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Psoriasis
Michael P. Schön, M.D., and W.-Henning Boehncke, M.D.
p
soriasis, a common inflammatory skin disorder, has received
attention as a target for new pathogenesis-oriented biologic therapies. In this
article, we review the genetic, clinical, and pathogenic aspects of psoriasis and
discuss their implications for new therapies.
epidemiologic and genetic features
Though psoriasis is a common skin disease, its definition by Ferdinand von Hebra as a
distinct entity dates back only to the year 1841, and estimates of its prevalence —
around 2 percent, according to standard textbooks — stem from only a few population-based studies. Perhaps the most comprehensive field study was performed in the
Faroe Islands, where 2.8 percent of the inhabitants were reported to be affected.1 This
prevalence rate is higher than that in central Europe, where prevalence is approximately 1.5 percent, according to a more recent analysis.2 Ethnic factors also appear to influence the prevalence of psoriasis, which ranges from no cases in the Samoan population to 12 percent in Arctic Kasach’ye.2 The influence of ethnic factors is particularly
evident when one compares prevalence rates within the United States. The prevalence
among blacks (0.45 to 0.7 percent)3 is far lower than that in the remainder of the U.S.
population (1.4 to 4.6 percent).4
Numerous family studies have provided compelling evidence of a genetic predisposition to psoriasis, although the inheritance pattern is still unclear.5 The illness develops in as many as half of the siblings of persons with psoriasis when both parents are
affected, but prevalence falls to 16 percent when only one parent has psoriasis and to
8 percent when neither parent is affected.6 The concordance rate for monozygotic
twins is around 70 percent, as compared with some 20 percent for dizygotic twins, a
finding that further supports the concept of genetic predisposition.7,8 As many as 71
percent of patients with childhood psoriasis have a positive family history.9
Within the past decade, several putative loci for genetic susceptibility to the disease
have been reported on the basis of genome-wide linkage studies, but there has not
been widespread replication of the results — a problem that has also been encountered
in the investigation of other complex diseases.10,11 However, one locus in the majorhistocompatibility-complex (MHC) region on chromosome 6 has been replicated in
several populations12,13 (see Glossary for definitions of terms). This locus, termed
psoriasis susceptibility 1 (PSORS1), is considered the most important susceptibility locus. On the basis of association studies of three tightly linked susceptibility alleles
(HLA-Cw6,14 HCR*WWCC,15 and the HLA-associated S gene16), PSORS1 appears to be
associated with up to 50 percent of cases of psoriasis. Other susceptibility loci are located on chromosomes 17q25 (PSORS2),17 4q34 (PSORS3),18 1q (PSORS4),19 3q21
(PSORS5),20 19p13 (PSORS6),21 and 1p (PSORS7).22 Most recently, an additional gene
locus for psoriasis susceptibility has been discovered on chromosome 17q25.23 This
locus, a runt-related transcription factor 1 (RUNX1) binding-site variant, encodes for a
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From the Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, and the Department of Dermatology,
University of Würzburg, Würzburg (M.P.S.);
and the Department of Dermatology, University of Frankfurt, Frankfurt (W.-H.B.) —
both in Germany. Address reprint requests to Dr. Schön at the Rudolf Virchow
Center, DFG Research Center for Experimental Biomedicine and Department of
Dermatology, Julius Maximilians University, Versbacher Str. 9, 97078 Würzburg,
Germany, or at michael.schoen@virchow.
uni-wuerzburg.de.
N Engl J Med 2005;352:1899-912.
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Glossary
CC chemokines: A subfamily of small chemoattractant peptides that have two
N-terminal cysteine residues adjacent to each other.
Cutaneous lymphocyte-associated antigen (CLA): A selectin ligand bearing the
sialyl-Lewis X carbohydrate moiety; expressed preferentially by skin-homing lymphocytes.
CXC chemokines: A subgroup of leukocyte-attracting chemokines with a different amino acid between the two N-terminal cysteine residues.
Intercellular adhesion molecule 1 (ICAM-1): Also known as CD54, an adhesion
molecule of the immunoglobulin superfamily functioning as a counterreceptor for adhesion molecules of the integrin family; expressed on endothelial cells and some activated epithelial cells.
Interferon-g: A cytokine produced primarily by T lymphocytes, characteristic
for immune responses dominated by type 1 helper T (Th1) cells, including
psoriasis.
Leukocyte-function–associated antigen (LFA): CD11a–CD18, a heterodimeric
adhesion molecule of the integrin family expressed by lymphocytes; binds
to ICAM-1, ICAM-2, and ICAM-3.
