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Psoriatic arthritis 1
The pathogenesis of psoriatic arthritis
Douglas J Veale, Ursula Fearon

Psoriatic arthritis is a chronic, immune-mediated, inflammatory arthropathy that presents with inflammation of the Lancet 2018; 391: 2273–84
joints and entheses, including those of the axial skeleton, and is associated with increased mortality from cardiovascular See Editorial page 2185
disease. Diagnosis is primarily based on clinical phenotype because of the diversity of the associated features, which This is the first in a Series of
can include skin and nail disease, dactylitis, uveitis, and osteitis. Improved understanding of the pathogenesis of two papers about psoriatic
arthritis
psoriatic arthritis has led to the development of effective biologics and small-molecular drugs targeting specific
cytokines and signalling pathways, which can prevent disease progression and improve quality of life. However, at Rheumatology EULAR Centre
of Excellence, St Vincent’s
least 40% of patients with psoriatic arthritis have only a partial response or fail to respond to such treatments. Cytokine University Hospital and
inhibitors, mainly those specific for tumour necrosis factor and, more recently, the interleukin 23–T-helper-17 cell University College Dublin,
pathway, have been highly successful in the treatment of disease manifestations in several different tissues, although Dublin, Ireland
(Prof D J Veale MD,
targeting the interleukin 23–T-helper-17 cell pathway might be more effective in psoriasis than in arthritis. However,
Prof U Fearon PhD); and
the precise mechanisms underlying the pathogenesis of psoriatic arthritis—which include genetics, environmental Department of Molecular
factors, and immune-mediated inflammation—are complex, and the relationship between disease of the joint and Rheumatology, Trinity
that of other domains is poorly understood. Improving our understanding of psoriatic arthritis pathogenesis could Biomedical Science Institute,
Trinity College Dublin, Dublin,
help to establish validated biomarkers for diagnosis, predict therapeutic response and remission, develop precision
Ireland (Prof U Fearon)
medicines, and predict which patients will respond to which therapy. We discuss advances in pathogenetic translational
Correspondence to:
research that could inform these issues. Prof Douglas J Veale,
Rheumatology EULAR Centre of
Introduction precedes clinical joint involvement, although this notion Excellence, St Vincent’s
University Hospital, Dublin 4,
Psoriatic arthritis is a common inflammatory disease of remains controversial.7 The pathology of an entheseal
Ireland
the peripheral and axial skeleton. Psoriatic disease in lesion, in which mechanical stress is hypothesised to be a douglas.veale@ucd.ie
general remains poorly defined because of its varied trigger, can differ from that of the skin and the synovial
clinical features, which include enthesitis, dactylitis, nail joint.8 Dactylitis—inflammation of an entire digit—is also
dystrophy, uveitis, and osteitis, in addition to associated com­mon and is a useful diagnostic feature.9 Ultrasound
comorbidities such as obesity, metabolic syndrome, and scanning suggests that dactylitis is indicative of both joint
cardiovascular disease. Many studies of psoriatic arthritis synovitis and tenosynovitis, whereas MRI studies suggest
have focused on the skin and joints; however, in the past that it rep­resents enthesitis.9,10 Arthritis of the distal inter­
10 years, important advances have concentrated on the phalangeal joint is associated with inflammation of the
entheses—although in which tissue the disease begins nail bed, which might also represent enthesitis, as the nail
probably varies between individuals. The importance of bed and inter­phalangeal joint share common tendinous
associated comorbidities and their effects on mortality has insertions.11
also been recognised.1 In this Series paper, we focus on
gene–environment interactions, immune-mediated mech­ Genetic and environmental factors
anisms in the synovial tissue and entheses, and how these Psoriatic arthritis is characterised by complex genotypes,
factors could form the basis of new treatment strategies. a detailed account of which is beyond the scope of this
Synovial membrane inflammation, characterised by Series paper. In brief, genome-wide association studies
increased vascularisation and immune cell infiltration, is a and studies of heritability and HLA alleles have provided
key feature of psoriatic arthritis.2–4 The infiltrating immune substantial evidence that psoriatic arthritis has a genetic
cells release proinflammatory mediators that activate component that is stronger than and distinct from that of
fibroblast-like synoviocytes, which then invade adjacent psoriasis.12 Twin and family studies of psoriatic arthritis
cartilage and bone. Activation of monocytic progenitor in European populations have reported greater
cells to form osteoclasts further mediates bone resorption, concordance in monozygotic twins (80–100%) than in
resulting in joint deformity and loss of function.5 Synovial
inflammation and bone erosion are important features
with respect to diagnosis and treatment, as radiographic Search strategy and selection criteria
changes occur within 2 years of disease onset in up to We searched PubMed using the terms “psoriatic”, “arthritis”,
47% of patients.6 “pathogenesis”, “genetics”, and “inflammatory synovitis”. The
Enthesitis—inflammation of the connective tissue be­ search included all articles published in the English language
tween tendon or ligament and bone—is a common feature until March 16, 2018. We prioritised original articles specific
of psoriatic arthritis. MRI studies suggest that enthesitis, to psoriatic arthritis.
evidenced by bone marrow or soft tissue inflam­mation,

