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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 This article was updated on May 25, 2017,
in 1973; however, skeletal remains unearthed in 1983 from a Byzantine monastery in at NEJM.org.

the Judean Desert, dating to the fifth century a.d., showed visual and radiographic N Engl J Med 2017;376:957-70.
features consistent with psoriatic bone and joint disease.3,4 Psoriatic arthritis DOI: 10.1056/NEJMra1505557
Copyright 2017 Massachusetts Medical Society.
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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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 (first-degree relative), meets the criteria for pso-
with a positive test for antinuclear antibodies riatic arthritis.
and chronic uveitis and is often characterized by The psychological and functional burdens of
dactylitis (diffuse swelling of a toe or finger).12 the disease are considerable and similar in mag-
The second subtype (characterized by any num- nitude to those of axial spondyloarthritis and
ber of affected joints) develops between 6 years rheumatoid arthritis.14,15 One study showed that
and 12 years of age and is associated with HLA- psoriatic arthritis was significantly associated
B27; antinuclear antibodies are usually absent. with rates of absenteeism from work and pro-
This form has a 1:1 sex ratio, with dactylitis, ductivity at work and that these findings were
enthesitis (inflammation at tendon, ligament, or correlated with measures of disease activity and
joint-capsule insertions), nail pitting, onycholysis, physical functioning.16 Mortality rates among
and axial involvement occurring more frequently patients with psoriatic arthritis have fallen and
than in the first subtype. According to the Inter- are similar to those in the general population,
national League of Associations for Rheumatol- although some centers report an increase in
ogy classification system, psoriatic arthritis is mortality related to cardiovascular disease.17,18
distinct from other forms of juvenile idiopathic
arthritis and is defined by the coexistence of ar- Cl inic a l M a nife s tat ions
thritis and psoriasis in the absence of features
of other forms of juvenile idiopathic arthritis.13 Moll and Wright described five clinical subtypes
A child with arthritis who does not have psoria- of psoriatic arthritis that highlight the heteroge-
sis but who has two or more features of psori- neity of the disease (Fig.1).3 The oligoarticular
atic arthritis, such as dactylitis, nail pitting, subtype affects four or fewer joints and typically
onycholysis, or a family history of psoriasis occurs in an asymmetric distribution. The poly-

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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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.

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

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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.

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

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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.

or ligament).30 In the axial skeleton, changes are uncommon.) Magnetic resonance imaging
associated with psoriatic arthritis include uni- studies may reveal focal erosions, synovitis, and
lateral sacroiliitis and bulky paramarginal and bone marrow edema in the peripheral and axial
vertical syndesmophytes. (In contrast, in anky- structures, particularly at entheses. Bone marrow
losing spondylitis, sacroiliac involvement is typi- edema is best observed on T2-weighted, fat-sup-
cally bilateral and paramarginal syndesmophytes pressed, short-tau inversion recovery (STIR) se-

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Psoriatic Arthritis

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

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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

