The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

DanL. Longo, M.D., Editor

Psoriatic Arthritis
ChristopherT. Ritchlin, M.D., M.P.H., RobertA. Colbert, M.D., Ph.D.,
and DafnaD. Gladman, M.D.

P
soriasis is a common skin disease that is associated with multi- From the Allergy, Immunology, and Rheu-
ple coexisting conditions. The most prevalent coexisting condition, psoriatic matology Division, University of Roches-
ter Medical School, Rochester, NY (C.T.R.);
arthritis, develops in up to 30% of patients with psoriasis and is character- the Pediatric Translational Research
ized by diverse clinical features, often resulting in delayed diagnosis and treat- Branch, National Institute of Arthritis
ment. Initial reports emphasized a benign course in most patients, but it is now and Musculoskeletal and Skin Diseases,
Bethesda, MD (R.A.C.); and the Univer-
recognized that psoriatic arthritis often leads to impaired function and a reduced sity Health Network (UHN) Krembil Re-
quality of life.1,2 Fortunately, improved knowledge about disease mechanisms has search Institute, the Psoriatic Arthritis
catalyzed rapid development of effective targeted therapies for this disease. To help Program, and the Centre for Prognosis
Studies in the Rheumatic Diseases all
the clinician recognize and appropriately treat psoriatic arthritis, this review focuses at Toronto Western Hospital, Toronto
on epidemiologic and clinical features, pathophysiological characteristics, and (D.D.G.). Address reprint requests to Dr.
treatment. Ritchlin at the Allergy, Immunology, and
Rheumatology Division, University of
Rochester Medical School, 601 Elmwood
Ave., Box 695, Rochester, NY 14642, or at
Psor i at ic A r thr i t is a nd Sp ondy l oa r thr i t is christopher_ritchlin@urmc.rochester.edu.

The classic description of the clinical features of psoriatic arthritis was published N Engl J Med 2017;376:957-70.
in 1973; however, skeletal remains unearthed in 1983 from a Byzantine monastery in DOI: 10.1056/NEJMra1505557
Copyright 2017 Massachusetts Medical Society.
the Judean Desert, dating to the fifth century a.d., showed visual and radiographic
features consistent with psoriatic bone and joint disease.3,4 Psoriatic arthritis
shares genetic and clinical features with other forms of spondyloarthritis and is
grouped with these disorders.5,6 Diagnostic criteria for psoriatic arthritis have not
been validated, but the Classification Criteria for Psoriatic Arthritis (CASPAR
criteria), published in 2006, define psoriatic arthritis for the purpose of enrolling
patients in clinical trials and provide guidance to clinicians (Table1).7

Epidemiol o gy a nd Dise a se Bur den

The prevalence of psoriatic arthritis ranges from 6 to 25 cases per 10,000 people
in the United States, depending on the case definition.8 Psoriatic arthritis was
thought to be rare, but recent studies based on CASPAR criteria indicate that it
occurs in up to 30% of patients with psoriasis.9,10 These data suggest that the
prevalence of psoriatic arthritis is between 30 and 100 cases per 10,000, assuming
that 3% of the U.S. population has psoriasis. About 15% of patients with psoriasis
who are followed by dermatologists have undiagnosed psoriatic arthritis.9 The an-
nual incidence of psoriatic arthritis was reported to be 2 to 3% in a prospective
study of patients with psoriasis.11 The manifestation of psoriasis precedes that of
arthritis by 10 years on average, although in 15% of cases, arthritis and psoriasis
occur simultaneously or psoriatic arthritis precedes the skin disease. Psoriatic
arthritis is uncommon in Asians and blacks, and the male-to-female ratio is 1:1.
Psoriatic arthritis can begin during childhood. There are two clinical subtypes;
they are not mutually exclusive. Oligoarticular psoriatic arthritis (characterized by
four or fewer affected joints) has a peak onset at 1 to 2 years of age and occurs

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Classification Criteria for Psoriatic Arthritis (CASPAR).*

Criterion Explanation Points

Evidence of psoriasis
Current psoriasis Current psoriatic skin or scalp disease as judged by a dermatologist or rheu- 2
matologist
Personal history of psoriasis History of psoriasis according to the patient or a family doctor, dermatologist, 1
or rheumatologist
Family history of psoriasis History of psoriasis in a first- or second-degree relative according to the patient 1
Psoriatic nail dystrophy Typical psoriatic nail dystrophy (e.g., onycholysis, pitting, or hyperkeratosis) 1
according to observation during current physical examination
Negative test for rheumatoid factor Based on reference range at local laboratory; any testing method except latex, 1
with preference for ELISA or nephelometry
Dactylitis
Current dactylitis Swelling of an entire digit according to observation on current physical exam 1
ination
History of dactylitis According to a rheumatologist 1
Radiographic evidence of juxtaarticular Ill-defined ossification near joint margins (excluding osteophyte formation) 1
new bone formation on plain radiographs of hand or foot