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Locus Pathogenic function
HLA-B 6 Presents peptide to CD8-positive T cells
HLA-Cw6 6p21.3 Susceptibility marker for psoriasis
RUNX1 17q25 Transcription factor that promotes T-helper-17 cell differentiation
IL12B 5q33.3 Expressed by activated macrophages that serve as essential inducers of T-helper-1
cell development
TNFAIP3 6 Promotes survival of CD4-positive T cells; associated with inflammatory
autoimmune diseases
1p13 Lymphocyte-specific tyrosine phosphatase that regulates activation of several
PTPN22
immune cells
IL23R 1p32.1–1p31.2 Activation and maintenance of CD8-positive T cells and T-helper-17 cells
IL13 5q31.1 T-helper-2 cell-mediated immunity; gene–environment interaction with tobacco
Table 1: Key candidate genes with single-nucleotide polymorphisms with possible functional links to
psoriatic arthritis pathogenesis
dizygotic twins.12,13 For first-degree relatives (compared
with unrelated population controls), an Icelandic study
calculated a risk ratio of 40 for psoriatic arthritis,14 in
contrast to a risk ratio of 8 for psoriasis.15
Initial HLA studies identified the HLA-Cw6 locus as a
strong determinant of psoriasis and psoriatic arthritis;
however, a study published in 2016 indi­cated that this
locus is primarily associated with cutaneous psoriasis,16
and that specific HLA susceptibility genes might define
different subphenotypes of psoriatic arthritis. For
example, the HLA-B*27:05:02 haplotype was reported to
be positively associ­ated with enthesitis, dactylitis, and
symmetric sacro­ iliitis, whereas the HLA-B*08:01:01–
HLA-C*07:01:01 haplo­types were associated with joint
fusion, deformities, asym­ metrical sacroiliitis, and
dactylitis, and other alleles were protective.16 These
results reflect a cross-sectional cohort analysis and
require further validation in longitudinal cohorts.
Several reports have identified non-HLA loci associated
with psoriatic arthritis (table 1), including IL23R and
TNFAIP3.12,17 Other studies have reported an association
between psoriatic arthritis and the IL13 gene locus at
chromosome 5q31,18–20 although larger studies now link
this susceptibility locus specifically to psoriasis.21,22 Pheno­
type misclassification remains a possible con­founder in
such studies, as patients with psoriasis might have
undiagnosed psoriatic arthritis. More recently, a large,
case-control, genotyping association study identified
a psoriatic arthritis-specific variant at the IL23R locus
and a novel association with chromosome 5q31.23 Fur­
ther analysis revealed a specific single-nucleotide
polymorphism mapped to a chromosomal site encoding
transcription factors that are important for the differ­
entiation of CD8-positive memory T cells. This evidence
indicates a potential gene–environment inter­action. These
genetic associ­ations implicate specific cytokine pathways,
such as those of tumour necrosis factor (TNF) and
interleukin 23, in the pathogenesis of psoriatic arthritis.
IL23R and other cytokine-related genes—including IL12B,
IL21, IL4, and IL5—have been implicated in psoriatic
arthritis by studies of single-nucleotide poly­morphisms.24
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IL23R was the most strongly associated gene in the largest
genome-wide association study,12 and it has been
implicated in enthesitis linked to interleukin 17 production
in an animal model of the disease.25 As in ankylosing
spondylitis, HLA-B27 is consistently associated with axial
skeletal involvement in psoriatic arthritis.15
Environmental factors, including infections, trauma,
stress, obesity, and smoking, have been implicated in the
triggering of psoriatic arthritis in genetically susceptible
subjects. Trauma is a known factor in psoriatic skin
lesions—a mechanism known as the Koebner pheno­
menon. One longitudinal study reported evidence of local
trauma before the development of psoriatic arthritis in
24·6% of patients.26 More recently, preceding bone or
joint trauma was associated with psoriatic arthritis, with
multivariate hazard ratios of 1·46 and 1·50, respectively.27
The increased prevalence of streptococcal antibodies in
patients with psoriatic arthritis indicates a role for
infection as a gene–environment interaction.28 Further
evidence includes the identification of 16S ribosomal
RNA (a molecular marker for strepto­coccal species) in
the peripheral blood and synovial fluid of patients
with psoriatic arthritis.29 The increased incidence of
psoriatic arthritis in HIV-endemic popu­lations of sub-
Saharan Africa suggests roles for both infection and
T cells.30 HIV-associated depletion of CD4-positive T cells
has been shown to induce remission of rheumatoid
arthritis, but induced acute onset or exacerbation of
psoriatic arthritis.31 It is unclear whether psoriatic disease
is directly triggered by viral infection, or by the depletion
of CD4-positive T cells and the predominance of
CD8-positive T cells.
The possible role of microbiota in the gene–environ­
ment interaction in psoriasis and psoriatic arthritis has
generated considerable interest. In a small but well-
controlled study of faecal bacteria in patients with psoriatic
arthritis compared with healthy controls, there were
significant reductions in Akkermansia, Ruminococcus, and
Pseudobutyrivibrio species.32 Faecal supernatants also
showed increased soluble IgA and decreased TNF
superfamily member 11 (RANKL) con­ centrations,
suggesting a possible link between the alteration of gut
microbiota and immune system dysfunction.
Smoking appears to increase the risk of developing
psoriatic arthritis in healthy controls but not in patients
with psoriasis.18 Smoking has been suggested to be
protective in psoriasis (the so-called smoking paradox)—
an effect related to polymorphisms in the IL13 gene.33
However, methodological limitations might explain this
observation.
Synovial pathology and cellular infiltrates
Synovial angiogenesis—the formation of new blood
vessels—facilitates leucocyte migration from the peri­
pheral blood, which results in persistent infiltration
of immune cells into the inflamed joint. In psoriatic
arthritis, activated immune cells release cytokines that
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Site of expression Source Key functions

