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Home , Arthritis mutilans, Bone erosion, Psoriatic arthritis

The new england journal of

Review Article

Dan L. Longo, M.D., Editor Psoriatic

Christopher T. Ritchlin, M.D., M.P.H., Robert A. Colbert, M.D., Ph.D., and Dafna D. Gladman, M.D.​​

soriasis is a common skin disease that is associated with multi- From the , , and Rheu- ple coexisting conditions. The most prevalent coexisting condition, psoriatic matology Division, University of Roches- ter , Rochester, NY (C.T.R.); arthritis, develops in up to 30% of patients with and is character- the Pediatric Translational Research P Branch, National Institute of Arthritis ized by diverse clinical features, often resulting in delayed diagnosis and treat- 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 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 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 Division, University of Rochester Medical School, 601 Elmwood Ave., Box 695, Rochester, NY 14642, or at Psoriatic Arthritis and Spondyloarthritis ­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 and 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 (Table 1).7

Epidemiology and Disease Burden 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 ) 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., , pitting, or ) 1 according to observation during current physical examination Negative test for Based on reference range at local laboratory; any testing method except latex, 1 with preference for ELISA or nephelometry 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 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 (first-degree relative), meets the criteria for pso- and chronic and is often characterized by riatic arthritis. dactylitis (diffuse swelling of a toe or finger).12 The psychological and functional burdens of The second subtype (characterized by any num- the disease are considerable and similar in mag- ber of affected joints) develops between 6 years nitude to those of axial spondyloarthritis and and 12 years of age and is associated with HLA- .14,15 One study showed that B27; antinuclear antibodies are usually absent. psoriatic arthritis was significantly associated This form has a 1:1 sex ratio, with dactylitis, with rates of absenteeism from work and pro- ( at tendon, ligament, or ductivity at work and that these findings were joint-capsule insertions), nail pitting, onycholysis, correlated with measures of disease activity and and axial involvement occurring more frequently physical functioning.16 Mortality rates among than in the first subtype. According to the Inter- patients with psoriatic arthritis have fallen and national League of Associations for Rheumatol- are similar to those in the general population, ogy classification system, psoriatic arthritis is although some centers report an increase in distinct from other forms of juvenile idiopathic mortality related to cardiovascular disease.17,18 arthritis and is defined by the coexistence of ar- thritis and psoriasis in the absence of features Clinical Manifestations of other forms of juvenile idiopathic arthritis.13 A child with arthritis who does not have psoria- Moll and Wright described five clinical subtypes sis but who has two or more features of psori- of psoriatic arthritis that highlight the heteroge- atic arthritis, such as dactylitis, nail pitting, 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 , with telescoping of digits and asymmetric and differential involvement of adjacent digits. Panel E shows the subtype. Panel F shows enthesitis of the Achilles’ tendon (arrow). Panel G shows dactylitis of the big toes.

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A B

C D

E F

G

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Table 2. Differentiation among Various Forms of Arthritis.*

Variable Psoriatic Arthritis Rheumatoid Arthritis 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 Common Absent Absent Absent

* NA denotes not assessed.

subtype affects four or fewer joints and typically vidual patient.24 The personal history and family occurs in an asymmetric distribution. The poly- history of psoriasis are often positive. Inflam- 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 or onycholysis, as well as the presence of spinal , 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 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 , iliac crest, epicondyles, for 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 Differential Diagnosis chronic (swelling without inflammation).21 Dacty- litis is often associated with severe disease that It is necessary to differentiate psoriatic arthritis is characterized by , , from rheumatoid arthritis, osteoarthritis, gout, and new bone formation.22 pseudogout, systemic 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.

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

Ankylosing IBD-Associated Feature Psoriatic Arthritis Spondylitis 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) 40–50 90 70 30

* IBD denotes inflammatory bowel disease.