Major-histocompatibility-complex (MHC) molecules: Surface molecules important for antigen presentation to T lymphocytes.
PSORS: Psoriasis-susceptibility locus, one of several genomic sequences associated with psoriasis.
SCID mice: Mice with severe combined immunodeficiency due to a spontaneous mutation and lacking functional B and T lymphocytes; used for transplantation and immunologic transfer studies.
Transforming growth factor a (TGF-a): A cytokine involved in some tissue alterations in psoriatic skin.
Vascular cell adhesion molecule 1: Also known as CD106; a vascular adhesion
molecule of the immunoglobulin superfamily, a counterreceptor for the
a4b1 integrin.
Vascular endothelial growth factor (VEGF): A key regulator of angiogenesis,
overexpressed in psoriatic skin.
gene involved in the development of blood cells,
including those of the immune system.
clinical and
histopathological features
People with psoriasis typically have sharply demarcated chronic erythematous plaques covered by silvery white scales, which most commonly appear
on the elbows, knees, scalp, umbilicus, and lumbar area (Fig. 1A to 1D). An inverse type of psoriasis
spares these sites and instead appears in intertriginous areas, where scaling is minimal (Fig. 1E).
Eruptive guttate psoriasis, which may be the initial
manifestation of the disease and is often preceded
by streptococcal infection by two to three weeks,24
exhibits small, disseminated erythematosquamous
papules and plaques (Fig. 1B). Psoriatic diaper rash
appears to be the most common type of psoriasis
in children under the age of two years.9
In addition to small pustules that may occur in
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Figure 1 (facing page). Clinical Features of Psoriasis.
The typical psoriatic lesion is a sharply demarcated
erythematous plaque covered by silvery white scales, often appearing on the elbow (Panel A). Initial eruptions of
psoriasis may exhibit a guttate distribution pattern and
are often triggered by streptococcal infections (Panel B).
In a dark-skinned patient, erythrodermic psoriasis (Panel
C), a clinical subtype of the disease, affects the entire
body surface. Psoriatic erythroderma may arise from any
type of psoriasis. Scalp involvement is seen in approximately 50 percent of patients with psoriasis, and the lesions typically extend a short distance beyond the region
covered by terminal hair (Panel D). Inverse psoriasis
(Panel E) is located at intertriginous areas and usually
shows only scant scaling. In patients with psoriasis vulgaris, small sterile pustules may develop (Panel F, which
is a magnification of the periumbilical region from Panel
B). Generalized pustular psoriasis may start from coalescing disseminated pustules on deeply erythematous
skin (Panel G). Localized forms of psoriasis include acrodermatitis continua suppurativa, or Hallopeau’s disease
(Panel H, which shows the fingers of a patient with severe onychodystrophy). Approximately 5 to 20 percent of
patients with psoriasis have psoriatic arthritis (Panel I).
Nail involvement is frequent in patients with psoriasis,
and mild cases are characterized by small pits and yellowish discoloration of the nail plate (Panel J). Psoriatic
nail pits were recreated in a wax-model moulage manufactured approximately 100 years ago (Panel K, which is
item 1766 from the collection of the Johann Wolfgang
Goethe University, Frankfurt, Germany).
lesions of psoriasis vulgaris, various forms of pustular psoriasis have been described (Fig. 1F). Generalized pustular psoriasis (Fig. 1G) is characterized
by disseminated deep-red erythematous areas and
pustules, which may merge to extensive lakes of pus.
In contrast, there are two localized variants termed
palmoplantar pustulosis and acrodermatitis continua suppurativa (Fig. 1H, depicting onychodystrophy in the latter condition). Despite its wider
clinical spectrum, pustular psoriasis is quite rare as
compared with nonpustular forms. Both pustular
and the more common vulgar forms may progress
to psoriatic erythroderma affecting the entire body
surface (Fig. 1C).
Psoriatic arthritis is an extracutaneous manifestation that affects at least 5 percent and perhaps as
many as 20 percent of patients with psoriasis (Fig.
1I).25,26 The nails are affected in the majority of patients with psoriatic arthritis, but nail involvement
can be seen in all types of psoriasis. The fingernails
are more frequently affected than are toenails (on
average, in 50 percent of patients as compared with
35 percent), and lesions range from pits and yel-
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A
B
C
D
F
I
E
H
G
J
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lowish discoloration (Fig. 1J and 1K) to severe onychodystrophy, a typical complication of acrodermatitis continua suppurativa (Fig. 1H).25,26
For many patients, the symptoms of psoriasis
improve in the summer and worsen in the winter, reflecting the well-established notion that the course
of the disease is influenced by various environmental factors. Physical trauma may trigger psoriatic lesions at sites of injury (Koebner’s phenomenon),
possibly through the release of proinflammatory cytokines, the unmasking of autoantigens, or both.27
In fact, some treatments for psoriasis that have
proinflammatory potential (e.g., anthralin and phototherapy) appear to trigger psoriasis if applied too
aggressively — for example, in high initial doses.
