Spondyloarthritis

2795CHAPTER 362

restricted to patients with a definite diagnosis and active disease

that is inadequately responsive to therapy with at least two different

NSAIDs. Before initiation of anti-TNF therapy, all patients should

be tested for latent tuberculosis (TB) and for hepatitis B, and treated

appropriately if either is found. Contraindications to TNF inhibitors

include active infection or high risk of infection; multiple sclerosis;

and history of hematologic malignancy, SLE, or related autoimmunity. Pregnancy and breast-feeding are no longer considered contraindications if appropriate precautions are taken. Certolizumab

pegol’s label includes minimal transplacental or breast milk transfer.

However, infants exposed to anti-TNF in utero should not be given

live vaccines before age 6 months. Switching to a second anti-TNF

agent may be effective, especially if there was a response to the first

that was lost, rather than primary failure.

Secukinumab, a human monoclonal antibody to IL-17A, and

ixekizumab, a humanized monoclonal antibody to IL-17A, are

FDA-approved for use in AS and show efficacy similar to that of

anti-TNF. Both are effective in some patients who have failed or not

tolerated anti-TNF therapy, as well as in patients naïve to biologic

therapy. Both are also effective in nr-axSpA. The recommended

Present

Ankylosing

spondylitis

≥4 Spondyloarthritis

features

2–3 Spondyloarthritis

features

0–1 Spondyloarthritis

features

HLA-B27 HLA-B27

HLA-B27

Compelling clinical picture

Yes No

Yes No

MRI

Positive Negative

Compelling

clinical picture

Consider other

diagnoses

Axial

spondyloarthritis*

Axial

spondyloarthritis

Axial

spondyloarthritis

Axial

spondyloarthritis

Consider other

diagnoses

Positive Negative

Positive Negative

Positive Negative

Absent

Presence of other spondyloarthritis features: age of onset <45 yr,

inflammatory back pain, heel pain (enthesitis), dactylitis, uveitis,

positive family history for axial spondyloarthritis, inflammatory bowel

disease, alternating buttock pain, psoriasis, asymmetrical arthritis,

positive response to NSAIDs, elevated ESR or C-reactive protein level

Low back pain for >3 months

Definite radiographic sacroiliitis

FIGURE 362-2 Algorithm for the diagnosis or exclusion of axial spondyloarthritis. The algorithm is designed for use in patients with at least a 3-month history of unexplained

chronic low-back pain. Definite radiographic sacroiliitis is based on the modified New York criteria for ankylosing spondylitis (van der Linden S et al: Arthritis Rheum 27:361,

1984). The algorithm is adapted from van den Berg R et al: Ann Rheum Dis 72:1646, 2013. The determination of whether or not a clinical picture is compelling is based on

the relative weights of the spondyloarthritis features (Feldtkeller E et al: Rheumatology [Oxford] 52:1648, 2013) and on clinical judgment. The list of clinical features includes

features of both axial and peripheral spondyloarthritis. *Confirming MRI is recommended. (From Taurog JD et al: N Engl J Med 374:2563, 2016.)

2796 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

dose of secukinumab is 150 mg subcutaneously weekly for 4 weeks,

and then at 4-week intervals. The recommended initiation of

ixekizumab is with two 80 mg injections, followed by 80 mg every

4 weeks. Precautions regarding infection are similar to those for

anti-TNF agents. An additional concern is potential exacerbation of

underlying IBD, whether previously recognized or not, and careful

monitoring is advised.

Two antibodies targeting IL-23, ustakinumab and risankizumab,

failed to show efficacy in AS, whereas both show efficacy in psoriatic arthritis (see Fig. 362-3).

Sulfasalazine, in doses of 2–3 g/d, is used for peripheral arthritis.

Methotrexate, although widely used, has not been shown to be of

benefit in AS, nor has any therapeutic role for oral glucocorticoids

been documented.