tration of interleukin-23 led to an enthesis-centered ed in the adjacent synovial lining.62 The RANKL
inflammatory arthritis that was similar to spon- cytokine binds to RANK on the surface of osteo-
dyloarthritis, with bone erosion and new bone clast precursors derived from circulating CD14+
formation.52 Inflammation was linked to a novel monocytes. This ligandreceptor interaction trig-
population of innate lymphocytes residing in the gers proliferation of the osteoclast precursors and
entheses that produce interleukin-17.53 Inflam- their differentiation into multinucleated osteo-
mation and bone erosion were mediated by TNF clasts, which resorb bone. Moreover, a study has
and interleukin-17. Another murine model has shown that osteoclast precursors derived from
shown that overexpression of interleukin-23 can circulating CD14+ monocytes are markedly ele-
also lead to an inflammatory, erosive arthritis vated in the peripheral blood of patients with
phenotype, which may reflect differences in the psoriatic arthritis, as compared with healthy con-
dose or timing of interleukin-23 delivery, microbial trols, and that treatment with anti-TNF agents
heterogeneity, or differences in mouse strains.54 significantly reduces the level of circulating pre-
Several other murine models of spondyloarthri- cursors, a finding that supports a central effect
tis with enthesitis, psoriasiform skin lesions, and of TNF in the generation of precursor forma-
arthritis have subsequently been reported, all of tion.63 Molecules and pathways associated with
which have been linked to interleukin-23.55,56 pathologic bone formation include interleukin-
Microbial infections are known triggers of cer- 17A, bone morphogenetic protein, transforming
tain forms of spondyloarthritis, and reports of growth factor , prostaglandin E2, and mole-
an elevated frequency of subclinical gut inflam- cules in the Wnt signaling pathway, although
mation and dysbiosis (decreased microbial diver- their roles in psoriatic arthritis are unknown.64,65
sity) in patients with psoriatic arthritis, as com-
pared with healthy controls, support a potential Ou t c ome Me a sur e s for Psor i at ic
gutjoint axis in the pathogenesis of psoriatic A r thr i t is
arthritis.57,58
The synovial tissues in patients with psoriatic It is important to evaluate each of the musculo-
arthritis bear a closer resemblance to the synovi- skeletal domains, along with the severity and
um in patients with spondyloarthritis than to the extent of psoriasis, in patients with suspected
synovium in those with rheumatoid arthritis, psoriatic arthritis. Assessments should include
with more vascularity, a greater influx of neutro- examination of 68 joints for tenderness and 66
phils, and the absence of antibodies to citrulli- joints for swelling; spinal range of motion and
nated peptides.59 As compared with rheumatoid pain; enthesitis, assessed with the use of one of
synovial tissue, psoriatic synovial tissue has a the enthesitis indexes, such as the Leeds Enthesi-
lower number of infiltrating T lymphocytes and tis Index (assessment of six entheses) or the
plasma cells, but the expression of TNF and inter- Spondyloarthritis Research Consortium Canada
leukin-1, 6, and 18 is similar in the two diseases.60 (SPARCC) Enthesitis Index; and dactylitis, as-
Bone involvement in psoriatic arthritis is het- sessed with the use of either a dactylitis digit
erogeneous both among patients and within the count or the Leeds Dactylitis Index.66 Psoriasis
individual patient. Spinal involvement may be should be assessed on the basis of the involved
similar to that in ankylosing spondylitis, and de- body-surface area or the Psoriasis Area and Sever-
structive peripheral-joint features may resemble ity Index (PASI),67 and nails should be examined
those of rheumatoid arthritis. Pathologic new for onycholysis or pitting. In clinical trials, out-
bone formation, including joint ankylosis and come measures adapted from instruments used
syndesmophyte formation, typically occurs at to assess outcomes of rheumatoid arthritis in-
sites of soft-tissue inflammation surrounding clude the American College of Rheumatology
the enthesis.61 In psoriatic synovium, marked (ACR) 20, ACR 50, and ACR 70 response rates
up-regulation of the receptor activator of NF-B (indicating reductions in the number of both
(RANK) ligand (RANKL) and low expression of tender and swollen joints of at least 20%, 50%,
its antagonist, osteoprotegerin, have been detect- and 70%, respectively, with improvement in at

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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

