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Psoriasis 1
Pathogenesis and clinical features of psoriasis
Christopher E M Griffiths, Jonathan N W N Barker

Psoriasis, a papulosquamous skin disease, was originally thought of as a disorder primarily of epidermal keratinocytes, Lancet 2007; 370: 263–71
but is now recognised as one of the commonest immune-mediated disorders. Tumour necrosis factor α, dendritic See Perspectives page 213
cells, and T-cells all contribute substantially to its pathogenesis. In early-onset psoriasis (beginning before age This is the first in a Series of two
40 years), carriage of HLA-Cw6 and environmental triggers, such as β-haemolytic streptococcal infections, are major papers about psoriasis
determinants of disease expression. Moreover, at least nine chromosomal psoriasis susceptibility loci have been Dermatology Centre, Hope
identified. Several clinical phenotypes of psoriasis are recognised, with chronic plaque (psoriasis vulgaris) accounting Hospital, University of
Manchester, Manchester
for 90% of cases. Comorbidities of psoriasis are attracting interest, and include impairment of quality of life and M6 8HD, UK
associated depressive illness, cardiovascular disease, and a seronegative arthritis known as psoriatic arthritis. A more (C E M Griffiths MD); and St
complete understanding of underlying pathomechanisms is leading to new treatments, which will be discussed in John’s Institute of
Dermatology, Guy’s Hospital
the second part of this Series.
Campus, King’s College
London, London, UK
Introduction Site-specific variants of psoriasis vulgaris exist. (J N W N Barker MD)
“I think it also necessary…to express the scaly psora by a Flexural (inverse) psoriasis in intertriginous sites is Correspondence to:
distinctive appellation; for this purpose, the term shiny, red, and typically devoid of scales (figure 3); Professor C E M Griffiths
psoriasis…” So wrote Robert Willan in his treatise On sebopsoriasis, which can be confused with seborrhoeic Dermatology Centre, Hope
Hospital, University of
Cutaneous Diseases,1 published in 1808. Willan, a British dermatitis, has greasy scales and occurs in eyebrows, Manchester, Manchester
dermatologist, is credited with the first accurate description nasolabial folds, and postauricular and presternal sites. M6 8HD, UK
of psoriasis and thereby helping to distinguish the disorder Psoriasis vulgaris will probably prove to be several christopher.griffiths
from leprosy. Psoriasis, one of the few skin diseases closely related but phenotypically and genotypically @manchester.ac.uk

common and distinctive enough to be recognised by
medical students (and most doctors) remains something
of an enigma. Relatively little attention has been paid to
identifying clinical phenotypes of psoriasis, or
understanding the natural history and prognosis of the
disease. In the past quarter century, substantial advances
have been made in our understanding of the genetics and
pathomechanisms of psoriasis. Debate continues as to
whether psoriasis is an autoimmune disorder. Belatedly,
researchers and clinicians have started to recognise and
document the substantial impairment to quality of life
caused by psoriasis, resulting in recognition that the
disease leads to marked loss of productivity2 in those it
afflicts. In this review, we will detail and put into clinical
context recent advances in the understanding of psoriasis.
Clinical features
The commonest type of psoriasis, accounting for 90% of
all cases, is psoriasis vulgaris, in which papulosquamous
plaques are well-delineated from surrounding normal
skin. The plaques are red or salmon pink in colour,
covered by white or silvery scales (figure 1), and may be
thick, thin, large or small. They are most active at the edge:
rapidly progressing lesions may be annular, with normal
skin in the centre. Plaques are usually distributed sym-
metrically, and occur most commonly on the extensor
aspects of elbows and knees; scalp (where they rarely
encroach beyond the hairline),3 lumbosacral region, and
umbilicus (figure 2). Active inflammatory psoriasis is
characterised by the Koebner phenomenon, in which new
lesions develop at sites of trauma or pressure.
distinct conditions,4 which might account for the
variability of response to therapy, particularly with the
T-cell targeted biological agents.
Children and adolescents can develop an acute form of
psoriasis known as guttate psoriasis (from the Latin
gutta meaning droplet), in which papules less than 1 cm
in diameter erupt on the trunk about 2 weeks after a
β-haemolytic streptococcal infection such as tonsillitis or
pharyngitis, or a viral infection. Guttate psoriasis is
self-limiting, resolving within 3–4 months of onset,
although its long-term prognosis is unknown. One study
indicated that only a third of individuals with guttate
psoriasis develop classic plaque disease.5
Generalised pustular psoriasis (von Zumbusch psoriasis)
is an acute form in which small, monomorphic sterile
pustules develop in painful inflamed skin. The patient has
Search strategy and selection criteria
We identified publications relating to psoriasis pathogenesis
and psoriasis in general by searching Medline, Ovid, and the
Cochrane Library databases with the term “psoriasis” alone or
in combination with the terms “pathogenesis”, “genetics”,
“psychosocial”, “history”, “immunology”, “comorbidity”,
“angiogenesis”, “prevalence”, “epidemiology”, “innate
immunity”, “adaptive immunity”, “keratinocyte”, “animal
models”, and “phenotype”. We preferentially selected the
most recent papers and authoritative articles. Additional
articles known to the authors were also included. Date and
language were not limited.

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Figure 1: Single plaque of psoriasis, well demarcated and heavily scaled
Figure 2: Chronic plaque psoriasis
a fever and is systemically unwell. Precipitants of
generalised pustular psoriasis include intercurrent
infection, and the abrupt withdrawal of systemic and, on
occasion, ultrapotent topical corticosteroids.
Palmoplantar pustulosis, consisting of yellow-brown,
sterile pustules on palms and soles, is still described in
textbooks of dermatology as a subtype of psoriasis.