* Psoriatic arthritis is considered to be present in patients with inflammatory musculoskeletal disease (disease involving the joint, spine, or enthe-
sis) whose score on the five criteria listed in the table totals at least three points; the evidence of psoriasis criterion can account for either one
point or two points. The criteria have a specificity of 98.7% and a sensitivity of 91.4%. ELISA denotes enzyme-linked immunosorbent assay.

predominantly in girls. This form is associated onycholysis, or a family history of psoriasis

with a positive test for antinuclear antibodies
and chronic uveitis and is often characterized by
dactylitis (diffuse swelling of a toe or finger).12
The second subtype (characterized by any num-
ber of affected joints) develops between 6 years
and 12 years of age and is associated with HLA-
B27; antinuclear antibodies are usually absent.
This form has a 1:1 sex ratio, with dactylitis,
enthesitis (inflammation at tendon, ligament, or
joint-capsule insertions), nail pitting, onycholysis,
and axial involvement occurring more frequently
than in the first subtype. According to the Inter-
national League of Associations for Rheumatol-
ogy classification system, psoriatic arthritis is
distinct from other forms of juvenile idiopathic
arthritis and is defined by the coexistence of ar-
thritis and psoriasis in the absence of features
of other forms of juvenile idiopathic arthritis.13
A child with arthritis who does not have psoria-
sis but who has two or more features of psori-
atic arthritis, such as dactylitis, nail pitting,
(first-degree relative), meets the criteria for pso-
riatic arthritis.
The psychological and functional burdens of
the disease are considerable and similar in mag-
nitude to those of axial spondyloarthritis and
rheumatoid arthritis.14,15 One study showed that
psoriatic arthritis was significantly associated
with rates of absenteeism from work and pro-
ductivity at work and that these findings were
correlated with measures of disease activity and
physical functioning.16 Mortality rates among
patients with psoriatic arthritis have fallen and
are similar to those in the general population,
although some centers report an increase in
mortality related to cardiovascular disease.17,18
Cl inic a l M a nife s tat ions
Moll and Wright described five clinical subtypes
of psoriatic arthritis that highlight the heteroge-
neity of the disease (Fig.1).3 The oligoarticular

Figure 1 (facing page). Clinical Features of Psoriatic Arthritis.

Panel A shows the distal subtype of psoriatic arthritis, with adjacent onycholysis. Panel B shows the oligoarticular
subtype. Panel C shows the polyarticular subtype. Panel D show arthritis mutilans, with telescoping of digits and
asymmetric and differential involvement of adjacent digits. Panel E shows the spondylitis subtype. Panel F shows
enthesitis of the Achilles tendon (arrow). Panel G shows dactylitis of the big toes.

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 Psoriatic Arthritis

A B

C D

E F

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Differentiation among Various Forms of Arthritis.*

Variable Psoriatic Arthritis Rheumatoid Arthritis Gout Osteoarthritis

Joint distribution at onset Asymmetric Symmetric Asymmetric Asymmetric
No. of affected joints Oligoarticular Polyarticular Monoarticular or oligo- Monoarticular or oligo
articular articular
Sites of hands or feet involved Distal Proximal Distal Distal
Areas involved All joints of a digit Same joint across digits Usually monoarticular Same joints across digits
Tenderness (kg on a dolorimeter) 7 4 NA NA
Purplish discoloration Yes No Yes No
Spinal involvement Common Uncommon Absent Noninflammatory
Sacroiliitis Common Absent Absent Absent

* NA denotes not assessed.

subtype affects four or fewer joints and typically
occurs in an asymmetric distribution. The poly-
articular subtype affects five or more joints; the
involvement may be symmetric and resemble
rheumatoid arthritis. The distal subtype, which
affects distal interphalangeal joints of the hands,
feet, or both, usually occurs with other subtypes,
occurring alone in only 5% of patients. Arthritis
mutilans, a deforming and destructive subtype of
arthritis that involves marked bone resorption or
osteolysis, is characterized by telescoping and
flail digits. The axial or spondyloarthritis sub-
type primarily involves the spine and sacroiliac
joints. These patterns may change over time.19
Enthesitis is observed in 30 to 50% of pa-
tients and most commonly involves the plantar
fascia and Achilles tendon, but it may cause
pain around the patella, iliac crest, epicondyles,
and supraspinatus insertions.20 Dactylitis is re-
ported in 40 to 50% of patients and is most
prevalent in the third and fourth toes but may
also involve the fingers. Dactylitis can be either
acute (swelling, redness of the skin, and pain) or
chronic (swelling without inflammation).21 Dacty-
litis is often associated with severe disease that
is characterized by polyarthritis, bone erosion,
and new bone formation.22
The diagnosis of psoriatic arthritis is based
on the recognition of clinical and imaging fea-
tures, since there are no specific biomarkers
(Fig.1).23 Involvement of at least five domains is
possible; these include psoriasis, peripheral joint
disease, axial disease, enthesitis, and dactylitis.
Patients should be carefully assessed for these
domains, with the understanding that various
domain combinations may be present in an indi-
vidual patient.24 The personal history and family
history of psoriasis are often positive. Inflam-
matory arthritis, enthesitis, dactylitis, and joint
distribution provide important clues, as do extra
articular features such as inflammatory bowel
disease and uveitis. It is important to look for
psoriatic skin lesions, particularly in the groin,
umbilical area, hairline, ears, and natal (i.e.,
intergluteal) cleft. Nail lesions, including pits and
onycholysis, as well as the presence of spinal
disease, support the diagnosis.
It is important that dermatologists and pri-
mary care physicians caring for patients with
psoriasis identify psoriatic arthritis early. Patients
with psoriasis should be questioned about joint
pain, morning stiffness, and evidence of sau-
sage digits (dactylitis). Screening questionnaires
for dermatology or primary care offices have
high sensitivity for the presence of musculoskel-
etal disease but moderate specificity for psoriatic
arthritis.25
Differ en t i a l Di agnosis
It is necessary to differentiate psoriatic arthritis
from rheumatoid arthritis, osteoarthritis, gout,
pseudogout, systemic lupus erythematosus, and
other forms of spondyloarthritis (Tables 2 and 3).
Rheumatoid arthritis is characterized by proxi-
mal, symmetric involvement of the joints of the
hands and feet, with sparing of the distal inter-
phalangeal joints, whereas in more than 50% of
patients with psoriatic arthritis, the distal joints
are affected; the involvement tends to be charac-
terized by a ray distribution, with all the joints
of the same digit involved and other digits spared.