Molecular mechanisms underlying drug-induced
flares of psoriasis are incompletely understood.
Mechanisms for certain medications are partially
delineated. For example, beta-adrenergic blockers
may induce epidermal hyperproliferation associated with a decrease of intraepidermal cyclic AMP;
lithium may elevate proinflammatory cytokines,
thereby stimulating cutaneous leukocyte recruitment; and chloroquine blocks epidermal transglutaminase, an enzyme that is pivotally involved
in the terminal differentiation of keratinocytes.28
Infections, particularly streptococcal infections
of the upper respiratory tract, have long been recognized as triggers of psoriasis.24 In addition, exacerbation or even initial manifestation of psoriasis has been observed in patients infected with the
human immunodeficiency virus (HIV). However,
because of clinical similarities, psoriasis in patients
with HIV infection may be misinterpreted as seborrheic eczema.29
Psoriatic skin exhibits pathological changes in
most, if not all, cutaneous cell types. The typical
erythematosquamous plaque contains histopathological hallmark features that include hyperproliferation of epidermal keratinocytes and hyperkeratosis, as well as infiltration of immunocytes along
with angiogenesis, with resultant typical thickening and scaling of the erythematous skin. Mitotic
activity of basal keratinocytes is increased by as
much as a factor of 50 in psoriatic skin, so keratinocytes need only 3 to 5 days in order to move from
the basal layer to the cornified layer (instead of the
normal 28 to 30 days). This dramatically shortened
maturation time is accompanied by altered differentiation, reflected by the focal absence of the granular layer of the epidermis and parakeratosis, or
nuclei still present in the thickened cornified layer
(Fig. 2A through 2D).
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Figure 2 (facing page). Complex Pathological Tissue
Alterations in Psoriatic Skin.
As compared with normal skin (Panel A), the epidermis
in psoriatic skin (Panel B) is characterized by dramatic
histopathological alterations, including profound acanthosis (thickening of the viable cell layers) with elongation of epidermal rete ridges (arrowheads), marked
hyperkeratosis (thickening of the cornified layer), loss of
the granular layer, and parakeratosis (nuclei in the stratum corneum). In addition, dermal blood vessels are increased in number and size (by both angiogenesis and
dilatation); they are contorted and reach up to locations
directly underneath the epidermis (arrows). Finally, a
mixed leukocytic infiltrate is seen in both dermis and epidermis. As a histopathological hallmark of psoriatic lesions, neutrophilic granulocytes transmigrate through
the epidermis (Panel C, arrow) and form the telltale
Munro microabscesses underneath the stratum corneum (Panel C, arrowhead). As the lesions progress, these
microabscesses are transported to the upper layers of
the stratum corneum, where they slough off (Panel D, arrow). (Panels A through D show staining with hematoxylin and eosin.) Focal expression of intercellular adhesion
molecule 1 (ICAM-1) in psoriatic epidermis (Panel E) indicates the activation of keratinocytes. Immunostaining
of CD3, a T-cell receptor–associated antigen, shows that
abundant T lymphocytes are present in psoriatic skin
within both the dermis and the epidermis (Panel F). The
integrin aE(CD103)b7, an adhesion receptor that binds
to epidermal E-cadherin, is expressed almost exclusively
by intraepidermal T cells (Panel G). (Panels E through G
are highlighted with an immunoperoxidase stain.) It is
thought that ICAM-1, the aE(CD103)b7 integrin, and other adhesion receptors contribute to the recruitment of
pathogenic lymphocytes to psoriatic skin.