About 25% of people with palmoplantar pustulosis also
have chronic plaque psoriasis. The disease has different
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demographics to psoriasis vulgaris in that patients are
predominantly women (9:1 female:male ratio), and
either current or previous smokers (95%), and onset
occurs in the 4th or 5th decades of life. Moreover,
genetic analysis has implied that palmoplantar
pustulosis and psoriasis vulgaris have different causes.6
The condition may therefore be a comorbidity rather
than a form of psoriasis.
In erythroderma, the whole body surface is affected by
psoriasis—which can lead to hypothermia, hypo-
albuminaemia, and high output cardiac failure. Erythro-
derma can be a life-threatening condition and can be
caused by other diseases, including atopic dermatitis,
drug eruptions, and cutaneous T-cell lymphoma.
About 50% of patients with psoriasis have distinctive
nail changes related to the disease: the commonest is
pitting, which is best seen under oblique lighting
conditions; onycholysis (nail plate separation); oil spots
(orange-yellow sub-ungual discolouration), and dystrophy
(figure 4) similar to that observed in onychomycosis.
Psoriatic nail disease occurs most commonly in patients
with psoriatic arthritis.
Psoriatic arthritis, as originally defined by Moll and
Wright,7 is a seronegative inflammatory arthritis that
occurs in the presence of psoriasis (figure 5). Five types
of psoriatic arthritis have been proposed: distal
interphalangeal joint only; asymmetrical oligoarthritis;
polyarthritis; spondylitis; and arthritis mutilans. Classic
psoriatic arthritis consists of oligoarthritis, distal
interphalangeal joint involvement, dactylitis, and
calcaneal enthesitis.8 Recently presented data indicate
that its prevalence has been greatly underestimated, and
may be as high as 25% in people with psoriasis.9 In about
10% of people with psoriatic arthritis, the arthritis
appears before skin manifestations of psoriasis. The
prevailing view that the skin condition and arthritis
represent different manifestations of the same disease is
under challenge. Genetic evidence dissociates the two,
as do immunological studies and responses to various
treatments.10,11
Despite advances in our understanding of the
pathogenesis of psoriasis, relatively little is known about
the natural history of the disease, particularly predictors
of disease severity. The few longitudinal studies that have
been done suggest that spontaneous remission (for as
long as 54 years) might occur in about a third of patients.12
The determinants of spontaneous remission, and the
roles that comorbidities and age play in the prognosis
and activity of psoriasis are poorly understood.
The underlying activity of psoriasis can be different
from its expression, particularly when a patient is
receiving treatment. No biomarkers are known to be
representative or predictive of psoriasis activity—
C-reactive protein, soluble adhesion molecules, and
soluble cytokine receptors have all been studied, but
found to be unreliable. If a patient appears to have been
cleared of psoriasis by systemic therapy, there is no
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Figure 3: Inverse psoriasis
reliable way to ascertain whether control is absolute
other than reducing the dose of, or withdrawing, therapy.
Clinical assessment relies on the classical skills of
history and examination.
Epidemiology
Accurate figures for the prevalence of psoriasis are
difficult to obtain because of an absence of validated
diagnostic criteria. Moreover, rates vary greatly between
people of different ethnic backgrounds: psoriasis is most
common in white people, but is estimated to affect only
0·3% of the general population in China,3 and is very
Figure 4: Dystrophic nail psoriasis
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Series
rare or absent in some isolated populations. Latitude also
seems to affect prevalence, probably because of the
beneficial effect of sunlight on the disease.13 However, the
prevalence of psoriasis is estimated to be between 1·5%
and 3% of the general population of Northern Europe
and Scandinavia,3 with men and women equally affected.
The incidence in white individuals is estimated to be
60 cases per 100 000 head of population per year.3
Psoriasis can appear at any time of life. However, the
mean age of onset for psoriasis vulgaris was recently
estimated at 33 years, with 75% of cases occurring before
46 years of age.14 Some studies suggest that onset is
bimodal, with peaks between 16 years and 22 years and
later at 57–60 years.15 The age of onset seems to be slightly
earlier in women than in men.
Comorbidity
Awareness is increasing that psoriasis as a disease is
more than skin deep and that it is associated with
systemic disorders,16 including Crohn’s disease, diabetes
mellitus (notably type 2),17 metabolic syndrome,18
depression,19 and cancer. It is unclear whether cancers,
particularly lymphoma20 and skin cancer,21 are related to
psoriasis or to its treatment. For example, the risk of
developing non-melanoma skin cancer is increased by
the excessive use of photochemotherapy—and can be
compounded by the subsequent use of ciclosporin.
Of emerging concern is the relation between psoriasis
and cardiovascular disease.22 Although no excess risk
seems to exist for patients with mild psoriasis, moderate
and severe disease is associated with a relative risk of
almost three.23 In part, this association is due to the
over-representation of Framingham risk factors in the
psoriatic population, but evidence indicates that psoriasis
per se is an independent risk factor.24 Potential
mechanisms could therefore include the presence of
circulating proinflammatory factors and endothelial
activation,24 analogous to the situation noted in
rheumatoid arthritis. If confirmed, such mechanisms
would have major implications for future therapeutic
strategies.
Figure 5: Psoriatic arthritis
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Histological features
Psoriasis has three principal histological features:
epidermal hyperplasia; dilated, prominent blood vessels
in the dermis; and an inflammatory infiltrate of leucocytes,
predominantly into the dermis (figure 6). Histology of
uninvolved, clinically symptomless areas of skin is
normal.
The hyperplastic epidermal changes are associated with
an underexpression of markers of keratinocyte differ-
entiation, including keratins K1 and K10; loss of the
granular cell layer; parakeratosis (retention of nuclei in
cells of the stratum corneum); elongation of rete ridges;
and the presence of micropustules of Kogoj and
microabscesses of Munro. Keratinocytes of the hair follicle
are unaffected.25
Of the three main histological features of psoriasis,
increased vascularity in the dermis is probably the most
overlooked. Indeed, relatively little research has been
devoted to this area since Braverman’s descriptions more
than 30 years ago.26 Angiogenic factors produced by
epidermal keratinocytes are now recognised as drivers of
abnormal dermal vascular proliferation and angiogenesis.