Tumour necrosis factor Increased in synovial tissue
and synovial fluid
Interleukin 23a Increased in synovial tissue,
synovial fluid, and enthesis
Interleukin 17A/F Increased in synovial tissue,
synovial fluid, and enthesis
Interleukin 22 Increased in synovial tissue,
synovial fluid, and enthesis
Interleukin 9 Increased in synovial tissue
Interleukin 6 Increased in synovial tissue
and serum
Interleukin 15 Increased in synovial tissue
Interleukin 12 Increased in synovial tissue
and synovial fluid
Interleukin 1 Increased in synovial tissue
Granulocyte-macrophage Increased in synovial tissue
colony-stimulating factor
Interferon γ Increased in synovial tissue
Interleukin 10 Decreased in synovial tissue
Macrophages, T cells,
fibroblast-like synoviocytes, B cells production of cytokines, adhesion molecules, chemokines, and
Macrophages, dendritic cells
T cells, mast cells, natural killer cells
T cells, innate lymphoid cells
T cells
Macrophages, activated
fibroblast-like synoviocytes, B cells
Macrophages
Macrophages, dendritic cells
Macrophages, neutrophils, B cells
T cells, macrophages,
fibroblast-like synoviocytes
T cells
T cells, macrophages,
fibroblast-like synoviocytes
Activation of circulating and resident cells to induce
matrix metalloproteinases; activation of osteoclasts to
enhance cartilage and bone resorption
Promotion of T-helper-17 cell differentiation and
granulocyte-macrophage colony-stimulating factor production
Activation of fibroblast-like synoviocytes, chondrocytes, and
osteoclasts; stimulation of proinflammatory cytokine and matrix
metalloproteinase production, and neutrophil recruitment
Activation of fibroblast-like synoviocytes; induction of
osteoclastogenesis and bone resorption via RANKL
Activation of peripheral blood mononuclear cells; stimulation
of proliferation of pathogenic T cells
Activation of STAT3 signalling to enhance proinflammatory
cytokine production
Promotion and maintenance of T-cell and natural killer cell
activation
Promotion of T-helper-1 cell differentiation through STAT4
Proinflammatory signalling
Recruitment and activation of immune cells
Promotion of macrophage phagocytosis, T-cell activation, and
RANKL secretion
Anti-inflammatory signalling

RANKL=TNF superfamily member 11. STAT=signal transducer and activator of transcription.

Table 2: Key cytokines and their expression, source, and function in psoriatic arthritis

drive inflammation (table 2). Fibroblast-like synoviocytes
show an abnormal phenotype characterised by increased
proliferation and invasiveness, transforming the synovial
membrane into a tumour-like pannus capable of des­
troying articular cartilage and bone (figure 1).
Angiogenesis
Espinoza and colleagues were the first to identify
vascular changes—characterised by endothelial cell
swelling and inflammatory cell infiltration—in the
psoriatic syno­vium.34 Notably, there are increased blood
vessels in the synovial lining layer in psoriatic arthritis,
in contrast to the thickened, avascular synovial lin­
ing seen in rheumatoid arthritis.35 The most striking
difference in psoriatic arthritis is the macroscopic
vascular pattern, characterised by elongated, tortuous,
dilated vessels, compared with the straight, regularly
branching blood vessels observed in rheumatoid
arthritis.36,37 In psoriatic arthritis, a substantial number
of vessels in the synovium are immature, in contrast to
normal tissue, where complete recruitment of pericytes
is observed.38 The presence of immature vessels suggests
that many of the vessels remain in a plastic state and,
thus, primed for endothelial cell activation and sprout­
ing. Consistent with this notion, decreased endothelial
apoptosis, along with increased synovial expression of
various angiogenic growth factors—including vascular
endothelial growth factor (VEGF) and its receptors
(VEGFR1 [also known as FLT1] and VEGFR2 [KDR]), and
angiopoietin 1 and 2 and their receptor TIE2 (TEK)—as
well as cytokines (TNFα, transforming growth factor β,
and interleukin 17A) and neural cell adhesion molecule
have been detected in synovium of patients with psoriatic
arthritis.38–41 The increased expression of growth factors
in the synovium in early psoriatic arthritis compared
with rheuma­toid arthritis suggests that the mechanisms
regulating the distinct vascular morphology occur at an
early stage of disease.42 Consistent with this notion,
VEGF and angiopoietin 2—which synergistically in­
duce the Notch–Dll4 interaction, a key signalling path­
way involved in vessel sprouting—are more highly
expressed in the synovium in psoriatic arthritis
(compared with that in rheumatoid arthritis or
oligoarthritis) and in skin affected by psoriasis compared
with normal skin.43
As the psoriatic synovium is highly metabolically
active, it is hypoxic despite its increased vascularity.38,44
Synovial pO2 correlates inversely with synovitis, immune
cell infiltration, and activation of proinflammatory
mediators. Emerging evidence suggests that this hypoxic
microenvironment induces a switch in the metabolic
phenotype of synovial cells to maintain energetic
homoeostasis. Altered mitochondrial function, oxidative
damage, and increased glycolytic enzymes have been
observed in the psoriatic synovium.45–48 This metabolic
shift towards glycolysis results in the activation of T cells,

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Dysfunctional blood vessels

Endothelial cells

Leucocyte invasion

Th1 Th2 Treg Th9 Th22 Th17 ILC NK MAIT

Dendritic cell Macrophage Mast cell Neutrophil

TNFα, IL-4, IL-10, IL-9, IL-22, IL-17A, IL-17A, IFNγ, IL-17A, IL-23, IL-6, TNFα, IL-18, IL-17A, IL-1B, OSM,
IFNγ, IL-5, IL-35, IL-17, TNFα IL-17F, IL-22 TNFα IFNγ IL-12, IL-18, IL-6, IL-12, IL-17F IL-6, IL-17,
IL-2, IL-10, TGFβ IL-21 IL-22, IL-21, IL-23, IL-15, IL-19, IL-18, TNFα,
RANTES IL-13 TNFα IL-33, TNFα, IL-20, IL-23, GM-CSF,
IFNγ, TGFβ IL-24, IL-26, MMPs, MIF
IL-32, IL-33,
IL-38, OSM,
GM-CSF,
ROS, NO

