinocyte
proliferation, and decreases vascular adhesion, resulting
in improvement in psoriatic lesions (Richardson and
Gelfand, 2008).
Because TNF- inhibitors alter immune responses,
patients on all anti-TNF- agents are at increased risk for
serious infection. They also are theoretically at increased
risk for malignancies, because TNF is involved in normal
innate immunity and natural killer cell–mediated destruction
of tumor cells (Tzu and Kerdel, 2008). Other adverse
events related to TNF- inhibitors include exacerbation of
congestive heart failure and demyelinating disease in predisposed
patients (Menter and Griffiths, 2007). Therefore,
all patients should be screened for tuberculosis, personal
or family history of demyelinating disorder, cardiac failure,
active infection, or malignancy prior to starting anti-
TNF- therapy.
Etanercept. Etanercept (ENBREL) is a soluble, recombinant,
fully human TNF receptor fusion protein consisting
of two molecules of the ligand-binding portion of the
TNF receptor (p75) fused to the Fc portion of IgG 1
.
Etanercept binds soluble and membrane-bound TNF,
thereby inhibiting the action of TNF (Krueger and Callis,
2004). There are several case series and a large randomized
controlled study supporting the safety and efficacy
of etanercept at 0.4 mg/kg twice weekly in pediatric psoriasis
(Sukhatme and Gottlieb, 2009). Etanercept use is
associated with an increased risk of infections (bacterial