Levels of one such factor—vascular endothelial growth
factor (VEGF), also known as vascular permeability
factor—are significantly raised in plaques of psoriasis;27 its
serum concentration correlates with the clinical severity of
Figure 6: Histology of psoriasis showing epidermal acanthosis, elongation of
rete ridges and inflammatory infiltrate (haematoxylin and eosin)
Scale bar=200 μm.
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the disease.28 The interaction between VEGF and the
angiopoietin/Tie signalling pathway is modulated by
tumour necrosis factor α (TNFα):29,30 results of a recent
clinical study31 suggests that infliximab, a TNF-blocking
chimeric monoclonal antibody, exerts part of its benefit in
psoriasis by inhibition of this key VEGF/angiopoietin/Tie
pathway.
The immune response in psoriasis
Until the early 1980s, psoriasis was believed to be a disease
primarily of epidermal keratinocyte proliferation, and the
cutaneous inflammatory infiltrate to be a secondary
event.32 However, strong evidence now exists that the
cell-mediated adaptive immune response is crucial in
psoriasis. The leucocyte infiltrate in psoriasis consists
predominantly of CD4-positive and CD8-positive T-cells
(figure 7), and may precede epidermal hyperplasia.33 Some
adhesion molecules which promote leucocyte adherence
are highly expressed in psoriatic skin: intercellular
adhesion molecule-1 is expressed on epidermal
keratinocytes and along with E-selectin on dermal
capillaries.34
Cytokines of the Th1 pathway—interferon-γ,
interleukin 2, and interleukin 12—predominate in plaques.
Psoriasis is classified as a Th1 disease,35 which is consistent
with the relative under-representation of Th2 diseases,
such as atopic dermatitis, in patients with psoriasis.16,36
T-cell-targeted immunosuppressants such as ciclosporin
are efficacious in psoriasis,37 as is denileukin diftitox, an
interleukin-2 diphtheria fusion toxin cytolytic for activated
T cells.38 Moreover, bone marrow transplantation can
appear to transmit39 or clear40 psoriasis.
T cells in the cutaneous infiltrate are predominantly of
the memory effector CD45 RO+ designation41 and most
are positive for cutaneous lymphocyte-associated antigen,
a marker for skin-homing leucocytes.42 There is evidence
that these cells form clones in the epidermis of psoriatic
plaques.43 However, no definitive autoantigen or
immunogen has yet been identified to which the
inflammatory response is directed. If psoriasis is indeed
an autoimmune disease, an epidermal component,
perhaps keratin, might be the most likely candidate for
such an antigen.
In recent years, clinical and basic science observations
have shown that innate as well as adaptive immunity is
crucial in the initiation and maintenance of psoriatic
plaques. Indeed, since the epidermis is the body’s main
barrier to environmental insult, epidermal hyperplasia
forms a key component of the innate immune response.
Natural killer cells and natural killer T cells are part of the
cutaneous inflammation in psoriasis;44 at times,
neutrophils form a large proportion of the leucocytic
infiltrate, particularly in generalised pustular disease.45
Recent studies have considered the role of dendritic cells
and endogenous antimicrobial peptides. Three types of
dendritic cells appear likely to be involved in the
development of psoriasis: Langerhans cells in the
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Figure 7: CD4-positive T cells in a plaque of psoriasis
Scale bar=100 μm.
epidermis; dermal factor XIIIa-positive dendritic cells; and
a subset of dendritic cells, known as plasmacytoid dendritic
cells, which are found in involved psoriatic skin but not in
normal skin. Langerhans cells are the outermost sentinels
of the immune system: they recognise and capture
antigens, and migrate to local draining lymph nodes,
where they present them to T cells.46 The migration of
epidermal Langerhans cells in response to cytokine and
allergic stimuli is impaired in patients with early-onset
psoriasis, implying that these cells may be acting in a
regulatory manner to maintain cutaneous immune
homoeostasis.47 Plasmacytoid dendritic cells are distinct
from dermal factor XIIIa-positive dendritic cells and
Langerhans cells in that they express CD123 and HLA-DR,
but lack CD11c.48 After activation via surface Toll-like
receptors, plasmacytoid dendritic cells produce interferon
α—which, hypothetically, leads to the formation of plaques
in predisposed individuals by driving Th1 responses,
forming a further link between the innate and adaptive
arms of the immune response.
Endogenous anti-microbial peptides—cathelicidins
and β defensins—are overexpressed in psoriatic skin, by
contrast with atopic dermatitis, in which such peptides
are underexpressed.49 This observation is congruent with
the clinical observation that psoriatic skin is rarely
secondarily infected, whereas in atopic dermatitis
secondary infection is a substantial problem. The activity
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of TNFα, a key pro-inflammatory cytokine of the innate
immune response, is substantially increased in psoriasis.
The central role of this cytokine in psoriasis came to light
through observations of the efficacy of anti-TNF biological
therapies for the disease.50,51
Genetic contributions to psoriasis
Population studies show that the incidence of psoriasis
vulgaris is greater in first and second degree relatives of
patients than in the general population.52 About 30% of
individuals with psoriasis vulgaris have an affected first
degree relative.53 If both parents and a sibling are affected,
a further child has a 50% chance of developing psoriasis
vulgaris; if the sibling is affected but not the parents, the
risk drops to 8%.53 The risk of psoriasis vulgaris is two to
three times greater in monozygotic than in dizygotic
twins.52
There appears to be more than one pathway to the
development of psoriasis vulgaris. In a small minority of
families, the disease seems to follow Mendelian patterns
(autosomal dominant and recessive), implying a defect in a
single gene. However, in general psoriasis vulgaris appears
to arise through multiple genetic risk factors interacting
with each other and with environmental factors such as
β-haemolytic streptococcal infection, HIV, stress, and
drugs, including β blockers and lithium (figure 8).54 This
concept is further supported by substantial genetic
heterogeneity.