Inflammation

IL-1B, IL-6, IL-8, IL-15, IL-18, IL-19, MMPs, NO, RANKL Cathepsin K,
IL-20, IL-26, IL-34,IL-38, MIF, MMPs, ADAMTS MMPs
GM-CSF, growth factors, RANKL

Fibroblast Chondrocyte Osteoblast Osteoclast

Synovitis, cartilage damage, and bone erosion

Disability

Figure 1: Key cell types and secretion of key inflammatory mediators in psoriatic arthritis
T-cell subpopulations Th1, Th2, Th17, Th9, Th22, and Treg cells secrete proinflammatory or anti-inflammatory cytokines. Dendritic cells, macrophages, ILCs, MAIT
cells, NK cells and mast cells produce mostly proinflammatory cytokines. These proinflammatory mediators activate resident cells, including synovial fibroblasts,
chondrocytes, osteoblasts, and osteoblasts, which in turn secrete more proinflammatory mediators that can further recruit immune cells into the joints, creating a
self-perpetuating inflammatory response. Additionally, synovial fibroblasts secrete matrix-degrading enzymes and RANKL, resulting in cartilage degradation and
bone resorption. The inflamed synovial microenvironment leads to the formation of the synovial pannus, entheseal inflammation, and joint destruction. Th=T-helper
cell. Treg=regulatory T cell. ILC=innate lymphoid cell. MAIT=mucosal-associated invariant T. NK=natural killer. RANKL=TNF superfamily member 11. TNFα=tumour
necrosis factor α. IFNγ=interferon γ. IL=interleukin. TGFβ=transforming growth factor β. RANTES=C-C motif chemokine ligand 5. OSM=oncostatin M.
GM-CSF=granulocyte-macrophage colony-stimulating factor. ROS=reactive oxygen species. NO=nitric oxide. MMPs=matrix metalloproteinases. MIF=macrophage
migration inhibitory factor. ADAMTS=ADAM metallopeptidase with thrombospondin type 1 motif.

macrophages, fibroblast-like synoviocytes, and dendritic
cells, further perpetuating the inflammatory response.49–54
Furthermore, several studies of fibroblast-like syno­
viocytes, endothelial cells, T cells, synovial explants, and
animal models of arthritis have shown that targeting
specific metabolic enzymes inhibits inflammatory
mechanisms and joint destruction.50,53–57 In this hypoxic
and inflam­ matory microenvironment, immune cells
adapt to survive through altering their metabolism,
which in turn leads to the activation of key signalling
pathways, cytokine production, and increased systemic
inflammation. This interaction between metabolic
alterations and immune system perturbation might
underlie the increase in comorbidities associated with
psoriatic arthritis, in the absence of conventional risk
factors.58