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 Psoriatic Arthritis

Table 3. Clinical Features of Various Forms of Spondyloarthritis.*

Ankylosing IBD-Associated
Feature Psoriatic Arthritis Spondylitis Reactive Arthritis Arthritis
Age at onset (yr) 36 20 30 30
Male:female ratio 1:1 3:1 3:1 2:1
Peripheral joints affected 96 30 90 30
(% of cases)
Axial joints affected (% of cases) 50 100 100 30
Dactylitis Common Absent Uncommon Absent
Enthesitis Common Common Uncommon Uncommon
Psoriasis (% of cases) 100 10 10 10
Nail lesions 87% of cases Uncommon Uncommon Uncommon
HLA-B*27 (% of cases) 4050 90 70 30

* IBD denotes inflammatory bowel disease.

This is noticeable both clinically and radio-
graphically. At its onset, psoriatic arthritis tends
to be oligoarticular and less symmetric than
rheumatoid arthritis, although with time, psori-
atic arthritis may become polyarticular and sym-
metric.26,27 The affected joints are less tender in
psoriatic arthritis than in rheumatoid arthritis
and may have a purplish discoloration.28 Spinal
involvement (sacroiliac joints or the lumbar,
thoracic, or cervical spine) occurs in more than
40% of patients with psoriatic arthritis but is
uncommon in patients with rheumatoid arthritis.
Psoriatic monoarthritis, particularly involving
the toes, or dactylitis may be misdiagnosed as
gout or pseudogout. The uric acid level may be
elevated in patients with psoriatic arthritis, as well
as in those with gout, making the differential
diagnosis difficult, particularly if crystal analysis
of joint fluid is negative or cannot be performed.
The distal-joint involvement that is characteristic
of psoriatic arthritis is also observed in osteoar-
thritis. In psoriatic arthritis, palpation of distal
joints reveals soft swelling due to inflammation,
whereas in osteoarthritis, swelling arises from a
bony osteophyte and is solid. Moreover, involve-
ment of distal interphalangeal joints and nail
disease (pitting or onycholysis) occur frequently
in psoriatic arthritis but not in osteoarthritis.
Ankylosing spondylitis typically begins late
in the second decade of life or early in the third
decade, whereas psoriatic spondyloarthritis is
more likely to develop in the fourth decade of life.
Psoriatic spondyloarthritis may be less severe
than ankylosing spondylitis, with less pain and
infrequent sacroiliac-joint ankylosis; an asymmet-
ric distribution of syndesmophytes (bony growths
originating inside a ligament of the spine) is
more common in cases of psoriatic arthritis.29
It may be difficult to distinguish between psori-
atic arthritis and reactive arthritis. Both condi-
tions may be associated with joint and skin le-
sions, and the skin lesions can be difficult to
ascribe pathologically to one condition or the
other. The psoriasiform lesions of subacute cuta-
neous lupus can mimic psoriasis vulgaris, but
patients with cutaneous lupus do not have the
other defining features of psoriatic arthritis.
L a bor at or y a nd Im aging
Findings
Tests for rheumatoid factor, anticyclic citrulli-
nated peptide antibodies, or both are negative in
95% of patients with psoriatic arthritis. When a
test result is positive, clinical and imaging fea-
tures must be used to differentiate psoriatic from
rheumatoid arthritis. Approximately 25% of pa-
tients with psoriatic arthritis are HLA-B27posi-
tive. Increases in the serum C-reactive protein
level, the erythrocyte sedimentation rate, or both
are seen in only 40% of patients.
The occurrence of bone and cartilage destruc-
tion with pathologic new bone formation is one
of the most distinctive aspects of psoriatic ar-
thritis (Fig.2). Radiographs of peripheral joints
often show evidence of bone loss with eccentric
erosions and joint-space narrowing, as well as
new bone formation characterized by periostitis,

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B C
Joint resorption

Ankylosis

Erosion

D E F G

H I

Achilles tendon
MC PP

Calcaneus

MC PP

Figure 2. Radiographic Features of Psoriatic Arthritis.