Several genome-wide scans have now been reported in
extended and nuclear families. At least nine chromosomal
loci have been identified for which statistically significant
evidence for linkage to psoriasis has been observed
(nomenclature PSORS1–9).55 Of particular interest are:
PSORS2, a replicated locus on chromosome 17q, at which
a polymorphism associated with psoriasis has been
identified, the polymorphism causing loss of binding to
the RUNX1 transcription factor;56 PSORS4,57 which is
located within the epidermal differentiation complex on
chromosome 1q; and PSORS8,58 which overlaps with the
Crohn’s disease locus on chromosome 16q. PSORS8 is
notable because psoriasis and Crohn’s disease are
observed together more frequently than would be expected
by chance.59 Despite this observation, several studies have
failed to find an association between psoriasis and the
CARD15/NOD2 mutation linked to Crohn’s disease.
By far the major genetic determinant of psoriasis is
PSORS1, which probably accounts for 35–50% of the
heritability of the disease,60 and has been replicated in
virtually all linkage studies of psoriasis.61 PSORS1 is
located in the MHC on chromosome 6p, spanning a
segment of about 300 kb in the class I region telomeric of
HLA-B. The region contains less than ten genes, of which
three have been the major focus of attention for
investigators, because of strong associations between
polymorphic coding sequence variants of these genes
and psoriasis vulgaris. HLA-C (associated variant
HLA-Cw6) encodes a class I MHC protein. CCHCR1
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1 2 Modifier 3 4
genes
Comorbidities
Genetic
Disease mechanisms Psoriasis including
Innate Adaptive
susceptibility (clinical cardiovascular and
disease) psoriatic arthritis
Vascular
effects
Environmental Epidermal/
factors barrier effects
Disease Disease Outcome Concomitant
prevention measures, therapy,
measures
treatment
biomarkers preventable?
Phenotypic classification
Pharmacogenetics
Figure 8: The march of psoriasis
This schematic combines information that is currently accepted and under active investigation. Boxes under dotted
line refer to clinical issues and intervention strategies; the latter would be better informed by use of validated
pharmacogenetic and phenotypic classification tools. Step 1—PSORS1 harbours the main genetic determinant for
psoriasis. With or without (depending on pedigree) involvement of environmental factors, genetic mutations or
polymorphisms drive disease-specific pathogenic processes. Future disease prevention measures will target these
aspects as well as disease mechanisms. Step 2—evidence indicates key roles for innate and adaptive immune
responses; changes in epidermis are also important. Vascular changes are prominent. Genes controlling degree of
expression or function of key molecules in these pathways determine disease severity; these might include
polymorphisms in VEGF and TNFα. Present treatments target key elements of these pathways, including TNFα
(etanercept, infliximab), T cells (ciclosporin, efalizumab), and epidermal changes (vitamin D₃ analogues). Step 3—the
consequence of activation of these processes is disease expression, including distribution and area of expression,
phenotype, and duration of disease. Improvements in outcome measures including identification of biomarkers
would significantly improve our ability to predict disease responses and natural history. Step 4—substantial
comorbidities, particularly cardiovascular disease, are likely to result from chronic inflammation. Up to 25% of
psoriasis is associated with arthritis; whether as a comorbidity or a direct consequence of the psoriatic process
remains to be ascertained. Treatment approaches need to take account of these issues to minimise morbidity and
mortality, but can themselves also lead to comorbidity.
(variant WWCC) encodes the coiled-coil x-helical rod
protein 1, a ubiquitously expressed protein that is
overexpressed in psoriatic epidermis.62 CDSN
(variant=allele 5) encodes corneodesmosin, a protein that
is uniquely expressed in the granular and cornified layers
of the epidermis and is upregulated in psoriasis.63
Absolute identification of the causative gene at this locus
has been hampered by extensive linkage disequilibrium
within the MHC. Although evidence suggests a genetic
event close to (or within) HLA-Cw6 as the susceptibility
factor at PSORS1,64 no mutations have been identified,
and variants in regulatory sequences potentially affecting
several downstream genes cannot be excluded.
Nevertheless, HLA-Cw6 is a strong marker for early-onset
psoriasis. In one study, 85% of patients with onset before
age 40 years had at least one HLA-Cw6 allele, compared
with 15% of those with onset after this age.15
Investigations have shown that the phenotypic variants
of psoriasis are genetically heterogeneous at least at the
level of PSORS1. Thus guttate psoriasis (an acute onset
form, usually occurring in adolescents) is strongly
associated with PSORS1,6 whereas palmoplantar
pustulosis and late onset (age >50 years) psoriasis vulgaris
268
are not.65 The implications for disease management are
yet to be ascertained.
Potential contribution of genetic studies to
treatment
Without definitive identification of a major susceptibility
gene for psoriasis, prediction of how genetic discovery
might inform disease pathogenesis is difficult at present.
Nevertheless, several recent genetic observations show
how pathogenic models can integrate perturbations in
the epidermal barrier and inflammation. For example, in
mice, disruption in keratinocyte signalling, either by
abrogation of activation protein 1 (AP1) pathways66 or by
upregulation of signal transduction and activation of
transcription 3 (STAT3) pathways, leads to psoriasiform
hyperplasia.67 Mutations in filaggrin, a key protein that
facilitates terminal differentiation and formation of the
skin barrier, are strongly associated with atopic dermatitis
(eczema),68 another common inflammatory skin disease,
which shares many phenotypic features with psoriasis
(erythema, induration, and scale formation with a
symmetrical distribution). These findings suggest that
primary defects in the epidermis lead to T-cell mediated
immune events, which are at present the target for most
therapeutic intervention. Furthermore, findings of
several studies show an association of psoriasis vulgaris
with functional polymorphisms in genes for factors that
control inflammation (eg, TNFα69) and vascular growth
(eg, VEGF70). These data suggest the existence of modifier
genes that can regulate the severity of disease in
susceptible individuals. Finally, and most compelling, is
the recent observation that missense mutations in the
interleukin-23 receptor gene and SNPs in the untranslated
region of interleukin-12B identify psoriasis risk genes.71
The importance of these genetic observations is
emphasised by two key facts. First, a human antibody to
p40, a component of interleukin 12 and of interleukin 23,
when administered to individuals with psoriasis, leads to
a rapid and sustained improvement in the disease.72
Second, intradermal injection of interleukin 23 into
mouse skin stimulates epidermal hyperplasia,73 a
hallmark of psoriasis. Interleukin 23 is important for the
production of Th17 cells, which secrete interleukin 17.