This is noticeable both clinically and radio- infrequent sacroiliac-joint ; an asymmet- graphically. At its onset, psoriatic arthritis tends ric distribution of syndesmophytes (bony growths 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 , 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 Laboratory and Imaging 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, anti–cyclic 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-B27–posi- 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- 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 ,

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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 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 in the second and third lumbar vertebrae in a patient with severe psoriasis and a new onset of . The high-frequency (15-MHz) gray-scale ultrasound image in Panel H shows 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 losing spondylitis, sacroiliac involvement is typi- bony projections at the attachment of a tendon cally bilateral and paramarginal syndesmophytes 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

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edema is best observed on T2-weighted, fat-sup- B*27, B*38, and B*39 have been observed, with pressed, short-tau inversion recovery (STIR) se- specific subtypes of those alleles linked to sub- 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, , 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- Outcomes ants in nuclear factor κB (NF-κB) gene expression (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-κB.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 ; se- rare. In an observational trial involving patients vere psoriasis; scalp, genital, and inverse (or inter- treated with anti– (TNF) triginous) psoriasis; nail disease; and trauma or agents, the rate of partial remission was 23%.35 deep lesions at sites of trauma (Koebner’s 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. Coexisting Conditions A central role for CD8+ T cells in disease patho- 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- Crohn’s disease and subclinical colitis is increased leukin-22), in addition to CD4+CD8+ lympho- in these patients. cytes, are increased in psoriatic as compared with rheumatoid synovial fluid.47,48 Causes and Pathophysiological Recent studies highlight the importance of Features the interleukin-23–interleukin-17 and TNF path- ways in the pathogenesis of psoriasis, psoriatic Psoriatic arthritis is a highly heritable polygenic arthritis, and axial .47-49 In disease. The recurrence risk ratio (defined as the psoriasis, expression of interferon-α 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 . 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,

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Skin Enthesis

IL-12 Pathologic bone LL-37 IL-17 Achilles’ tendon formation IL-22 Biomechanical stress IFN-α Osteoprogenitor TNF-α 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-α 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-α (IFN-α) 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 α (TNF-α), along with a range of chemo- kines and other cytokines. Additional IL-17–secreting (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-κB (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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synovitis, and altered bone remodeling were ob- (RANK) ligand (RANKL) and low expression of served in a murine model in which the adminis- its antagonist, osteoprotegerin, have been detect- 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 ligand–receptor 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 β, 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 Outcome Measures for Psoriatic gut–joint axis in the pathogenesis of psoriatic Arthritis 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-κB (indicating reductions in the number of both

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tender and swollen joints of at least 20%, 50%, scribed in practice.72 is effective for and 70%, respectively, with improvement in at peripheral arthritis but not psoriasis.73 Compel- least three of the following five additional mea- ling data show that anti-TNF agents (adalimu­ sures: patient and global assessments, mab, certolizumab, , and ) 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 , 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 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 , (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- ment of psoriasis.78 Phosphodiesterase 4 inhibi- The treatment of psoriatic arthritis is compli- tion with 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 , 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, , 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 Table 4 summa- kin-12–interleukin-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