Psoriatic epidermis demonstrates aberrant expression of antigens associated with hyperproliferation, such as the heterodimer keratin 6–keratin 16
and heat-shock proteins. In addition, induced expression of MHC class II antigens and intercellular
adhesion molecule 1 (ICAM-1) is observed.4,30
These molecules are involved in interactions with
lymphocytes such as adhesion or antigen recognition (Fig. 2E). Moreover, vascular endothelial cells
are primed to take part in angiogenesis in psoriasis, and blood vessels that are associated with psoriatic lesions become dilated and contorted, reaching directly beneath the epidermis in the dermal
papillar regions (Fig. 2B). The involved vascular endothelial cells express increased levels of ICAM-1
(CD54), E-selectin (CD62E), vascular-cell adhesion
molecule 1 (CD106), and MHC class II antigens,
indicating activation.31 Then a mixed inflammatory infiltrate that contains activated CD3+ T lymphocytes within both the dermis and epidermis is
evident (Fig. 2F),32 within which CD4+ T cells are
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B
D
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distributed randomly. In contrast, the majority of
CD8+ T cells, some of which express epithelial-specific adhesion receptors (Fig. 2G),33 reside preferentially within the epidermis.34
Many T cells within psoriatic skin exhibit an acn engl j med 352;18
tivated phenotype characterized by increased expression of costimulatory molecules such as CD2,
adhesion molecules including leukocyte-function–associated antigen 1 (LFA-1) and cutaneous
lymphocyte-associated antigen (CLA), or the high-
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affinity interleukin-2 receptor. Neutrophils localize
to the dermis, migrate focally into the epidermis,
and form Munro microabscesses, which become
translocated upward within the epidermal stratum
corneum (Fig. 2C and 2D).35 In addition, psoriatic
skin contains an increased number of dermal mast
cells and dendritic cells.36
immunopathogenesis
Psoriasis is an instructive model for studying interactions of immigrating immunocytes with resident
epithelial and mesenchymal cells. This disease vividly highlights the pathogenic importance of T cells
and simultaneously illustrates how advances in our
understanding of molecular immune mechanisms
can be translated into innovative therapies.
Although many factors that contribute to the
generation of psoriatic lesions remain obscure,
compelling circumstantial and experimental evidence suggests a primary T-lymphocyte–based immunopathogenesis (Fig. 3).30 The response of psoriasis to treatment with compounds that act on
lymphocytes, such as cyclosporine, first described
for use in psoriasis in 1979, is an early example.38
More recently, other compounds specifically targeting T-cell functions were found to alleviate psoriasis. These include interleukin-2 fused to truncated
diphtheria toxin (DAB389IL-2)39 and antibodies directed against CD2,40 CD11a,41,42 or, in some cases, CD4.43,44 In addition, there is a possible linkage
of the psoriasis-susceptibility gene PSORS2 with a
gene involved in the regulation of interleukin-2.17
Furthermore, psoriasis may not recur after bone
marrow transplantation (performed in order to treat
disorders unrelated to psoriasis) from healthy
donors45 or may develop for the first time after bone
marrow transplantation from a donor with psoriasis.46 The aforementioned association of psoriasis
with certain MHC alleles — such as HLA-B13,
HLA-B17, HLA-Bw57, and HLA-Cw6 — also suggests a pathogenic role of T cells.4 Indeed, some
investigators have reported that there is a restricted
use of T-cell receptor variable genes within psoriatic lesions, a finding that implies antigen-specific
T-cell responses.47 Although the pathogenic relevance of this oligoclonal T-cell expansion is not entirely clear,48 it is possible that the failure to demonstrate oligoclonality in some cases of psoriasis
is due, at least in part, to the colonization of psoriatic lesions by bacteria that produce superantigen,
triggering the T-cell receptor without using the var-
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Figure 3 (facing page). Putative T-Cell Responses
in the Pathogenesis of a Psoriatic Lesion.
To generate a cutaneous T-cell response, antigen-presenting cells (Langerhans’ cells in the epidermis) take up and
process autoantigens and migrate to the regional lymph
nodes. There, they come in contact with naive T lymphocytes (CD45RA+). Within an immunologic synapse (inset), molecular interactions result in T-cell activation.37
According to the putative theory, antigen-presenting cells
present processed antigen bound to major-histocompatibility-complex (MHC) molecules to the T-cell receptor
(TCR). MHC class II molecules present antigen to CD4+
T cells, whereas MHC class I molecules present antigen to
CD8+ T cells. Additional signals are transmitted through
interactions of costimulatory molecules with their ligands
such as CD2 with CD58, CD28 with either CD80 or CD86,
or both. In addition, adhesive interactions (e.g., by integrins and their immunoglobulin superfamily ligands)
also stabilize the immunologic synapse and transmit additional signals. Following the activating signals, T cells
differentiate into CD45RO+ memory T cells and express
skin-homing receptor cutaneous lymphocyte-associated
antigen (CLA). Once activated, T cells (CD45RO+ and
CLA+) reenter the circulation and preferentially extravasate at sites of cutaneous inflammation. In the skin, on
encountering the respective antigen, T cells exert their effector functions, which include the secretion of proinflammatory cytokines. Psoriasis is characterized by a chronically
persisting response in effector T cells. ICAM-1 denotes intercellular adhesion molecule 1.