least three of the following five additional mea- ling data show that anti-TNF agents (adalimu
sures: patient and physician global assessments, mab, certolizumab, etanercept, and golimumab)
pain, disability, and an acute-phase reactant) and suppress skin and joint inflammation and retard
the Disease Activity Score (DAS), which is used radiographic progression.74 These agents are ef-
to assess peripheral arthritis. A number of com- fective for enthesitis, dactylitis, and also for axial
posite measures have recently been developed disease on the basis of data from trials involving
specifically for psoriatic arthritis, including the patients with ankylosing spondylitis.6
Psoriatic Arthritis Disease Activity Score (Table S1 Use of the anti-p40 antibody ustekinumab,
in the Supplementary Appendix, available with directed against the shared subunit of interleu-
the full text of this article at NEJM.org), the kin-12 and interleukin-23, is effective for the
Composite Psoriatic Disease Activity Index (Ta- treatment of psoriasis and psoriatic arthritis,
ble S2 in the Supplementary Appendix), and the although results in the skin are more impressive
GRACE (Group for Research and Assessment of than those in the joints.75 Secukinumab and
Psoriasis and Psoriatic Arthritis [GRAPPA] Com- brodalumab, agents that block interleukin-17
posite Exercise) instrument (Table S3 in the Sup- and the interleukin-17 receptor, respectively, are
plementary Appendix).66 In addition, minimal effective in psoriatic arthritis, with demonstrated
disease activity, defined by clinically significant improvement in both skin and musculoskeletal
improvement in five of seven response measures features. However, trials of brodalumab were
or domains is a validated instrument for assess- suspended because of safety concerns that were
ing treatment response in psoriatic arthritis not observed with secukinumab.76,77 Ixekizumab,
(Table S4 in the Supplementary Appendix).68 another interleukin-17 blocker, showed efficacy in
phase 3 trials involving patients with psoriatic
arthritis and was recently approved for the treat-
Ther a py
ment of psoriasis.78 Phosphodiesterase 4 inhibi-
The treatment of psoriatic arthritis is compli- tion with apremilast has been approved for the
cated by heterogeneity in the presentation of the treatment of psoriasis and psoriatic arthritis.
disease and its course, often resulting in a de- Skin responses to treatment with apremilast are
layed diagnosis. To address this complexity, it is similar to those with methotrexate, but joint re-
important to identify disease activity in each of sponses are somewhat lower than those observed
the domains. The domain with the highest level with biologic agents.79 Finally, abatacept, a T-cell
of activity drives the treatment choices, and it is activation blocker that targets CD80 and CD86
very common for a patient to have involvement costimulatory molecules, is moderately effective
of several domains. in psoriatic arthritis for joint involvement but not
Evidence-based treatment recommendations for skin disease.80 Anti-TNF agents, the interleu-
have recently been published.69,70 Table4 summa- kin-12interleukin-23 antagonist ustekinumab,
rizes current therapies and treatment responses. and the interleukin-17 monoclonal antibodies
For patients with a mild oligoarticular presenta- secukinumab and ixekizumab inhibit radiograph-
tion, nonsteroidal antiinflammatory medications ic progression in patients with psoriatic arthritis
combined with intraarticular injections, when who have peripheral-joint involvement. Apremi-
appropriate, can be effective.71 For patients with last, brodalumab, and secukinumab are not ef-
more severe symptoms, disease-modifying anti- fective for the treatment of rheumatoid arthritis,
rheumatic drugs (DMARDs) are typically pre- whereas rituximab and abatacept are highly ef-
scribed as an initial treatment. Unfortunately, fective. Collectively, these contrasting findings
data from randomized clinical trials of tradi- from clinical trials suggest that rheumatoid ar-
tional DMARDs for the treatment of psoriatic thritis and psoriatic arthritis have different under-
arthritis are limited. A trial of methotrexate as lying mechanisms. In contrast, the pathophysio-
compared with placebo did not show a signifi- logical pathways that underlie psoriatic skin and
cant treatment effect, although the study may joint disease overlap considerably. Nevertheless,
have been underpowered and the dose of oral cyclosporine and methotrexate are more effec-
methotrexate was lower than that typically pre- tive in psoriasis than is leflunomide in psoriatic
scribed in practice.72 Leflunomide is effective for arthritis. These findings, coupled with the greater
peripheral arthritis but not psoriasis.73 Compel- response to agents that target the interleukin-12

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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 Moderate Moderate response Injection-site reactions,
every 4 wk response 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

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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
response

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* 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-

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

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

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Patagonia Glacier Steven Rosner, M.D.

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