966 n engl j med 376;10 nejm.org March 9, 2017 The New England Journal of Medicine Downloaded from nejm.org by LUIS ERNESTO GONZALEZ SANCHEZ on April 16, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved. Psoriatic Arthritis Renal effects Renal Cardiac effects Cardiac ­ hepatic effects loss hair infections infections infections infections fections infections Candida infections Candida Candida infections Candida Weight loss, diarrhea loss, Weight Common Side Effects Hair loss, nausea, loss, Hair effects, renal Diarrhea, diarrhea Neutropenia, Injection-site reactions, Injection-site Gastrointestinal effects Gastrointestinal Injection-site reactions, Injection-site reactions, Injection-site reactions, Injection-site Infusion reactions, in - reactions, Infusion Injection-site reactions, Injection-site of Joints* Not assessed Not assessed Not assessed Not Not assessed Not Not assessed Not Mild response Mild Mild response Mild response Mild Moderate response Moderate Moderate response Moderate response Moderate response Moderate Moderate response Moderate Structural Modification — — Skin Excellent Excellent Excellent ­ response ­ response ­ response ­ response ­ response ­ response Moderate Moderate Very good Very Not assessed Not Mild response Mild Mild response Mild response Mild Mild response Mild — Signs and Symptoms Joints ­ response ­ response ­ response ­ response ­ response ­ response ­ response ­ response ­ response Moderate Very good Very Very good Very good Very good Very Very good Very Very good Very Very good Very Very good Very Mild response Mild Mild response Mild Mild response Mild Skin 15–25 mg/wk 15–25 Not applicable Not applicable Not Not applicable Not applicable Not Not applicable Not Not applicable Not applicable Not 50 mg twice/wk mg 50 80 mg every 2 wk 2 every mg 80 30 mg twice daily twice mg 30 later, then 40 mg every 2 wk 2 every mg 40 then later, then every 8 wk 8 every then monthly <100 kg) or 90 mg/kg (formg/kg 90 or kg) <100 0,at kg) ≥100 of weight body wk 12 every then wk, 12 and 4, 80 mg loading dose, 40 mg 1 wk 1 mg 40 dose, loading mg 80 5–10 mg/kg at 0, 2, and 6 wk, 6 and 2, 0, mg/kg at 5–10 300 mg weekly from 0–4 wk, then wk, 0–4 from weekly mg 300 45 mg/kg (for body weight ofweight body (for mg/kg 45 Dose According to Site Joints 2–3 g/day 2–3 20 mg/day 20 50 mg weekly mg 50 15–25 mg/wk 15–25 50 mg monthly mg 50 100/150 mg/day 100/150 100–150 mg/day 100–150 40 mg every 2 wk 2 every mg 40 80 mg every 2 wk 2 every mg 80 30 mg twice daily twice mg 30 750–1000 mg/day 750–1000 every 4 wk 4 ­ every and 6 wk, then every 8 wk 8 every then wk, 6 and then monthly then <100 kg) or 90 mg/kg (formg/kg 90 or kg) <100 at 0,kg) ≥100 of weight body wk 12 every then wk, 12 and 4, 200 mg every 2 wk or 400 mg 400 or wk 2 every mg 200 5 mg/kg of body weight at 0, 2,0, at weight body of mg/kg 5 150 mg weekly from 0–4 wk, 0–4 from weekly mg 150 45 mg/kg (for body weight ofweight body (for mg/kg 45 23 agent: ustekinumab agent: 23 (SC) Leflunomide (oral) Leflunomide (oral) Methotrexate (oral or SC) or (oral Methotrexate (SC) Certolizumab (SC) Certolizumab (oral) Naproxen (oral) Indomethacin (oral) Indomethacin Etanercept (SC) Etanercept infusion) (SC, Golimumab (infusion) Secukinumab (SC) Secukinumab Ixekizumab (SC) Ixekizumab Efficacy and Side Effects of Drugs for the Treatment of Psoriatic Arthritis. Psoriatic of Treatment the for Drugs of Effects Side and Efficacy 4. Table Drug (Mode of Administration) NSAIDs DMARDs agents Anti-TNF Anti–interleukin-17 agents Anti–interleukin-17 Anti–interleukin-12–interleukin- PDE4 inhibitor: apremilast (oral) apremilast inhibitor: PDE4 Recent trials of these agents involved patients with little disease progression, resulting in a smaller effect on structural mo dification as compared earlier trials, which with more severe disease and progression. For drugs that were not assessed respect to structural modification of join ts, observational data suggest no response. Dashes indicate that there was no appreciable response. DMARDs denotes disease-modifying antirheumatic drugs, NSAIDs nonsteroidal antiinflammat ory PDE4 phosphodiesterase 4, SC subcutane - ous injection, and TNF tumor necrosis factor. * 

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

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