Together, these findings suggest that products of these
genes have a fundamental role in the pathogenesis of
psoriasis.
Gene studies might allow the identification of molecules
that contribute to pathogenesis, and can be targeted by
therapies. In addition, modifier genes may exist that can
regulate the severity of disease in susceptible individuals.
Studies of such mechanisms in validated models are
urgently needed.
Animal models
Psoriasis vulgaris is unique to human beings. However,
transgenic knockout/deletion animal models of psoriasis
have been proposed as surrogates for the disease.
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Epidermal overexpression of VEGF in mice produces a
phenotype of chronic inflammation, psoriasiform
hyperplasia, and vascular proliferation reminiscent of
psoriasis.74 Mice that are transgenic for epidermal
keratinocyte expression of STAT367 have a psoriasiform
appearance. A recently described mouse model in which
epidermal expression of the c-Jun component of AP1 is
deleted is characterised by persistent epidermal hyperplasia
and an accompanying inflammatory arthritis.66 This
finding implies that changes in the epidermis can initiate
extracutaneous pathology. The most faithful replicants of
psoriasis itself are chimeras comprising biopsies of
uninvolved, symptomless skin from patients with psoriasis
grafted onto the flank of immunodeficient mice. This
approach takes two main forms. First, use of the severe
combined immunodeficient (SCID) mouse, in which a
graft of uninvolved skin from a psoriasis patient can be
transformed into psoriasis by virtue of injections with
activated T cells or natural killer T cells.75,76 The resulting
graft provides clinical, histological, and immunological
features consistent with psoriasis. Second, the AGR129
mouse,77 which is more immunosuppressed than its SCID
counterpart because it lacks T and B cells, has impaired
natural killer cell function and is deficient in types I and II
interferon receptors and recombination activating gene-2.
A graft of uninvolved psoriatic skin onto the AGR129
mouse spontaneously transforms into psoriasis, with the
implication that the grafting process can stimulate
expansion of resident immune cells in the graft. Anti-CD3
and anti-TNFα agents injected into the graft can prevent
conversion of uninvolved to involved skin. A recently
described mouse model has emphasised the previously
underappreciated role of macrophages in psoriasis.78,79
Psychosocial aspects
Psoriasis is rarely life-threatening; however, it is
life-ruining for the majority of patients. Dennis Potter80
and John Updike81 have written eloquently and movingly
about the despair and social isolation that accompany
psoriasis. Although Willan1 separated psoriasis from
leprosy, the stigma of psoriasis persists. These difficulties
manifest as significant impairment of quality of life82 and
profound psychosocial disability.83 Studies have shown
reliably that psoriasis produces a decrease in quality of
life at least equal to and often greater than that of
conditions such as diabetes, ischaemic heart disease, and
chronic obstructive pulmonary disease.84 The dermatology
life quality index is a questionnaire used increasingly to
assess improvements in quality of life resulting from
therapeutic intervention.85 The stress caused by living
with psoriasis can manifest as avoidance behaviours; for
example, unwillingness to attend local swimming pools
for fear of the ignominy of being asked to leave by a
member of the public with unwarranted concerns about
the contagiousness of the condition. Objective studies
have emphasised the role of automatic vigilance86 for
threat in patients with psoriasis, and indeed their coping
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behaviours are similar to those used by patients with
cancer or chronic pain.87 Concerns about chronicity of
disease and the absence of a cure are an important
undercurrent: even patients in whom systemic therapy
causes remission maintain high levels of anxiety because
of the fear of relapse.88 Psychological sequelae of the
disease can impair response to treatment: patients with
pathological levels of anxiety are less likely to respond to
photochemotherapy.89 Even patients’ partners and close
relatives are less attuned to the psychosocial sequelae of
the disease than might be expected.90 Doctors experienced
in the management of psoriasis remain fairly poor at
identifying and subsequently addressing depression and
anxiety in their patients.91 An understanding of the
psychosocial difficulties encountered by patients with
psoriasis and other chronic skin diseases, and how a
biopsychosocial model could be used in the management
of such conditions, are unmet needs.
Conclusion
The past 20 years, and in particular the past 5 years, have
witnessed great advances in our knowledge of the
pathogenesis of psoriasis, courtesy of genetic and
immunological techniques. It is now accepted that
psoriasis is a chronic, immune-mediated inflammatory
disease that can act as a paradigm for other diseases of
this genre. These basic science observations have catalysed
the development of targeted biological treatments that
will revolutionise the management of psoriasis. There are
still gaps in our basic understanding of psoriasis,
specifically clinical observational work on phenotypes and
the natural history of the disease; the role of angiogenesis;
the association with metabolic syndrome; and an in-depth
analysis of psychosocial factors relating to the disease.
However, slowly but surely psoriasis vulgaris is giving up
its secrets to clinicians and cutaneous biologists.
Conflict of interest statement
CEMG has received research support or has acted as a consultant or
lecturer for Abbott, Amgen, Biogen-IDEC, Centocor, Essex Pharma,
Galderma, Leo Pharma, Novartis, Novo Nordisk, Schering-Plough,
Serono, Stiefel, UCB Pharma, and Wyeth. JNWNB has acted as a
consultant to Abbott, Centocor, Janssen Cilag, Novartis, Schering-Plough,
Serono, and Wyeth, and has lectured at sponsored symposia for the
above companies. He has no shares in any of these companies.