Panel A show arthritis mutilans, with pencil-in-cup deformities (arrow) and marked bone resorption (osteolysis) in phalanges of the right
hand. The hand radiograph in Panel B shows joint resorption, ankylosis, and erosion in a single ray. Panel C shows enthesophytes at the
plantar fascia and Achilles tendon insertions. Panel D shows syndesmophytes involving the cervical spine, with ankylosis of facet joints
(arrow). Panel E shows bilateral grade 3 sacroiliitis. Panel F shows a paramarginal syndesmophyte bridging the fourth and fifth lumbar
vertebrae. Panel G shows bone marrow edema in the second and third lumbar vertebrae in a patient with severe psoriasis and a new onset
of back pain. The high-frequency (15-MHz) gray-scale ultrasound image in Panel H shows synovitis of the metacarpophalangeal joint. Dis-
tention of the joint capsule is evident (arrows). The confluent red signals (box in the lower part of the image) with power Doppler ultra-
sonography indicate synovial hyperemia. MC denotes metacarpal head, and PP proximal phalanx. The high-frequency (15-MHz) ultrasound
image in Panel I shows enthesitis. The confluent red signals with power Doppler ultrasonography represent hyperemia at the tendon near
its insertion into the calcaneus. Normally, the tendon is poorly vascularized.

bony ankylosis, and enthesophytes (abnormal
bony projections at the attachment of a tendon
or ligament).30 In the axial skeleton, changes
associated with psoriatic arthritis include uni-
lateral sacroiliitis and bulky paramarginal and
vertical syndesmophytes. (In contrast, in anky-
losing spondylitis, sacroiliac involvement is typi-
cally bilateral and paramarginal syndesmophytes
are uncommon.) Magnetic resonance imaging
studies may reveal focal erosions, synovitis, and
bone marrow edema in the peripheral and axial
structures, particularly at entheses. Bone marrow

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 Psoriatic Arthritis
edema is best observed on T2-weighted, fat-sup-
pressed, short-tau inversion recovery (STIR) se-
quences. Power Doppler ultrasound imaging can
be used to identify synovitis, enhanced blood
flow, tenosynovitis, enthesophytes, and early ero-
sive disease.31
Ou t c ome s
Psoriatic arthritis is a severe form of arthritis in
which deformities and joint damage develop in a
large number of patients.1,2 Bone erosions are ob-
served in 47% of patients within the first 2 years,
despite the use of traditional disease-modifying
medications in more than half the patients.32
Furthermore, severe disease at presentation and
an elevated C-reactive protein level are risk fac-
tors for radiographic progression.33,34 Spontane-
ous remission of psoriatic arthritis is extremely
rare. In an observational trial involving patients
treated with antitumor necrosis factor (TNF)
agents, the rate of partial remission was 23%.35
However, relapse rates are high when biologic
agents are discontinued.36,37
C oe x is t ing C ondi t ions
Psoriatic arthritis is associated with obesity,
type 2 diabetes, hypertension, the metabolic syn-
drome, fatty liver, and an increased risk of car-
diovascular events.38 Uveitis affecting anterior
and posterior poles of the eye occurs in 8% of
patients with psoriatic arthritis; the prevalence of
Crohns disease and subclinical colitis is increased
in these patients.
C ause s a nd Pathoph ysiol o gic a l
Fe at ur e s
Psoriatic arthritis is a highly heritable polygenic
disease. The recurrence risk ratio (defined as the
risk of disease manifestation in siblings vs. the
risk in the general population) is greater than
27, which is substantially higher than the recur-
rence risk ratio for psoriasis or rheumatoid arthri-
tis.39 In contrast to rheumatoid arthritis, which
is associated with class II major histocompati-
bility complex (MHC) alleles, psoriasis and pso-
riatic arthritis are associated with class I MHC
alleles. Most notably, HLA-C*06 is a major risk
factor for psoriasis but not for psoriatic arthritis.
In psoriatic arthritis, frequencies of HLA-B*08,
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B*27, B*38, and B*39 have been observed, with
specific subtypes of those alleles linked to sub-
phenotypes, including symmetric or asymmetric
axial disease, enthesitis, dactylitis, and synovitis.40
Genomewide association scans have shown that
certain polymorphisms in the gene encoding
interleukin-23 receptor (IL23R), along with vari-
ants in nuclear factor B (NF-B) gene expression
(TNIP1) and signaling (TNFAIP3), and TNF ex-
pression are associated with psoriatic arthritis.
A polymorphism at chromosome 5q31, rs715285,
maps to an intergenic region flanked by the
genes CSF2 and P4HA2.41 Association studies have
identified additional risk alleles in patients with
psoriasis and in those with psoriatic arthritis,
including interleukin-12A (IL12A), interleukin-12B
(IL12B), IL23R, and genes that regulate NF-B.42,43
There are several environmental risk factors
for psoriatic arthritis. These include obesity; se-
vere psoriasis; scalp, genital, and inverse (or inter-
triginous) psoriasis; nail disease; and trauma or
deep lesions at sites of trauma (Koebners phe-
nomenon).44,45
It has been shown consistently that T cells
are important in psoriasis and psoriatic arthritis.
A central role for CD8+ T cells in disease patho-
genesis is supported by the association with
HLA class I alleles, oligoclonal CD8+ T-cell expan-
sion, and the association of psoriatic arthritis
with human immunodeficiency virus disease.46
Type 17 cells, which include CD4+ type 17
helper T (Th17) cells, and type 3 innate lympho-
cytes (cells that produce interleukin-17A and inter-
leukin-22), in addition to CD4+CD8+ lympho-
cytes, are increased in psoriatic synovial fluid as
compared with rheumatoid synovial fluid.47,48
Recent studies highlight the importance of
the interleukin-23interleukin-17 and TNF path-
ways in the pathogenesis of psoriasis, psoriatic
arthritis, and axial spondyloarthropathies.47-49 In
psoriasis, expression of interferon- by plasma-
cytoid dendritic cells activates dermal dendritic
cells that trigger the differentiation of type 1
helper T (Th1) cells and Th17 cells in draining
lymph nodes. These lymphocytes return to the
dermis and orchestrate a complex immune-
mediated inflammatory response (Fig.3).50 Addi-
tional genetic factors, environmental factors, or
both are likely to trigger inflammatory arthritis.
In an alternative disease model, the enthesis
is proposed to be the initial site of musculoskel-
etal disease.51 In support of this view, enthesitis,
963
 The n e w e ng l a n d j o u r na l of m e dic i n e