iable antigen-recognition sites.49 The permissive
role of bacterial superantigens in the pathogenesis of psoriasis is well established.49 In addition, sequence similarities between streptococcal M peptides and human keratins, such as keratin 17, led to
the hypothesis that keratinocyte proteins function
as autoantigens in psoriasis.50
The generation of psoriasis-like skin lesions
has been described in animal models, by a process
based on T-cell dysregulation without prior epithelial abnormalities.51,52 In addition, the role of
T lymphocytes as key effector cells is strongly supported by work from various groups in xenotransplantation models. Injection of activated T lymphocytes from patients with psoriasis into unaffected
skin transplanted from the same patients onto SCID
(severe combined immunodeficiency) mice resulted in the generation of psoriatic lesions in the animals.53-55 Although additional rodent models support the prominent role of T lymphocytes, it is also
clear that these T lymphocytes can trigger the disease only in a susceptible environment, since these
results are obtained with skin from psoriatic, but
not from healthy, donors.56
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Psoriatic plaque
Release of chemokines
and cytokines
Lymphocyte
Neutrophils
Uninvolved skin
Epidermis
Macrophages
Dermis
Migration to
lymph nodes
Proliferation of
lymphocytes
Activation of
lymphocytes
CD80
Putative antigen
or
presented by
CD86
MHC
MHC
CD3
CD58
Recirculation of lymphocytes
ICAM-1
LFA-1
CD4
CD2
TCR
CD28
T cell
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cytokines, chemokines,
and adhesion molecules
Psoriasis may serve as a model of a disease that
clearly shows the central role of cytokines and chemokines and the functional interaction of these
proteins with adhesion molecules in the recruitment of tissue-specific lymphocytes.57,58 Cytokine
dysregulation may explain, at least in part, the complex tissue alterations in psoriasis (Fig. 4). Proinflammatory cytokines59-62 induce the expression of
adhesion molecules on endothelial cells and keratinocytes, allowing them to interact with leukocytes.
This results in leukocyte extravasation at the site of
inflammation, along with migration through the
cutaneous matrix toward the epidermis.63,64 Numerous studies have identified tumor necrosis factor a (TNF-a) as a particularly relevant cytokine
regulating this complex inflammatory cascade.
Its key role is underlined by the therapeutic efficacy of compounds that interfere with TNF-a functions.41,65,66 Psoriatic skin is further characterized
by increased angioneogenesis in a milieu rich in
proangiogenic factors.31,67 Complementary to the
up-regulation of proinflammatory cytokines, reduced levels of the antiinflammatory cytokine interleukin-10, along with the relative dominance of
type 1 helper T (Th1) cytokines, such as interferon-g
and interleukin-2, add to a milieu with mediator
imbalance.68-70 The exact mechanisms by which
these cytokines regulate the microenvironment that
influences psoriasis need further clarification.
Recent evidence strongly suggests that chemokines are pivotal for the trafficking and compartmentalization of leukocytes in the psoriatic disease
process (Fig. 4).58,71 The effector-T-cell population that is putatively the most relevant in psoriasis is characterized by the expression of skin-homing receptor CLA and the CC chemokine receptor 4
(CCR4).72 Other chemokines that are implicated
in the recruitment of T cells into psoriatic plaques
include CCL20 (macrophage inflammatory protein
3a, or MIP-3a),58 CCL27 (cutaneous T-cell–attracting chemokine, or CTACK),71 monokine induced
by interferon-g (MIG),73 or RANTES (regulated on
activation, normal T-cell expressed and secreted),
and monocyte chemotactic protein 1 (MCP-1).
It is thought that neutrophils, another leukocyte
population abundantly present in psoriatic infiltrates, are recruited by the neutrophil-attracting
chemokine interleukin-8 (CXCL8). However, this
pathway is probably not the exclusive means of
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Figure 4 (facing page). The Cytokine and Chemokine
Network.