Acknowledgments
We thank Sarah Smith and Val Hill for help with preparation of the
manuscript and Thomas Brenn for supplying figure 6.
References
1 Willan R. On cutaneous diseases. London: J Johnson, St Paul’s
Churchyard, 1808.
2 Finlay AY, Coles EC. The effect of severe psoriasis on the quality of
life of 369 patients. Br J Dermatol 1995; 132: 236–44.
3 Griffiths CEM, Camp RDR, Barker JNWN. Psoriasis. In: Burns DA,
Breathnach SM, Cox NH, Griffiths CEM, eds. Rook’s textbook of
dermatology, 7th edn. Oxford: Blackwell, 2005: 35.1–35.69.
4 Griffiths CEM, Christophers E, Barker JNWN, et al. A new
classification of psoriasis according to clinical phenotype.
Br J Dermatol 2007; 156: 258–62.
5 Martin BA, Chalmers RJG, Telfer NR. How great is the risk of
further psoriasis following a single episode of a guttate psoriasis?
Arch Dermatol 1996; 132: 717–18.
269
 Series
6 Asumalahti K, Ameen M, Suomela S, et al. Genetic analysis of
PSORS1 distinguishes guttate psoriasis and palmoplantar
pustulosis. J Invest Dermatol 2003; 120: 627–32.
7 Moll JMH, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973;
3: 55–78.
8 Helliwell PS, Taylor WJ. Classification and diagnostic criteria for
psoriatic arthritis. Ann Rheum Dis 2005; 64: ii3-ii8.
9 Zachariae H. Prevalence of joint disease in patients with psoriasis:
implications for therapy. Am J Clin Dermatol 2003; 4: 441–47.
10 Ho P, Bruce IN, Silman A, et al. Evidence for common genetic
control in pathways of inflammation for Crohn’s disease and
psoriatic arthritis. Arthritis Rheum 2005; 52: 3596–602.
11 Pitzalis C, Cauli A, Pipitone N, et al. Cutaneous lymphocyte
antigen-positive T lymphocytes preferentially migrate to the skin
but not to the joint in psoriatic arthritis. Arthritis Rheum 1996; 39:
137–45.
12 Farber EM, Nall ML. The natural history of psoriasis in
5600 patients. Dermatologica 1974; 148: 1–18.
13 Braathen LR, Botten G, Bjerkedak T. Prevalence of psoriasis in
Norway. Acta Derm Venereol (Stockh) 1989; 142: 5–8.
14 Nevitt GJ, Hutchinson PE. Psoriasis in the community: prevalence,
severity and patients’ beliefs and attitudes towards the disease.
Br J Dermatol 1996; 135: 533–37.
15 Henseler T, Christophers E. Psoriasis of early and late onset:
characterization of two types of psoriasis vulgaris.
J Am Acad Dermatol 1985; 13: 450–56.
16 Henseler T, Christophers E. Disease concomitance in psoriasis.
J Am Acad Dermatol 1995; 32: 982–86.
17 Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB,
Gelfand JM. Prevalence of cardiovascular risk factors in patients
with psoriasis. J Am Acad Dermatol 2006; 55: 829–35.
18 Sommer DM, Jenisch S, Suchan M, Christophers E,
Weichenthal M. Increased prevalence of the metabolic syndrome in
patients with moderate to severe psoriasis. Arch Dermatol Res 2006;
298: 321–28.
19 Esposito M, Saraceno R, Giunta A, Maccarone M, Chimenti S. An
Italian study on psoriasis and depression. Dermatol 2006; 212:
123–27.
20 The risk of lymphoma in patients with psoriasis. J Invest Dermatol
2006; 126: 2194–201.
21 Lindelof B, Eklund G, Liden S, Stern RS. The prevalence of
malignant tumors in patients with psoriasis. J Am Acad Dermatol
1990; 22: 1056–60.
22 Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ,
Troxel AB. Risk of myocardial infarction in patients with psoriasis.
JAMA 2006; 296: 1735–41.
23 Mallbris L, Akre O, Granath F, et al. Increased risk for
cardiovascular mortality in psoriasis inpatients but not in
outpatients. Eur J Epidemiol 2004; 19: 225–30.
24 Mrowietz U, Elder JT, Barker J. The importance of disease
associations and concomitant therapy for the long-term
management of psoriasis patients. Arch Dermatol Res 2006; 298:
309–18.
25 Krueger JG, Bowcock A. Psoriasis pathophysiology: current
concepts of pathogenesis. Ann Rheum Dis 2005; 64 (suppl II):
ii30–36.
26 Braverman IM, Yen A. Microcirculation in psoriatic skin.
J Invest Dermatol 1974; 62: 493–502.
27 Detmar M, Brown LF, Claffey KP, et al. Overexpression of vascular
permeability factor/vascular endothelial growth factor and its
receptors in psoriasis. J Exp Med 1994; 180: 1141–46.
28 Creamer D, Allen MH, Groves RW, Barker JNWN. Circulating
vascular permeability factor/vascular endothelial growth factor
erythroderma. Lancet 1996; 348: 1101.
29 Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption,
regression and growth in tumors mediated by angiopoientins and
VEGF. Science 1999; 284: 1994–98.
30 Kuroda K, Sapadin A, Shoji T, Fleischmajer R, Lebwohl M. Altered
expression of angiopoietins and Tie2 endothelium receptor in
psoriasis. J Invest Dermatol 2001; 116: 713–20.
31 Markham T, Mullan R, Golden-Mason L, et al. Resolution of
endothelial activation and down-regulation of Tie2 receptor in
psoriatic skin after infliximab therapy. J Am Acad Dermatol 2006; 54:
1003–12.
270
32 Bos JD, de Rie MA, Teunissen MB, Piskin G. Psoriasis:
dysregulation of innate immunity. Br J Dermatol 2005; 152: 1098–107.