The oral Janus kinase (JAK) inhibitors, tofacitinib, upadacitinib,

and filgotinib, have all shown efficacy in AS in clinical trials, with

reduction of inflammation evident on MRI, and further clinical

trials are in progress. Precautions regarding infection are similar to

those for anti-TNF agents, with additional concern for herpes zoster.

The most common indication for surgery in patients with AS is

severe hip joint arthritis, the pain and stiffness of which are usually

dramatically relieved by total hip arthroplasty. Rare patients may

benefit from surgical correction of extreme flexion deformities of

the spine or of atlantoaxial subluxation.

Attacks of uveitis are usually managed effectively with local

glucocorticoids and mydriatic agents, although systemic glucocorticoids, immunosuppressive drugs, or anti-TNF therapy may be

required. TNF inhibitors may reduce the frequency of attacks of

uveitis in patients with ax-SpA. Cases of new or recurrent uveitis

with use of a TNF inhibitor have been observed, especially with

etanercept. Adalimumab is FDA approved to treat intermediate,

posterior, or panuveitis. These presentations are rare in AS but

not unusual in psoriatic or IBD-associated arthritis (see below).

Anti-IL-17A agents have not been directly studied as treatment

for SpA-associated uveitis, but secukinumab-treated AS patients

showed no increased incidence of uveitis in clinical trials.

Spinal manipulation is strongly discouraged and can be particularly dangerous in patients with osteoporosis or structural lesions

on x-ray.

Management of axial osteoporosis is similar to that used for

primary osteoporosis because data specific for AS are not available.

REACTIVE ARTHRITIS

ReA refers to acute nonpurulent arthritis complicating an infection

elsewhere in the body. In recent years, the term has been used primarily

to refer to SpA following enteric or urogenital infections.

Other forms of reactive and infection-related arthritis not associated with B27 and showing a spectrum of clinical features different

from SpA, such as Lyme disease, rheumatic fever, and poststreptococcal ReA, are discussed in Chaps. 186 and 359.

■ HISTORIC BACKGROUND

The association of acute arthritis with episodes of diarrhea or urethritis has been recognized for centuries. A high incidence during World

Enthesitis Uveitis

Peripheral arthritis Psoriasis

Axial arthritis IBD

IL-17,

IL-12/23p40,

TNF, IL-23p19

TNF, IL-17,

IL-23p19,

IL-12/23p40

IL-17, TNF

TNF,

IL-12/23p40 ?

IL-17, IL-23p19,

IL-12/23p40,

TNF

TNF,

IL-12/23p40,

IL-23p19

FIGURE 362-3 Proposed hierarchy of cytokine participation in disease pathogenesis in affected tissues in spondyloarthritis, based on the therapeutic response in clinical

trials to biologic agents targeting the indicated cytokines. Peripheral arthritis, enthesitis, and psoriasis respond to agents targeting IL-17A, IL-23 (p19 subunit), IL-12/23 (p40

subunit), and TNF. Axial arthritis responds to anti-TNF and anti-IL17A, but failed to respond to anti-IL-23 and anti-IL12/23. Uveitis responds to anti-TNF, and anecdotally to

anti-IL-12/23. The effect of anti-IL-17A in uveitis is not yet resolved. IBD responds to anti-TNF, anti-IL-23, and anti-IL-12/23, but failed to respond to anti-IL-17A and anti-IL-17

receptor. (Adapted from S Siebert et al: Ann Rheum Dis 78:1015, 2019.)

Spondyloarthritis

2797CHAPTER 362

Wars I and II focused attention on the triad of arthritis, urethritis, and

conjunctivitis, often with additional mucocutaneous lesions, which

became known by eponyms that are now of historic interest only.