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Innate immune cells
Dendritic cells
Dendritic cells activate the adaptive immune response
through antigen presentation and cytokine secretion to
generate distinct subsets of T cells.59 The ratio of myeloid
dendritic cells to plasmacytoid dendritic cells is signifi­
cantly increased in the synovial fluid in psoriatic
arthritis, indicating a predominance of an immature
phenotype among these dendritic cells, which remain
responsive to Toll-like receptor ligands.60,61 This immature
pheno­type might further perpetuate disease by allowing
the cells to respond to the synovial microenvironment
and arthritogenic antigens. Immature dendritic cells in
psori­atic arthritis show upregulated expression of Toll-
like receptor 2, but not Toll-like receptor 4, and this
phenotype induces a T-helper-1 (Th1) cell response
with increased production of TNFα, interferon γ, and
interleukin 12.62
The expression of CLEC9A is specific to CD141-positive
dendritic cells, which are localised in close proximity
to CD8-positive T cells, and CLEC9A is reduced after
TNF inhibitor treatment, suggesting a novel mechanism
for TNF inhibitor therapy and providing further evidence
of the role of CD8-positive T cells in the pathogenesis
of psoriatic arthritis.63 The co-localisation of these
two cell types is consistent with the specialised ability of
den­dritic cells to cross-present exogenous antigens to
naive CD8-positive T cells. Thus, the prevalence of syno­
vial CD8-positive T cells in psoriatic arthritis might
be partly explained by the inappropriate activation of
dendritic cells.64
Impaired secretion of proinflammatory cytokines by
dendritic cells isolated from patients with psoriatic
arthritis following in-vitro challenge with mycobacteria
and Toll-like receptor 2 ligands has been shown, paralleled
by an increase in the intracellular expression of SOCS3
and TNFAIP3.65 Dendritic cells in psoriatic arthritis also
express the immune response molecules ATG16L1,
NADPH oxidase 2, and LL37, which can be trans­ported to
endosomes to activate Toll-like receptors, leading to the
produc­tion of pro­inflammatory cyto­kines.65,66 Furthermore,
the dendritic cell-derived cyto­ kines interleukin 23 and
interleukin 12 orchestrate the differentiation of the distinct
Th17 and Th1 subsets of T  cells, respectively, which are
known to be important in the pathology of psoriatic
arthritis.67
Macrophages
Activated macrophages promote various proinflammatory
mechanisms in the synovium. M1 macrophages are
classically activated and proinflammatory, and play a
central role in host defence against infection, whereas
M2 macrophages are alternatively activated and associ­
ated with anti-inflammatory responses and tissue re­
modelling. Abundant secretion of proinflammatory
cyto­kines by macrophages is a striking feature of psoriatic
arthritis. Macrophages also secrete large amounts of
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matrix metalloproteinases and inducible nitric oxide
synthase, present antigens to T cells and B cells, and
drive bone resorption, suggesting a predominant M1
macrophage phenotype in inflammatory arthritides.68
Histological analysis shows that macrophages are a
prominent cell type in the synovium in psoriatic arth­
ritis; however, comparative studies have shown
significantly lower numbers of synovial CD68-positive
macrophages in psoriatic arthritis than in rheumatoid
arthritis.2,69 Fewer interleukin 1β-positive cells are present
in the synovial membrane lining layer in psoriatic arth­
ritis, paralleled by decreases in TNFα and interleukin
15 expression.69 However, the amounts of newly re­
cruited CD14-positive macrophages—which predom­
inantly secrete monokines—are similar in psoriatic
arthritis and rheumatoid arthritis in the synovium.69
Although clini­cally effective biological agents consistently
reduce synovial infiltration of CD68-positive macro­
phages in psoriatic arthritis, 70 studies of remission show
high residual amounts of CD68-positive, CD3-positive,
and CD31-positive cells, which might partly explain the
high proportion of patients who relapse after the discon­
tinuation of treatment.71
No difference in M2 cytokine expression but an
increase in M1 cytokine expression in rheumatoid arth­
ritis versus psoriatic arthritis has been observed,72
suggesting alternative polarisation of macrophages in
the two arthritides. However, it is now apparent that
macrophage phenotypes within the joint are more
complex than this simplistic view suggests, showing
remarkable plasticity and diversity in response to
environmental cues, which induce different macro­
phage populations between the M1 and M2 phenotypes
with distinct functions.68
Innate lymphoid cells
Innate lymphoid cells are a rare immune cell population
that are implicated in the development of psoriatic skin
lesions, where they play a key role in epithelial prolif­
eration and cytokine production.73 Type 3 innate lymphoid
cells are enriched in the synovial fluid in psoriatic
arthritis compared with rheumatoid arthritis, show
increased expression of CCR6 and NK-p44, and potently
produce interleukin 17A.74 A significant increase in
circulating type 3 innate lymphoid cells (producing
interleukin 17 and interleukin 22) and a decrease in
type 2 innate lymphoid cells (pro­ducing interleukin 4,
interleukin 5, interleukin 9, and interleukin 13) have
been shown in patients with psoriatic arthritis com­
pared with healthy controls, with the ratio of
type 2 to type 3 innate lymphoid cells significantly
correlated with joint inflammation and bone damage.75
In animal studies, treatment with interleukin 9 promoted
type 2 innate lymphoid cell-dependent activation of
regulatory T cells, leading to resolution of inflam­mation
and a decrease in cartilage destruction and bone loss.76
These find­ings suggest a key role for differ­ent subsets of
 Series
innate lymphoid cells and the Th17–interleukin 22 axis in
psoriatic arthritis.
Mucosal-associated invariant T cells and natural killer cells
Mucosal-associated invariant T (MAIT) cells and natural
killer cells are also important innate cells implicated in
autoimmune diseases. Although little is known about
MAIT cells in psoriatic arthritis, a study using an animal
model of arthritis showed that adoptive transfer of
MAIT cells induced inflammation and exacerbated dis­
ease severity.77 MAIT cells are enriched in the syn­
ovial fluid of patients with ankylosing spondylitis, and
potent­ly produce interleukin 17A,78 an effect primed by
interleukin 7 and not interleukin 23. Furthermore, an
increase in interleukin 17A-producing CD8-positive
MAIT cells has been shown in psoriatic skin and in
synovial fluid in psoriatic arthritis.79,80 Thus, MAIT cells
serve as an alternative source of interleukin 17A at the
site of inflammation.
Natural killer cells have both protective and pathogenic
roles, which are regulated by activating receptors and
inhibitory receptors. Synovial natural killer cells in
psoriatic arthritis show increased expression of the
activation markers CD69 and NK-p44, with increased
production of interferon  γ and TNFα compared with
peripheral blood cells.81 Interleukin 15 in the joint
microenvironment can prime natural killer cells to kill
via activation of NKG2D and cPLA2.82 Increased amounts
of circulating CD16-positive CD56-positive natural killer
cells have also been shown during etanercept treatment
in patients with psoriatic arthritis, associated with a good
to moderate clinical response.83
Mast cells
Interleukin 17A-expressing mast cells are present in the
synovial fluid and synovial membrane in psoriatic arth­
ritis.84 Histamine and tryptase released from mast cells
can promote synovial angiogenesis and neutrophil
recruit­ment, suggesting that mast cells might play an
active role in the inflammatory cascade.85
Adaptive immune cells: T cells and B cells
Lymphocytes are the most frequent immune infiltrates
in psoriatic arthritis. Lymphoid aggregates of T cells
and B cells have been found in the psoriatic arthritis
synovium, and the absence of these aggregates is
associated with disease remission.86 Larger aggregates
are suggested to be associated with increased disease
activity.87 The role of B cells in the pathogenesis of
psoriatic arthritis is unclear; they might be involved
in antigen presentation, co-stimulation of T cells, or
synthesis of soluble mediators, but this remains to
be verified.
The key role of T cells in the pathogenesis of psori­
atic arthritis is evidenced by a substantial increase
in T-cell-derived cytokines—including interferon  γ,
interleukin 2, interleukin 4, TNFα, interleukin 17A, and
2278 www.thelancet.com Vol 391 June 2, 2018
granulocyte-macrophage colony-stimulating factor—in
the synovial fluid and inflamed synovium of patients
with psoriatic arthritis.88 Furthermore, the association
between clinical response and the effectiveness of T-cell-
targeted therapies in reducing the numbers of synovial
CD4-positive and CD8-positive cells demonstrates the
key role of T cells in psoriatic arthritis synovial pathology.
Further evidence for the role of T cells in psoriatic
arthritis pathogenesis is provided by the strong genetic
associations of the disease with MHC-I and MHC-II
molecules. CD4-positive and CD8-positive T cells are
abundant in psoriatic arthritis synovial tissue,2 and the
chemokine receptor CCR4 and its ligand MDC (CCL22),
which are required for T-cell migration, are also increased
in the synovial fluid and tissue.89 However, the decreased
ratio of CD4-positive to CD8-positive T cells in the
synovial fluid and tissue, along with the predominant
MHC-I association of CD8-positive T cells, suggests a
role for CD8-positive T cells in driving the pathogenesis
of psoriatic arthritis.90 CD8-positive T cells derived from
the psoriatic arthritis synovium are clonally expanded,
yet the self-peptide or pathogenic antigen for this clonal
expansion is yet to be identified.91,92
Psoriatic arthritis was originally considered to be a
Th1-mediated disease, with large amounts of interferon γ
and interleukin 12 produced.93 Subsequently, however,
other Th cell subpopulations and their cytokines have
been identified and are now thought to be crucially
involved in pathogenesis of the disease. For many years,
studies of T-cell cytokine expression in psoriatic arth­
ritis have focused on CD4-positive T cells, which ex­
press TNFα; however, much of the focus now is on
Th17 cells, interleukin 23, and interleukin 17.94 Naive
T cells differentiate into Th17 cells following acti­
vation by transforming growth factor β, interleukin 6,
interleukin 21, and interleukin 1β. Th17 cells pro­
duce a range of proinflammatory cytokines, including
interleukin 17A, interleukin 17F, interleukin 21, interleukin
22, interleukin 25, interleukin 26, and TNFβ.95,96 Several
studies have shown that the frequencies of Th17 cells are
increased in the circulation of patients with psoriatic
arthritis, and are further increased in the synovial fluid,96,97
where they show a highly differentiated and polyfunctional
pheno­type. Interleukin 17-positive CD8-positive T cells
are enriched in the synovial fluid in psoriatic arthritis,
and are associated with erosive disease.97 The accumu­
lation of interleukin 17-producing cells in the joint
in­duces synovial tissue inflammation and angiogen­
esis, acts synergistically with other cytokines (includ­
ing interleukin 1β, TNF, and oncostatin M) to
upreg­ ulate matrix metalloproteinases, and potently
increases osteo­clastogenic act­ivity.98–100 Single-nucleotide
poly­morphisms in IL12B, IL23A, IL23R, and STAT3, the
protein products of which are involved in the differ­
entiation of Th17 cells, confer susceptibility to psor­
iatic arthritis.24,101 CXCL4 potentiates the production
of proinflammatory cytokines—especially interleukin