33 Valdimarsson H, Baker BS, Jonsdottir I, Powles A, Fry L. Psoriasis:
a T-cell-mediated autoimmune disease induced by streptococcal
superantigens? Immunol Today 1995; 16: 145–49.
34 Robert C, Kupper T. Inflammatory skin diseases, T cells and
immune surveillance. N Engl J Med 1999; 341: 1817–28.
35 Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG. The
majority of epidermal T cells in Psoriasis vulgaris lesions can
produce type 1 cytokines, interferon-gamma, interleukin-2, and
tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte)
and TH1 effector populations: a type 1 differentiation bias is also
measured in circulating blood T cells in psoriatic patients.
J Invest Dermatol 1999; 113: 752–59.
36 Landgren E, Bråbäck L, Hedlin U, Hjern A, Rasmussen F. Psoriasis
in Swedish conscripts: time trend and association with T-helper 2-
mediated disorders. Br J Dermatol 2006; 154: 332–36.
37 Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med
1979; 301: 555.
38 Gottlieb SL, Gilleaudeau P, Johnson R, et al. Response of psoriasis
to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary
immune, but not keratinocytes, pathogenic basis. Nat Med 1995; 1:
442–47.
39 Wahie S, Alexandruff A, Reynolds NJ, Meggitt SJ. Psoriasis
occurring after myeloablative therapy and autologous stem cell
transplantation. Br J Dermatol 2006; 154: 194–95.
40 Eedy DJ, Burrows D, Bridges JM, Jones FG. Clearance of severe
psoriasis after allogenic bone marrow transplantation. BMJ 1990;
300: 908.
41 Vissers WH, Arndtz CH, Muys L, Van Erp PE, de Jong EM,
van de Kerkhof PC. Memory effector (CD45RO+) and
cytotoxic (CD8+) T cells appear early in the margin zone of
spreading psoriatic lesions in contrast to cells expressing natural
killer receptors, which appear late. Br J Dermatol 2004; 150: 852–59.
42 Davison SC, Ballsdon A, Allen MH, Barker JNWN. Early
migration of cutaneous lymphocyte-associated antigen (CLA)
positive cells into evolving psoriatic plaques. Exp Dermatol 2001;
10: 280–85.
43 Prinz JC, Vollmer S, Boehncke WH, Menssen A, Laisney I,
Trommler P. Selection of conserved TCR VDJ rearrangements in
chronic psoriatic plaques indicates a common antigen in psoriasis
vulgaris. Eur J Immunol 1999; 29: 3360–68.
44 Gaspari AA. Innate and adaptive immunity and the pathophysiology
of psoriasis. J Am Acad Dermatol 2006; 54 (suppl 2): S67–80.
45 Nickoloff BJ. Skin innate immune system in psoriasis: friend or
foe? J Clin Invest 1999; 104: 1161–64.
46 Griffiths CEM, Dearman RJ, Cumberbatch M, Kimber I. Cytokines
and Langerhans cell mobilisation in mouse and man. Cytokine
2005; 32: 67–70.
47 Cumberbatch M, Singh M, Dearman RJ, Young HS, Kimber I,
Griffiths CEM. Impaired Langerhans cell migration in psoriasis.
J Exp Med 2006; 203: 953–60.
48 Nestle FO, Conrad C, Tun-Kyi A, et al. Plasmacytoid predendritic
cells initiate psoriasis through interferon-alpha production.
J Exp Med 2005; 202: 135–43.
49 Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial
peptides and skin infections in atopic dermatitis. N Engl J Med
2002; 347: 1151–60.
50 Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as
monotherapy in patients with psoriasis. N Engl J Med 2003; 349:
2014–22.
51 Reich K, Nestle FO, Papp K, et al. Infliximab induction and
maintenance therapy for moderate-to-severe psoriasis: a phase III,
multicentre, double-blind trial. Lancet 2005; 366: 1367–74.
52 Farber EM, Nall NL, Watson W. Natural history of psoriasis in 61
twin pairs. Arch Dermatol 1974; 109: 207–11.
53 Andressen C, Henseler T. Inheritance of psoriasis. Analysis of
2035 family histories. Hautarzt 1982; 33: 214–17.
54 Barker JNWN. Pathophysiology of psoriasis. Lancet 1991; 338: 227–30.
55 Capon F, Trembath RC, Barker JNWN. An update on the genetics of
psoriasis. Dermatol Clin 2004; 22: 339–47.
56 Helms C, Cao L, Krueger JG, et al. A putative RUNX1 binding site
variant between SLC9A3R1 and NAT9 is associated with susceptibility
to psoriasis. Nat Genet 2003; 35: 349–56.
www.thelancet.com Vol 370 July 21, 2007

57 Capon F, Semprini S, Chimenti S, et al. Fine mapping of the PSORS4
psoriasis susceptibility region on chromosome 1q21. J Invest Dermatol
2001; 116: 728–30.
58 Karason A, Gudjonsson JE, Upmanyu R, et al. A susceptibility gene
for psoriatic arthritis maps to chromosome 16q: evidence for
imprinting. Am J Hum Genet 2003; 72: 125–31.
59 Lee FI, Bellary SV, Francis C. Increased occurrence of psoriasis in
patients with Crohn’s disease and their relatives. Am J Gastroenterol
1990; 85: 962–63.
60 Trembath RC, Clough RL, Rosbotham JL, et al. Identification of a
major susceptibility gene locus on chromosome 6p and evidence for
further disease loci revealed by a two stage genome-wide search in
psoriasis. Human Mol Genet 1997; 6: 813–20.
61 Capon F, Munro M, Trembath R, Barker J. Searching for the MHC
psoriasis susceptibility gene. J Invest Dermatol 2002; 118: 745–51.