Skin Enthesis

IL-12
LL-37 IL-17 Pathologic bone
Achilles
IL-22 tendon formation
Biomechanical stress Osteoprogenitor
IFN- TNF- or trauma
IL-23 Chemokines
Cytokines IL-23
IL-22 and other factors
IL-22 Osteoblast
Type 17 TNF

Bone marrow

Joints
OCP
Th1 Dendritic cell Macrophage
Type 17 Muscle

IL-23 TNF

IL-17, TNF
Gut Activated Synoviocyte
lymphocyte IL-17
TNF-
RANKL

OCP
Microbial dysbiosis
RANK+ Osteoclast Tendon
IL-23

CD68+

Figure 3. Pathogenic Pathways in Psoriatic Arthritis.

The events that potentially link inflammation in the psoriatic skin, bone marrow, and gut with enthesitis, synovitis,
and altered bone phenotypes are shown. The interaction between genetic and environmental factors triggers an in-
flammatory response at multiple sites. In the plaque that forms in the skin, DNA released by stressed keratinocytes
binds to the antibacterial peptide LL-37 and stimulates interferon- (IFN-) release by plasmacytoid dendritic cells,
activating dermal dendritic cells, which migrate to draining lymph nodes and trigger differentiation of type 1 helper T
(Th1) and type 17 helper T (Th17) cells. The Th1 and Th17 cells home to the dermis, where they release interleukin-12,
17, and 22 (IL-12, IL-17, and IL-22, respectively) and tumor necrosis factor (TNF-), along with a range of chemo-
kines and other cytokines. Additional IL-17secreting (i.e., type 17) cells in the dermis include innate lymphoid cells
and CD8+ T cells. The cytokine release in the dermis promotes keratinocyte proliferation; these keratinocytes in turn
release cytokines that act in a paracrine fashion on cells in the dermis. Expansion of Th1 and Th17 cells, along with
other type 17 cells and osteoclast precursors (OCPs), may also take place in the bone marrow. In the gut, microbial
dysbiosis may initiate inflammation in the ileocolon and trigger IL-23 release and type 17 cells. In the enthesis, IL-23
release in response to biomechanical stress or trauma at the tendon-insertion site activates type 17 cells and other
cytokines, including IL-22 and TNF, with resultant inflammation, bone erosion, and pathologic bone formation.
Mesenchymal cells differentiate into osteoblasts in response to IL-22 and other signaling pathways, forming enthe-
sophytes in peripheral entheses and joints and syndesmophytes in the spine. Type 17 cells, OCPs, and dendritic
cells reach the joint from adjacent entheses or the bloodstream. Increased expression of the receptor activator of
NF-B (RANK) ligand (RANKL) by synoviocytes in the lining, coupled with increased levels of TNF, IL-17, and RANKL
expressed by infiltrating cells, drives the differentiation of OCPs into osteoclasts, with synovitis and bone resorption.
Pathologic bone formation proceeds as outlined above in the enthesis.