17A—by human CD4-positive T cells, either directly or
indirectly (via myeloid antigen-presenting cells).102 Evi­
dence that Th17 cells play a key role in psoriatic arthritis
is supported by clinical responses to anti-interleukin 17A
antibodies.103 Expression of interleukin 17F, which is
structurally similar to interleukin 17A, is increased in
the psoriatic synovium, though its function has not
been examined.104 In rheumatoid arthritis, interleukin
17F has the ability to activate fibroblast-like synovio­
cytes,105 and a dual inhibitor of interleukin 17A and
interleukin 17F (bimekizumab) has shown clinical
efficacy for mild psoriasis.106
Although Th17 cells produce many cytokines, including
interleukin 22, data suggest that a subset of CD4-positive
T cells produce only interleukin 22, independently
of interleukin 17A, and these cells have been termed
Th22 cells.107 In patients with psoriatic arthritis,
interleukin 22 is increased in the synovial fluid compared
with the peripheral blood, and its concentration is
reduced after TNF inhibitor therapy.108 The number of
T cells expressing CCR6 and interleukin 23 receptor are
higher in the synovial fluid than in the peripheral blood
in patients with the disease.95 In peripheral blood,
increased proportions of both interleukin 17-positive
CCR6-positive and interleukin 17-positive CCR4-positive
cells are found in patients with psoriatic arthritis
compared with those with psoriasis. By contrast, al­
though elevated frequencies of CD4-positive interleukin
17-positive cells have been observed in the synovial fluid
compared with the peripheral blood, the frequencies of
CD4-positive interleukin 22-positive T cells are lower.95
The differential expression of these T-cell subsets at
disease sites—including the lower frequencies of
interleukin 22-positive CD4-positive T cells in the
joint com­ pared with the skin, and the absence of
interleukin 22 expression in the synovial tissue—suggests
that Th17 and Th22 cells might have different roles in
joint and skin disease. How­ever, interleukin 22 can acti­
vate fibroblast-like synoviocytes via the PI3K–mTOR
pathway,109 induce osteoclastogenesis (an effect mediated
by RANKL via activation of the p38 MAPK–NF-κB and
JAK2–STAT3 signalling pathways110) and promote the
proliferation, migration, and osteogenic differentiation of
mesen­ chymal stem cells.111 Furthermore, in a mouse
model of psoriatic arthritis (R26STAT3Cstopfl/fl CD4Cre
mice), augmentation of Th17-mediated inflammation
induced cutaneous and synovio-entheseal inflammation,
paralleled by bone resorption—effects that were med­iated
by interleukin 17A and interleukin 22.112 These studies
provide convincing evidence of a key role of interleukin 22,
in addition to interleukin 17, in the pathogenesis of
psoriatic arthritis.
Th9 cells, a newly recognised subset of effector T cells,
have been implicated in several autoimmune dis­
eases. Interleukin 9 signals through the JAK–STAT
system, the components of which are increased
in joints affected by psoriatic arthritis.113 In the
www.thelancet.com Vol 391 June 2, 2018 2279
Series
synovium, interleukin 9 and its receptor are pre­
dominant­ ly expressed on fibroblast-like syno­ viocytes,
syno­vial vessels, and Th9 cells in patients with psoriatic
arthritis.114 Th9 cells are also expanded in the peripheral
blood and syno­vial fluid, and their abundance correlates
with disease activity and is reduced following TNF
inhibitor and ustekinumab therapy.115
In inflammation, Th17 cells also produce interleukin 9,
blockade of which decreases the numbers of Th17 cells
and interleukin 6-producing macrophages in vivo.115
Further­more, interleukin 9 induces Th17 cell differen­
tiation and potentiates the suppressive effect of regulatory
T cells via activation of STAT3 and STAT5.116 One of the
main functional roles of the interleukin 9–interleukin
9 receptor axis in psoriatic arthritis is promoting the
proliferation and survival of pathogenic T cells.117 Ciccia
and colleagues,118 showed that activation of peripheral
blood mononuclear cells with recombinant interleukin 9
in psoriatic arthritis resulted in subsequent expan­
sion of Th9 and Th17 cells, with increased produc­
tion of interleukin 17 and the transcription factor
PU.1, paralleled by a decrease in interleukin 10. Thus,
the interleukin 9–interleukin 9 receptor axis contrib­
utes substantially to joint inflammation as a T-cell
growth factor.118
Synovial fibroblasts
The lining layer of the synovium consists of resident
macrophages and fibroblast-like synoviocytes, which are
fundamental to disease progression and actively drive joint
destruction.119 Fibroblast-like synoviocytes are character­
ised by increased proliferation, resistance to apoptosis,
anchorage independence, increased invasiveness, and the
production of proinflammatory cytokines and matrix-
degrading enzymes.119–123 Furthermore, cadherin 11, a key
protein involved the cytoskeletal dynamics of fibroblast-
like synoviocytes, is overexpressed in the synovium in
psoriatic arthritis.124
Activation of an abnormal pathogenic phenotype of
fibroblast-like synoviocytes occurs in response to autocrine
fibroblast growth factor signalling or via activation by
other cytokines produced within the joint (including
TNFα, interleukin 1, interleukin 17A, interleukin 22, and
interleukin 36α), the effects of which are mediated by
key signalling pathways, including NF-κB, JAK–STAT,
and PI3K–mTOR.98,109,119–123 MHC-II molecules have been
identified on fibroblast-like synoviocytes of the inflamed
synovium but not on normal fibroblast-like synoviocytes,
suggesting that these cells have the capacity for antigen
presentation to activate the adaptive immune response.125
Angiogenic growth factors, chemokines, and adhesion
molecules derived from fibroblast-like synoviocytes in­
duce angiogenic mechanisms, and recruit and facili­
tate the migration of immune cells into the inflamed
synovium.126–130 Additionally, fibroblast-like synoviocytes in
psoriatic arthritis contribute to osteoclastogenesis through
increased expression of RANKL, TNFα, and interleukin 7.131
 Series