62 Suomela S, Elomaa O, Asumalahti K, et al. HCR, a candidate gene for
psoriasis, is expressed differently in psoriasis and other
hyperproliferative skin disorders and is downregulated by
interferon-gamma in keratinocytes. J Invest Dermatol 2003; 121:
1360–64.
63 Allen M, Ishida-Yamamoto A, McGrath J, et al. Corneodesmosin
expression in psoriasis vulgaris differs from normal skin and other
inflammatory skin disorders. Lab Invest 2001; 81: 969–76.
64 Nair RP, Stuart PE, Nistor I, et al. Sequence and haplotype analysis
supports HLA-C as the psoriasis susceptibility 1 gene.
Am J Hum Genet 2006; 78: 827–51.
65 Allen MH, Ameen M, Veal C, et al. The major psoriasis susceptibility
locus PSORS1 is not a risk factor for late-onset psoriasis. J Invest Derm
2005; 124: 103–07.
66 Zenz R, Eferl R, Kenner L, et al. Psoriasis-like skin disease and
arthritis caused by inducible epidermal deletion of Jun proteins.
Nature 2005; 437: 369–75.
67 Sano S, Chan KS, Carbajal S, et al. Stat3 links activated keratinocytes
and immunocytes required for development of psoriasis in a novel
transgenic mouse model. Nat Med 2005; 11: 43–49.
68 Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common
loss-of-function variants of the epidermal barrier protein filaggrin are
a major predisposing factor for atopic dermatitis. Nat Genet 2006; 38:
441–46.
69 Mössner R, Kingo K, Kleensang A, et al. Association of TNF-238 and
-308 promoter polymorphisms with psoriasis vulgaris and psoriatic
arthritis but not with pustulosis palmoplantaris. J Inv Dermatol 2005;
124: 282–84.
70 Young HS, Summers AM, Bhushan M, Brenchley PEC,
Griffiths CEM. Single nucleotide polymorphisms of vascular
endothelial growth factor (VEGF) in psoriasis of early onset.
J Invest Dermatol 2004; 122: 209–15.
71 Cargill M, Schrodi SJ, Chang M, et al. A large scale genetic
association study confirms IL-12B and leads to IL-23R as
psoriasis-risk genes. Am J Hum Genet 2007; 80: 273–90.
72 Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-
12/23 monoclonal antibody for the treatment of psoriasis.
N Engl J Med 2007; 356: 580–92.
73 Chan JR, Blumenschein W, Murphy E, et al. IL-23 stimulates
epidermal hyperplasia via TNF and IL-20R2 – dependent
mechanisms with implications for psoriasis pathogenesis.
J Exp Med 2006; 203: 2577–87.
www.thelancet.com Vol 370 July 21, 2007
Series
74 Xia YP, Li B, Hylton D, Detmar M, Yancopoulos GD, Rudge JS.
Transgenic delivery of VEGF to mouse skin leads to an
inflammatory condition resembling human psoriasis. Blood 2003;
102: 161–68.
75 Wrone-Smith T, Nickoloff BJ. Dermal injection of immunocytes
induces psoriasis. J Clin Invest 1996; 98: 1878–87.
76 Nickoloff BJ, Bonish B, Huang BB, Porcelli SA. Characterization of
a T cell line bearing natural killer receptors and capable of creating
psoriasis in a SCID mouse model system. J Dermatol Sci 2000; 24:
212–25.
77 Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, Nestle FO.
Spontaneous development of psoriasis in a new models shows an
essential role for resident T cells and tumor necrosis factor-alpha.
J Exp Med 2004; 199: 731–36.
78 Wang H, Peters T, Kess D, et al. Activated macrophages are
essential in a murine model for T cell-mediated chronic
psoriasiform skin inflammation. J Clin Invest 2006; 116: 2105–14.
79 Stratis A, Pasparakis M, Rupec RA, et al. Pathogenic role for skin
macrophages in a mouse model of keratinocytes induced
psoriasis-like skin inflammation. J Clin Invest 2006; 116: 2094–104.
80 Potter D. The singing detective. London: Faber and Faber, 1986.
81 Updike J. Self-consciousness—memoirs. London: Deutsch, 1989.
82 Finlay AY, Kelly SE. Psoriasis—an index of disability.
Clin Exp Dermatol 1987; 12: 8–11.
83 Gupta MA, Gupta AK. Psychiatric and psychological co-morbidity in
patients with dermatologic disorders: epidemiology and
management. Am J Clin Dermatol 2003; 4: 833–42.
84 Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM.
Psoriasis causes as much disability as other major medical diseases.
J Am Acad Dermatol 1999; 41: 401–07.
85 Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)—a
single practical measure for clinical use. Clin Exp Dermatol 1994; 19:
210–16.
86 Fortune DG, Richards HL, Corrin A, Taylor RJ, Griffiths CEM,
Main CJ. Attentional bias for psoriasis-specific and psychosocial
threat in patients with psoriasis. J Behav Med 2003; 26: 211–24.
87 Fortune DG, Richards HL, Main CJ, Griffiths CEM. Patients’
strategies for coping with psoriasis. Clin Exp Dermatol 2002; 27:
177–84.
88 Fortune DG, Richards HL, Kirby B, McElhone K, Main CJ,
Griffiths CEM. Successful treatment of psoriasis improves
psoriasis-specific but not more general aspects of patients’
well-being. Br J Dermatol 2004; 151: 1219–26.
89 Fortune DG, Richards HL, Kirby B, et al. Psychological distress
impairs clearance of psoriasis in patients treated with
photochemotherapy. Arch Dermatol 2003; 139: 752–56.
90 Richards HL, Fortune DG, Chong SL, et al. Divergent beliefs about
psoriasis are associated with increased psychological distress.
J Invest Dermatol 3004; 123: 49–56.
91 Richards HL, Fortune DG, Weidmann A, Sweeney SK,
Griffiths CEM. Detection of psychological distress in patients with
psoriasis: low consensus between dermatologist and patient.
Br J Dermatol 2004; 151: 1227–33.
271