The transition from normal skin to the full-fledged psoriatic lesion is orchestrated by complex interactions of various cytokines and chemokines. Proinflammatory
cytokines are thought to account for many of the histopathological changes seen in psoriatic skin. For example,
interferon-g and tumor necrosis factor a (TNF-a) can
stimulate the expression of major-histocompatibilitycomplex (MHC) class II molecules and intercellular adhesion molecule 1 (ICAM-1). Vascular endothelial
growth factor (VEGF) and TNF-a stimulate angiogenesis. At the same time, interleukin-1 activates mast cells,
granulocyte–macrophage colony-stimulating factor
(GM-CSF) activates neutrophils, nerve growth factor
(NGF) stimulates the growth of cutaneous nerves, and
interleukin-6 and transforming growth factor a (TGF-a)
promote keratinocyte proliferation. TNF-a, in particular,
appears to affect the functions of many different cell
types in psoriatic skin. Thymus- and activation-regulated
chemokine (TARC) and macrophage-derived chemokine
(MDC) are expressed by the cutaneous vasculature and
contribute to the recruitment of CCR4+ T cells. Cutaneous T-cell–attracting chemokine (CTACK) contributes to
epidermal recruitment of T cells expressing its receptor,
CCR10. In addition, macrophage inflammatory protein
3a (MIP-3a) colocalizes in psoriatic epidermis with epidermal T cells expressing its receptor, CCR6, and can be
induced on keratinocytes by proinflammatory cytokines,
such as TNF-a. Another T-cell–attracting chemokine,
monokine induced by interferon-g (MIG), is expressed
by endothelial cells and macrophages directly underneath the hyperplastic psoriatic epidermis. Since MIG
can be induced by T-cell–derived interferon-g, there is
a microenvironmental T-cell–associated inflammationboosting loop. This process may be augmented by
RANTES (regulated on activation, normal T-cell expressed and secreted) and monocyte chemotactic protein 1 (MCP-1), both of which also attract mast cells to
psoriatic skin. Within psoriatic scales, there is a high
content of interleukin-8 and growth-related cytokine a
(GRO-a), both of which are neutrophil-attracting chemokines that contribute to the formation of Munro microabscesses, a hallmark of psoriatic epidermis. Keratinocyte
hyperproliferation in psoriatic skin also appears to be induced, at least in part, by interleukin-8 and GRO-a.
neutrophil recruitment, since an interleukin-8–
blocking monoclonal antibody had only modest efficacy in a clinical study.74
In addition to the mediators involved in leukocyte
recruitment and activation, substances such as neuropeptides appear to be involved in the pathogenesis of psoriasis. These include substance P and nerve
growth factor, along with its receptor, the p75 neurotrophin receptor, and tyrosine kinase A.75,76
That neuropathogenic mechanisms contribute to
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Neutrophils
Increased proliferation
and turnover of
keratinocytes
Keratinocytes
T lymphocytes
Macrophage
TARC
MDC
MCP-1
RANTES
Interleukin-8
GRO-a
Interleukin-1
Cutaneous
nerve
VEGF
GM-CSF
MIP-3a
MCP-1
RANTES
Mast cell
Interleukin-6
TGF-a
Interferon-g
Endothelial
cell
a
MIG
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the development of psoriasis is further suggested
by the increase in terminal cutaneous nerves within
psoriatic lesions. Finally, clinical observations, such
as the symmetric distribution pattern of psoriatic
lesions and the resolution of psoriasis at sites of administration of local anesthesia, are currently interpreted as evidence of the intimate involvement of the
nervous system in the pathogenesis of psoriasis.
As in other inflammatory disorders, leukocyte recruitment to psoriatic skin occurs in consecutive
steps mediated by complex interactions of cytokines, chemokines, and adhesion receptors.77,78
Although psoriasis-specific steps have not been
identified, this disease has served as a model for indepth investigations of several adhesion-molecule
interactions that are of general importance in the
generation of inflammatory reactions.41,42
The first step of leukocyte recruitment is the transition from free flow in the vascular lumen to a rolling motion along the endothelium of the vessel wall,
mediated primarily by a family of adhesion molecules called selectins.77-80 Activated endothelial
cells express P-selectin (CD62P) and E-selectin
(CD62E).81 The pivotal role of selectins in leukocyte rolling has been confirmed in many experimental approaches that interfere with their adhesive interactions.81 Selectin functions overlap to a
considerable extent, as can be concluded from the
efficacy of selectin-blocking strategies. A monoclonal antibody that was specifically directed against
E-selectin failed to alleviate psoriasis in a recent clinical trial, whereas less selective compounds, such
as efomycine M, which inhibits both E-selectin and
P-selectin, showed significant anti-psoriatic efficacy in animal models.82,83
Endothelial cells express E-selectin, which can
interact with specific ligands expressed by T cells.