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 Psoriatic Arthritis
synovitis, and altered bone remodeling were ob-
served in a murine model in which the adminis-
tration of interleukin-23 led to an enthesis-centered
inflammatory arthritis that was similar to spon-
dyloarthritis, with bone erosion and new bone
formation.52 Inflammation was linked to a novel
population of innate lymphocytes residing in the
entheses that produce interleukin-17.53 Inflam-
mation and bone erosion were mediated by TNF
and interleukin-17. Another murine model has
shown that overexpression of interleukin-23 can
also lead to an inflammatory, erosive arthritis
phenotype, which may reflect differences in the
dose or timing of interleukin-23 delivery, microbial
heterogeneity, or differences in mouse strains.54
Several other murine models of spondyloarthri-
tis with enthesitis, psoriasiform skin lesions, and
arthritis have subsequently been reported, all of
which have been linked to interleukin-23.55,56
Microbial infections are known triggers of cer-
tain forms of spondyloarthritis, and reports of
an elevated frequency of subclinical gut inflam-
mation and dysbiosis (decreased microbial diver-
sity) in patients with psoriatic arthritis, as com-
pared with healthy controls, support a potential
gutjoint axis in the pathogenesis of psoriatic
arthritis.57,58
The synovial tissues in patients with psoriatic
arthritis bear a closer resemblance to the synovi-
um in patients with spondyloarthritis than to the
synovium in those with rheumatoid arthritis,
with more vascularity, a greater influx of neutro-
phils, and the absence of antibodies to citrulli-
nated peptides.59 As compared with rheumatoid
synovial tissue, psoriatic synovial tissue has a
lower number of infiltrating T lymphocytes and
plasma cells, but the expression of TNF and inter-
leukin-1, 6, and 18 is similar in the two diseases.60
Bone involvement in psoriatic arthritis is het-
erogeneous both among patients and within the
individual patient. Spinal involvement may be
similar to that in ankylosing spondylitis, and de-
structive peripheral-joint features may resemble
those of rheumatoid arthritis. Pathologic new
bone formation, including joint ankylosis and
syndesmophyte formation, typically occurs at
sites of soft-tissue inflammation surrounding
the enthesis.61 In psoriatic synovium, marked
up-regulation of the receptor activator of NF-B
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(RANK) ligand (RANKL) and low expression of
its antagonist, osteoprotegerin, have been detect-
ed in the adjacent synovial lining.62 The RANKL
cytokine binds to RANK on the surface of osteo-
clast precursors derived from circulating CD14+
monocytes. This ligandreceptor interaction trig-
gers proliferation of the osteoclast precursors and
their differentiation into multinucleated osteo-
clasts, which resorb bone. Moreover, a study has
shown that osteoclast precursors derived from
circulating CD14+ monocytes are markedly ele-
vated in the peripheral blood of patients with
psoriatic arthritis, as compared with healthy con-
trols, and that treatment with anti-TNF agents
significantly reduces the level of circulating pre-
cursors, a finding that supports a central effect
of TNF in the generation of precursor forma-
tion.63 Molecules and pathways associated with
pathologic bone formation include interleukin-
17A, bone morphogenetic protein, transforming
growth factor , prostaglandin E2, and mole-
cules in the Wnt signaling pathway, although
their roles in psoriatic arthritis are unknown.64,65
Ou t c ome Me a sur e s for Psor i at ic
A r thr i t is
It is important to evaluate each of the musculo-
skeletal domains, along with the severity and
extent of psoriasis, in patients with suspected
psoriatic arthritis. Assessments should include
examination of 68 joints for tenderness and 66
joints for swelling; spinal range of motion and
pain; enthesitis, assessed with the use of one of
the enthesitis indexes, such as the Leeds Enthesi-
tis Index (assessment of six entheses) or the
Spondyloarthritis Research Consortium Canada
(SPARCC) Enthesitis Index; and dactylitis, as-
sessed with the use of either a dactylitis digit
count or the Leeds Dactylitis Index.66 Psoriasis
should be assessed on the basis of the involved
body-surface area or the Psoriasis Area and Sever-
ity Index (PASI),67 and nails should be examined
for onycholysis or pitting. In clinical trials, out-
come measures adapted from instruments used
to assess outcomes of rheumatoid arthritis in-
clude the American College of Rheumatology
(ACR) 20, ACR 50, and ACR 70 response rates
(indicating reductions in the number of both
965
 The n e w e ng l a n d j o u r na l
tender and swollen joints of at least 20%, 50%,
and 70%, respectively, with improvement in at
least three of the following five additional mea-
sures: patient and physician global assessments,