Endothelial cell
Monocyte
Dysfunctional angiogenesis

Pericyte

T cell and B cell

Macrophage

Dendritic cell
Immune cell infiltration

Synovium
B cell
IL-12, IFNγ
Antigens Th1 Bone
ILC
Macrophages IL-17A, IL-22
IL-4
Th2 NK MAIT Osteoclast
TNFα, IFNγ IL-17A, IFNγ
IL-23, IL-21,
Th17 IL-1, TNFα, IL-6
IL-6, TGFβ IL-23 Mast cell

IL-17
Synovial fibroblast
TNF, IL-6
Th22 IL-22 activation IL-17A, IL-17F
TNAIVE
Enthesis
Dendritic cell Cartilage damage
IL-4, TGFβ
Th9 IL-6, IL-8,
RANKL, MMPs
IL-23, IL-17A,
IL-12, TGFβ-1 MMPs, ADAMTS IL-22, TNF
Treg

Figure 2: Adaptive and innate immune cells and activated pathways in psoriatic arthritis
Dysfunctional angiogenesis and activation of endothelial cells are early events that facilitate immune infiltration of synovial tissues in psoriatic arthritis. DCs play a
key role in the activation and coordination of the inflammatory response, activating T cell subpopulations (Th1, Th2, Th17, Th9, Th22, and Treg), which secrete
proinflammatory or anti-inflammatory cytokines. Additionally, macrophages, ILCs, MAIT cells, NK cells, and mast cells are potent producers of predominantly
proinflammatory cytokines. The exact role of B cells is unclear, but they are able to present antigens to T cells. IL-23, TNF, IL-17, and IL-22 appear to be key cytokines in
driving inflammation and activating resident cells in the joint and at the enthesis, including synovial fibroblast-like synoviocytes, chondrocytes, osteoblasts, and
osteoclasts. These resident cells primarily secrete matrix-degrading enzymes and RANKL, resulting in cartilage degradation, bone erosion, and joint damage. The
activated resident cells also secrete proinflammatory mediators to recruit more immune cells, creating a persistent response. DC=dendritic cell. Th=T-helper cell.
Treg=regulatory T cell. ILC=innate lymphoid cell. MAIT=mucosal-associated invariant T. NK=natural killer. IL=interleukin. TNF=tumour necrosis factor. RANKL=TNF
superfamily member 11. TNAIVE=naive T cell. IFNγ=interferon γ. TGFβ=transforming growth factor β. MMPs=matrix metalloproteinases. ADAMTS=ADAM
metallopeptidase with thrombospondin type 1 motif.