The identification of bacterial species triggering the clinical syndrome and the finding of an association with HLA-B27 led to the

unifying concept of ReA as a clinical syndrome triggered by specific

etiologic agents in a genetically susceptible host. A characteristic spectrum of clinical manifestations can be triggered by enteric infection

with certain Shigella, Salmonella, Yersinia, and Campylobacter species;

by genital infection with Chlamydia trachomatis; and by many other

agents as well, apparently in some cases via nasopharyngeal infection

with Chlamydia pneumoniae or other agents. The “classic triad” represents a small part of the clinical spectrum and is present only in a

small minority of patients. For the purposes of this chapter, the use

of the term ReA will be restricted to those cases of SpA with at least

presumptive evidence for a related antecedent infection.

■ EPIDEMIOLOGY

In early reports, 60–85% of patients who developed ReA triggered by

Shigella, Yersinia, or Chlamydia were HLA-B27-positive. However, a

lower prevalence of B27 is found in ReA triggered by Salmonella, and

little or no B27 association is seen in Campylobacter-induced ReA.

Recent community-based or common-source epidemic studies showed

an overall prevalence of B27 in ReA <50%. The most common age

range is 18–40 years, but ReA can occur in children and older adults.

The reported attack rate of postenteric ReA ranges from 1% to about

30%, depending on the study and causative organism, whereas the

attack rate of postchlamydial ReA is ~4–8%. The gender ratio following

enteric infection is nearly 1:1, whereas venereally acquired ReA occurs

mainly in men. The overall prevalence and incidence of ReA are difficult to assess because of lack of validated diagnostic criteria, variable

prevalence and arthritogenic potential of the triggering microbes, and

varying genetic susceptibility in different populations. In Scandinavia,

an annual incidence of 10–28:100,000 has been reported. SpA was

formerly almost unknown in sub-Saharan Africa. However, ReA and

other peripheral SpAs became common in black Africans in the wake

of the AIDS epidemic, without association to B27, which is rare in

these populations. In Africans, ReA is often the first manifestation of

HIV infection and often remits with disease progression. In contrast,

Western white patients with HIV and SpA are usually B27-positive, and

the arthritis flares as AIDS advances.

■ PATHOLOGY

Synovial histology is similar to that of other SpAs. Enthesitis shows

increased vascularity and macrophage infiltration of fibrocartilage.

Microscopic histopathologic evidence of inflammation mimicking IBD

has routinely been demonstrated in the colon and ileum of patients

with postenteric ReA and less commonly in postvenereal ReA. The

skin lesions of keratoderma blennorrhagica, associated mainly with

venereally acquired ReA, are histologically indistinguishable from

pustular psoriasis.

■ ETIOLOGY AND PATHOGENESIS

Definite bacterial triggers of ReA include several Salmonella spp., Shigella

spp., Yersinia enterocolitica, Yersinia pseudotuberculosis, Campylobacter

jejuni, and Chlamydia trachomatis. These are all gram-negative bacteria

containing lipopolysaccharide (LPS). All Shigella species have been

implicated in cases of ReA, with S. flexneri and S. sonnei being the most

common. Yersinia species in Europe and Scandinavia may have greater

arthritogenic potential than elsewhere, and C. trachomatis appears to

be a common trigger worldwide. The ocular serovars of C. trachomatis

appear to be particularly, perhaps uniquely, arthritogenic.

There is also evidence implicating Clostridium difficile, Campylobacter

coli, certain toxigenic Escherichia coli, Ureaplasma urealyticum, and

Mycoplasma genitalium as potential triggers of ReA. Chlamydia

pneumoniae can trigger ReA, but far less commonly so than

C. trachomatis. There have been numerous isolated reports of acute

arthritis following many other bacterial, viral, or parasitic infections,

and arthritis following intravesicular bacillus Calmette-Guérin (BCG)

treatment for bladder cancer is well documented.