pain, disability, and an acute-phase reactant) and
the Disease Activity Score (DAS), which is used
to assess peripheral arthritis. A number of com-
posite measures have recently been developed
specifically for psoriatic arthritis, including the
Psoriatic Arthritis Disease Activity Score (Table S1
in the Supplementary Appendix, available with
the full text of this article at NEJM.org), the
Composite Psoriatic Disease Activity Index (Ta-
ble S2 in the Supplementary Appendix), and the
GRACE (Group for Research and Assessment of
Psoriasis and Psoriatic Arthritis [GRAPPA] Com-
posite Exercise) instrument (Table S3 in the Sup-
plementary Appendix).66 In addition, minimal
disease activity, defined by clinically significant
improvement in five of seven response measures
or domains is a validated instrument for assess-
ing treatment response in psoriatic arthritis
(Table S4 in the Supplementary Appendix).68
Ther a py
The treatment of psoriatic arthritis is compli-
cated by heterogeneity in the presentation of the
disease and its course, often resulting in a de-
layed diagnosis. To address this complexity, it is
important to identify disease activity in each of
the domains. The domain with the highest level
of activity drives the treatment choices, and it is
very common for a patient to have involvement
of several domains.
Evidence-based treatment recommendations
have recently been published.69,70 Table4 summa-
rizes current therapies and treatment responses.
For patients with a mild oligoarticular presenta-
tion, nonsteroidal antiinflammatory medications
combined with intraarticular injections, when
appropriate, can be effective.71 For patients with
more severe symptoms, disease-modifying anti-
rheumatic drugs (DMARDs) are typically pre-
scribed as an initial treatment. Unfortunately,
data from randomized clinical trials of tradi-
tional DMARDs for the treatment of psoriatic
arthritis are limited. A trial of methotrexate as
compared with placebo did not show a signifi-
cant treatment effect, although the study may
have been underpowered and the dose of oral
methotrexate was lower than that typically pre-
966 n engl j med 376;10nejm.org March 9, 2017
The New England Journal of Medicine
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Copyright 2017 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
scribed in practice.72 Leflunomide is effective for
peripheral arthritis but not psoriasis.73 Compel-
ling data show that anti-TNF agents (adalimu
mab, certolizumab, etanercept, and golimumab)
suppress skin and joint inflammation and retard
radiographic progression.74 These agents are ef-
fective for enthesitis, dactylitis, and also for axial
disease on the basis of data from trials involving
patients with ankylosing spondylitis.6
Use of the anti-p40 antibody ustekinumab,
directed against the shared subunit of interleu-
kin-12 and interleukin-23, is effective for the
treatment of psoriasis and psoriatic arthritis,
although results in the skin are more impressive
than those in the joints.75 Secukinumab and
brodalumab, agents that block interleukin-17
and the interleukin-17 receptor, respectively, are
effective in psoriatic arthritis, with demonstrated
improvement in both skin and musculoskeletal
features. However, trials of brodalumab were
suspended because of safety concerns that were
not observed with secukinumab.76,77 Ixekizumab,
another interleukin-17 blocker, showed efficacy in
phase 3 trials involving patients with psoriatic
arthritis and was recently approved for the treat-
ment of psoriasis.78 Phosphodiesterase 4 inhibi-
tion with apremilast has been approved for the
treatment of psoriasis and psoriatic arthritis.
Skin responses to treatment with apremilast are
similar to those with methotrexate, but joint re-
sponses are somewhat lower than those observed
with biologic agents.79 Finally, abatacept, a T-cell
activation blocker that targets CD80 and CD86
costimulatory molecules, is moderately effective
in psoriatic arthritis for joint involvement but not
for skin disease.80 Anti-TNF agents, the interleu-
kin-12interleukin-23 antagonist ustekinumab,
and the interleukin-17 monoclonal antibodies
secukinumab and ixekizumab inhibit radiograph-
ic progression in patients with psoriatic arthritis
who have peripheral-joint involvement. Apremi-
last, brodalumab, and secukinumab are not ef-
fective for the treatment of rheumatoid arthritis,
whereas rituximab and abatacept are highly ef-
fective. Collectively, these contrasting findings
from clinical trials suggest that rheumatoid ar-
thritis and psoriatic arthritis have different under-
lying mechanisms. In contrast, the pathophysio-
logical pathways that underlie psoriatic skin and
joint disease overlap considerably. Nevertheless,
cyclosporine and methotrexate are more effec-
tive in psoriasis than is leflunomide in psoriatic
 Table 4. Efficacy and Side Effects of Drugs for the Treatment of Psoriatic Arthritis.