These ligands are transmembrane glycoproteins
bearing a special carbohydrate moiety, called sialylLewisX, displayed on cell-surface proteins.81 T lymphocytes localizing to the skin express the sialylLewisX –bearing CLA,84 which is thought to confer
the tissue selectivity of these cells, at least in part.85
Once rolling leukocytes are subject to activation
by chemokines, they attach firmly to the endothelium through the interactions between b2 integrins
(e.g., LFA-1, or aL b 2 integrin) and adhesion molecules of the immunoglobulin superfamily, such as
ICAM-1 (CD54). Additional interactions occur between b1 integrins and their ligands, such as a4b1
integrin and vascular-cell adhesion molecule 1.
The importance of LFA-1 in T-cell recruitment into
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the skin is highlighted by the antipsoriatic efficacy
of efalizumab, a new monoclonal antibody directed against LFA-1.41,42
In contrast to the relatively well understood process of lymphocyte extravasation, little is known
about the subsequent migration through the cutaneous extracellular matrix and the processes determining the ultimate localization and arrest of lymphocytes within the epidermal compartment. The
epidermis of psoriatic skin is characterized by induced expression of ICAM-1 (Fig. 2E).63,86 ICAM-1,
induced by proinflammatory cytokines, enables activated lymphocytes to attach through their surface
molecules, such as LFA-1.42 In addition, other adhesion molecules may contribute to epidermal T-cell
localization.78 For example, the aE(CD103)b7 integrin (Fig. 2G), which binds to epidermal E-cadherin,87 has been implicated in epidermal recruitment of CD8+ T cells in psoriatic lesions.33,88
However, it is also possible that lymphocytes are
transported passively to the upper epidermal layers
owing to the accelerated upward migration of keratinocytes in psoriasis. Overall, given the central
role of T lymphocytes in the pathogenesis of psoriasis, agents that would influence the function or
recruitment of leukocytes are appealing therapeutic compounds.89,90
therapy
Most accepted treatments for psoriasis have been
developed empirically or were found by chance.
However, recent insights into the immunopathogenesis of psoriasis have further elucidated the
mode of action of some accepted compounds91,92
and have provided new treatment strategies.93,94
The severity of the disease usually determines the
therapeutic approach. Approximately 70 to 80 percent of all patients with psoriasis can be treated adequately with use of topical therapy. Mainly for
practical reasons, the vitamin D3 analogues (calcipotriol and tacalcitol) and the topical retinoid tazarotene — all of which affect keratinocyte functions and the immune response — are in wider use
than is either anthralin or coal tar. Since most of
the compounds that have been mentioned may irritate delicate areas of skin, topical corticosteroids
are used in combination with those compounds,
particularly in intertriginous areas.
In cases of moderate-to-severe psoriasis (e.g.,
affecting large surface areas), the use of phototherapy, systemic drugs, or both must be considered.
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Among the established regimens, various therapeutic methods may have distinct modes of action. For
example, fumarates and cyclosporine are primarily
immunosuppressive agents, whereas retinoids and
methotrexate also target keratinocyte functions. Rational combination treatments target inflammation
as well as epidermal alterations and may provide improved efficacy and safety. Thus, combinations of
topical vitamin D3 analogues with phototherapy or
systemic retinoids plus psoralen and ultraviolet A
phototherapy (RePUVA) are well-established treatment regimens for psoriasis.
Psoriasis in children, in pregnant women, or in
patients with the acquired immunodeficiency syndrome may provide considerable therapeutic challenges, arguably best handled by consultation with
a specialist. Likewise, severe nail involvement or
pustular psoriasis should be the province of the
specialist.
Although most established treatment regimens
are reasonably effective as short-term therapy for
psoriasis, extended disease control is difficult to
achieve because the safety profile of most therapeutic agents limits their long-term use.95 Another unmet medical need is for agents that can be applied
easily, since application of various currently available agents is difficult and thus compliance may be
problematic. More convenient preparations improve
adherence to recommended regimens.96 Patients
with severe psoriasis often become frustrated with
the management of their disease and the perceived
ineffectiveness of the therapies prescribed.97 Studies have indicated that the impairment of the quality of life caused by psoriasis equals or even exceeds
that due to other major illnesses such as diabetes,
rheumatoid arthritis, and cancer.4,98
As already noted, recent advances in psoriasis
research have provided a sound platform for the rational design of new biologic agents and biologicimmune-response modifiers that specifically target
key mechanisms of the pathogenesis of psoriasis.41
Three of these agents — alefacept, efalizumab, and
etanercept — are currently approved by the Food
and Drug Administration (FDA) for the treatment of
psoriasis; several others (e.g., infliximab) are in the
final phase of clinical development. The most promising compounds are monoclonal antibodies, cytokines, and fusion proteins. Three fundamental
modes of action are being explored: decreasing the
number of pathogenic T cells, blocking T-cell migration and adhesion, and antagonizing effector
cytokines (Fig. 5).
n engl j med 352;18
A
Inhibition of
T-cell activation
Antigenpresenting
cell
B
T cell
TCR/CD3
CD4
Adhesion molecules
Release of chemokines
TNF-a
Th2
Th1
Th2
Figure 5. New Pathogenesis-Oriented Therapeutic
Principles.