Functionally distinct fibroblast subsets, identified by their
expression of CD248, CD55, and podoplanin, have been
identified in the inflamed synovium, including that in
psoriatic arthritis, and their depletion in animal models
has been shown to result in attenuation of the disease.132,133
Using advanced high-throughput technologies, studies of
rheumatoid arthritis have further identified distinct
fibroblast-like synoviocytes that show functional diversity
in the inflamed joint.134 Expansion of these studies to
investigate psoriatic arthritis might identify pathogenic
subsets of synovial cells specific to the disease.
Structural changes: cartilage, bone, and entheses
The inflammatory synovium primarily causes damage to
the cartilage and bone as a result of synovial tissue
invasion and release of powerful matrix-degrading
enzymes (figure 2). The production of matrix metallo­
proteinases and other enzymes by fibroblast-like synovio­
cytes results in the breakdown of collagen, proteoglycans,
and gelatins, which facilitates the invasion of fibroblast-
like synoviocytes and endothelial cells.42 Fibrillation of
the cartilage surface develops, and chondrocytes under­
go apoptosis, resulting in permanent cartilage damage
that is visible as a narrowing of the joint space on
radiographs.135
Bony changes in psoriatic arthritis include bone erosion
and new bone growth within the same microenvironment.135
The bone erosions are architecturally distinct from those
seen in rheumatoid arthritis and oligoarthritis: distant
from the cartilage–pannus junction, they are often small

2280 www.thelancet.com Vol 391 June 2, 2018


and located close to to periosteal bone proliferation
(originally described as a fluffy periosteal reaction),
creating a so-called inverted omega appear­ance.136,137 Bone
erosion is initiated by cytokine (specifically RANKL)
activation of osteoclasts, which differentiate into mature
cells.138 Activated osteoclasts have cross-linked surface Fcγ
receptor IV, indicating that immune-complex binding is
directly involved in the differentiation and maturation
process.138 The mature osteoclasts act dir­ectly on the bone
at the articular margin, resulting in destruction and bone
erosion. Interleukin 17 does not appear to directly activate
osteoclasts, but stimu­lates osteoblasts to produce RANKL,
which results in osteoclastogenesis.138
Interleukin 22 is implicated as a proinflammatory
cytokine at the site of bone erosion; however, it also
promotes osteoblast function by upregulating expression
of the pro-osteogenic factors Wnt-3a, Wnt-10b, and bone
morphogenetic protein (BMP)4. Thus, interleukin 22
might contribute to the complex juxtaposition of bone
erosion and bone formation in psoriatic arthritis.139,140
Sherlock and colleagues developed an animal model of
enthesitis in which they identified activated Th17 cells
expressing the interleukin 23 receptor, ROR-γt, and
stem cell antigen 1 at the entheseal site, which produced
interleukin 6, interleukin 17, interleukin 22, and CXCL1
in response to interleukin 23 stimulation in vitro.25 It
therefore seems that interleukin 23 is the central
cytokine, with interleukin 17 and interleukin 22 also
involved, at the site of bone erosion and enthesitis in
spondylo­arthropathies. This collect­ive evidence provides
a strong rationale for targeting interleukin 17 with
monoclonal antibody therapy, which has already shown
some efficacy in psoriatic arthritis.141
New bone formation occurs through reactivation of
embryonic signalling pathways, and probably represents
an essential repair process to maintain bone homeostasis.
BMPs are key signalling molecules in this process. In
animal studies of arthritis, genetic transfer of the BMP
antagonist noggin prevented new bone formation and
progression of ankylosis in the arthritic joint.142 In the
same study, BMP2, BMP6, and BMP7 were specifically
expressed at sites of enthesitis undergoing ossification.
New bone formation is as important as bone erosion in
the development of functional impairment; however, the
regulation of bone formation in psoriatic arthritis
remains poorly understood, with conflicting data about
the roles of Wnt pathway components.
Conclusion
Psoriatic arthritis is a complex manifestation of a disease
characterised by diverse clinical phenotypes involving
the joints, skin, nails, entheses, and other tissues. The
genetic factors associated with arthritis and with skin
disease have become more clearly defined, and appear to
be quite distinct from one another. The evidence for
gene–environment interactions in the pathogenesis of
the disease has identified possible modifiable risk factors,
www.thelancet.com Vol 391 June 2, 2018 2281
Series
including smoking, trauma, and infection. Furthermore,
although only a small amount of data implicating the
microbiota is available, alterations in the skin and gut are
worthy of further investigation.
There is substantial evidence for immune-mediated
inflammation in the pathogenesis of psoriatic disease,
with many of the changes shared across the different sites
involved. Evidence for the role of pathogenic CD8-positive
memory T cells and activation of the TNF and
interleukin 23–Th17 pathways has led to the successful
development of a therapeutic strategy to target components
of these pathways. Therefore, although the cause remains
elusive, understanding of the genetic, cellular, and
molecular factors involved in pathogenesis has advanced.
Despite the advances in molecular -omic technologies,
as yet, there are no validated biomarkers for diagnosis,
prediction of therapeutic response, or remission. It is
hoped that, with advances in cellular isolation, single-cell
RNA sequencing, mass cytometry, and novel imaging
technologies (such as positron emission tomography),
these unmet needs can be addressed successfully. In the
clinical setting, it remains a challenge to assess disease
activity and accurately predict prognosis. As our know­
ledge of pathogenesis improves, it should become
possible to adopt personalised medicine approaches, to
define, at an early stage, which patients will respond to a
specific therapy, and to identify those in remission.
Contributors
UF and DJV contributed equally to the search, writing and editing of this
review, including the tables and figures.
Declaration of interests
DJV has advised, consulted, or participated as a speaker for AbbVie,
Actelion, BMS, Celgene, Novartis, Pfizer, MSD, Mundipharma, Roche,
and Regeneron and Sanofi. DJV and UF have received research grant
funding from AbbVie, Janssen, MSD, Novartis, Pfizer, and Roche.
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