Structural Modification
Drug (Mode of Administration) Dose According to Site Signs and Symptoms of Joints* Common Side Effects
Joints Skin Joints Skin
NSAIDs Mild response Not assessed
Naproxen (oral) 7501000 mg/day Not applicable Gastrointestinal effects
Diclofenac (oral) 100150 mg/day Not applicable Cardiac effects
Indomethacin (oral) 100/150 mg/day Not applicable Renal effects
DMARDs
Methotrexate (oral or SC) 1525 mg/wk 1525 mg/wk Mild response Moderate Not assessed Hair loss, nausea,
response hepatic effects
Leflunomide (oral) 20 mg/day Not applicable Mild response Mild response Not assessed Diarrhea, renal effects,
hair loss
Sulfasalazine (oral) 23 g/day Not applicable Not assessed Neutropenia, diarrhea
Anti-TNF agents
Adalimumab (SC) 40 mg every 2 wk 80 mg loading dose, 40 mg 1 wk Very good Moderate Moderate response Injection-site reactions,
later, then 40 mg every 2 wk response response infections
Certolizumab (SC) 200 mg every 2 wk or 400 mg Not applicable Very good Not assessed Moderate response Injection-site reactions,
every 4 wk response infections
Psoriatic Arthritis

Etanercept (SC) 50 mg weekly 50 mg twice/wk Very good Mild response Moderate response Injection-site reactions,
response infections
Golimumab (SC, infusion) 50 mg monthly Not applicable Very good Mild response Moderate response Injection-site reactions,

n engl j med 376;10nejm.org March 9, 2017

response infections

The New England Journal of Medicine

Infliximab (infusion) 5 mg/kg of body weight at 0, 2, 510 mg/kg at 0, 2, and 6 wk, Very good Excellent Moderate response Infusion reactions, in-
and 6 wk, then every 8 wk then every 8 wk response response fections
Antiinterleukin-17 agents
Ixekizumab (SC) 80 mg every 2 wk 80 mg every 2 wk Very good Excellent Mild response Candida infections

Copyright 2017 Massachusetts Medical Society. All rights reserved.

response response
Secukinumab (SC) 150 mg weekly from 04 wk, 300 mg weekly from 04 wk, then Very good Excellent Mild response Candida infections
then monthly monthly response response
Antiinterleukin-12interleukin- 45 mg/kg (for body weight of 45 mg/kg (for body weight of Very good Very good Mild response Injection-site reactions,
23 agent: ustekinumab <100 kg) or 90 mg/kg (for <100 kg) or 90 mg/kg (for response response infections
(SC) body weight of 100 kg) at 0, body weight of 100 kg) at 0,
4, and 12 wk, then every 12 wk 4, and 12 wk, then every 12 wk
PDE4 inhibitor: apremilast (oral) 30 mg twice daily 30 mg twice daily Moderate Mild response Not assessed Weight loss, diarrhea

Downloaded from nejm.org by R LOPEZ MATA on March 9, 2017. For personal use only. No other uses without permission.
response

* Recent trials of these agents involved patients with little disease progression, resulting in a smaller effect on structural modification as compared with earlier trials, which involved patients
with more severe disease and more progression. For drugs that were not assessed with respect to structural modification of joints, observational data suggest no response. Dashes indicate
that there was no appreciable response. DMARDs denotes disease-modifying antirheumatic drugs, NSAIDs nonsteroidal antiinflammatory drugs, PDE4 phosphodiesterase 4, SC subcutane-
ous injection, and TNF tumor necrosis factor.

967
 The n e w e ng l a n d j o u r na l of m e dic i n e

arthritis. These findings, coupled with the greater
response to agents that target the interleukin-12
interleukin-23 axis in the skin as compared
with the joints, underscore the divergent mecha-
nisms of inflammation in psoriatic plaques and
joints.
High-level evidence supporting specific treat-
ment algorithms for juvenile psoriatic arthritis
is not available. Current recommendations follow
the guidelines for juvenile idiopathic arthritis
and are based on measures of disease activity,
including the number of active joints, inflamma-
tory markers (erythrocyte sedimentation rate or
C-reactive protein level), and global assessments
by the physician and patient or parent.81,82 Indica-
tors of a poor prognosis, including involvement
of certain joints (e.g., the hip, wrist, ankle, joints
in the cervical spine, and the sacroiliac joint)
and evidence of radiographic damage are also
taken into account in considering both initial
therapy and escalation.
In addition to pharmacotherapy, patient edu-
cation about the importance of controlling in-
flammation is critical. Lifestyle modification,
including smoking cessation, weight reduction,
joint protection, physical activity, and exercise,
as well as stress management, is also vital in the
management of psoriatic arthritis.
Dr. Ritchlin reports receiving consulting fees from AbbVie,
Novartis Pharmaceuticals, Sun Pharmaceutical Industries, and
Pfizer and grant support from UCB Pharmaceuticals, Amgen,
Janssen Pharmaceuticals, and AbbVie; Dr. Colbert, being a prin-
cipal investigator on a Cooperative Research and Development
Agreement (CRADA) between his institute and Eli Lilly; and Dr.
Gladman, receiving honoraria from AbbVie, Amgen, Celgene,
Janssen Pharmaceuticals, Novartis Pharmaceuticals, UCB Phar-
maceuticals, and Bristol-Myers Squibb, consulting fees from Eli
Lilly, and grant support from Pfizer, AbbVie, Celgene, Janssen
Pharmaceuticals, Novartis Pharmaceuticals, and UCB Pharma-
ceuticals. No other potential conflict of interest relevant to this
article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Ralf Thiele, M.D., for the ultrasound images and
Ananta Paine, Ph.D., for editorial review of an earlier version of
the manuscript.

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