Five general therapeutic principles target the key pathogenic mechanisms of psoriasis. The first involves inhibition of T-cell activation through inhibition of molecules
involved in the formation of the immunologic synapse
(Panel A). The second principle is depletion of pathogenic
T cells (Panel B). This has been achieved by targeting molecules expressed specifically by activated T cells, such as
the high-affinity interleukin-2 receptor or CD4. The third
approach involves inhibition of leukocyte recruitment to
the inflamed skin — for example, by inhibiting key adhesion molecules such as selectins or certain integrins (Panel C). A prominent example is the use of efalizumab, a
monoclonal antibody that interferes with adhesion mediated by leukocyte-function–associated antigen 1 (LFA-1).
The fourth principle is functional inhibition of key inflammatory cytokines (Panel D). Perhaps the most important
example is tumor necrosis factor a (TNF-a), the functions
of which are targeted by several biologic agents, the
monoclonal antibodies infliximab and adalimumab, and
the fusion proteins etanercept and onercept. Finally, it is
possible to induce an immune deviation to shift the cytokine milieu dominated by type 1 helper T (Th1) cells to a
milieu weighted with type 2 helper T (Th2) cells, thus alleviating psoriasis. This has been demonstrated in principle
for interleukin-10 and interleukin-4 (Panel E).
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1909
The
new england journal
As demonstrated by antibody-mediated targeting of CD4 on helper T cells43,44,99 or by targeting
of the T-cell–expressed interleukin-2 receptor with
an interleukin-2–diphtheria toxin,39 psoriasis can
be alleviated by decreasing the number of pathogenic T cells. The first biologic agent approved by
the FDA for treating psoriasis was alefacept, a fusion protein in which the binding site of leukocytefunction–associated antigen 3 (LFA-3) and the human IgG Fc portion are combined. Alefacept binds
to CD2 on activated T cells, thus impairing costimulatory signals delivered by LFA-3 and (possibly the
best explanation for the long-lasting effect in the
subgroup of patients who respond to the drug) inducing apoptosis in circulating memory T cells.40
Interruption of the molecular cascade resulting in cutaneous recruitment of pathogenic leukocytes has been achieved by efalizumab, a humanized monoclonal antibody that is directed against
an extracellular epitope of the LFA-1 a chain, which
was approved by the FDA for the treatment of psoriasis in October 2003.42 Other substances, which
include small-molecule compounds, are currently
under development.78
A key cytokine in psoriasis (and in other inflammatory diseases) is TNF-a, which can be function-
of
medicine
ally inhibited by the chimeric antibody infliximab
or by the recombinant human TNF-receptor fusion protein etanercept. Both agents competitively inhibit interactions of TNF-a with cell-surface
receptors and show convincing efficacy in treating
psoriasis.65,66 Shifting the immunologic microenvironment in psoriatic skin, dominated by Th1-type
cytokines through substitution of type 2 helper
T-cell–type cytokines, such as interleukin-1069 and
interleukin-4,70 has been reported as effective in
some cases of psoriasis.
Numerous other biologic agents and immuneresponse modifiers are under development; all of
them use at least one of the mechanisms mentioned
above.100 As a class, these compounds have the potential to handle some of the unmet medical needs
in the treatment of psoriasis.
Supported by a Rudolf Virchow Award and a research grant (Scho
565/5-1) from the Deutsche Forschungsgemeinschaft (to Dr.
Schön).
Dr. Schön reports having received lecture fees from Serono and
grant support from 3M Pharmaceuticals. Dr. Boehncke reports having received consulting and lecture fees from Serono, Biogen, and
Wyeth and lecture fees from Schering AG.
We are indebted to Professor U. Mrowietz (University of Kiel, Kiel,
Germany) for helpful discussions and critical proofreading of the
manuscript and to Professor C.E.M. Griffiths (University of Manchester, Manchester, United Kingdom) for a helpful suggestion.
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