It is not known whether there is a common pathogenic mechanism

for triggering ReA that is shared by all of these microorganisms, nor

has the mechanism been elucidated for any particular trigger. Many of

the established triggers share a capacity to attack mucosal surfaces, to

invade host cells, and to survive intracellularly. Antigens from Chlamydia,

Yersinia, Salmonella, and Shigella have been found in synovium and/

or synovial fluid leukocytes of patients with ReA for long periods following the acute attack. In ReA triggered by Y. enterocolitica, bacterial

LPS and heat-shock protein antigens have been found in peripheral

blood cells years after the triggering infection. Yersinia DNA and C.

trachomatis DNA and RNA have been detected in synovial tissue from

ReA patients, suggesting the presence of viable organisms despite uniform failure to culture organisms from these specimens. The specificity

of these findings is unclear, however, since chromosomal bacterial

DNA and 16S rRNA from a wide variety of bacteria have also been

found in synovium in other rheumatic diseases, albeit less frequently.

Recent work has documented high levels of IL-17 in ReA synovial

fluid, but the source has not been identified. HLA-B27 seems to be

associated with more severe and chronic ReA, but its pathogenic role

remains to be determined. HLA-B27 significantly prolongs the intracellular survival of Y. enterocolitica and Salmonella enteritidis in human

and mouse cell lines. This may permit trafficking of infected leukocytes

from the site of primary infection to joints, where an innate and/or

adaptive immune response to persistent bacterial antigens may then

promote arthritis.

A recent study using 16S ribosomal RNA gene sequencing of

intestinal microbiota showed a higher abundance of Erwinia and

Pseudomonas species and an increased prevalence of typical enteropathogens in ReA patients, compared with controls. Correlations were

found between specific bacteria and disease manifestations, and there

was an HLA correlation with microbiome diversity.

■ CLINICAL FEATURES

The clinical manifestations of ReA range from an isolated, transient

monoarthritis or enthesitis to severe multisystem disease. A careful

history will often elicit evidence of an antecedent infection 1–4 weeks

before onset of symptoms of the reactive disease, particularly in postenteric ReA. However, in a sizable minority, no clinical or laboratory

evidence of an antecedent infection can be found, particularly in the

case of postchlamydial ReA. In cases of presumed venereally acquired

reactive disease, there is often a history of a recent new sexual partner.

Constitutional symptoms are common, including fatigue, malaise,

fever, and weight loss. The musculoskeletal symptoms are usually acute

in onset. Arthritis is usually asymmetric and additive, with involvement of new joints occurring over a few days to 1–2 weeks. The joints

of the lower extremities, especially the knee, ankle, subtalar, metatarsophalangeal, and toe interphalangeal joints, are most commonly

involved, but the wrist and fingers may be involved. The arthritis is

usually quite painful, and tense joint effusions are not uncommon,

especially in the knee. Dactylitis, or “sausage digit,” a diffuse swelling

of a solitary finger or toe, is a distinctive feature of ReA and PsA, but

can be seen in polyarticular gout and sarcoidosis. Tendinitis and fasciitis are particularly characteristic lesions, producing pain at multiple

entheses, especially the Achilles insertion, the plantar fascia, and sites

along the axial skeleton. Back and buttock pain are quite common and

may be caused by insertional inflammation, muscle spasm, acute sacroiliitis, or, presumably, arthritis in intervertebral joints.

Urogenital lesions may occur throughout the course of the disease.

In men, urethritis may be marked or relatively asymptomatic and may

be either an accompaniment of the triggering infection or a result

of the reactive phase of the disease; interestingly, it occurs in both

postvenereal and postenteric ReA. Prostatitis is common. In women,

cervicitis or salpingitis may be caused either by the infectious trigger

or by the sterile reactive process.

Ocular disease is common, ranging from transient, asymptomatic

conjunctivitis to an aggressive anterior uveitis that occasionally proves

refractory to treatment and may result in blindness.

Mucocutaneous lesions are frequent. Oral ulcers tend to be superficial, transient, and often asymptomatic. The characteristic skin lesion,

2798 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

keratoderma blennorrhagica, consists of vesicles and/or pustules that

become hyperkeratotic, ultimately forming a crust before disappearing. They are most common on the palms and soles but may occur

elsewhere as well. In patients with HIV infection, these lesions are

often severe and extensive, sometimes dominating the clinical picture

(Chap. 202). Lesions on the glans penis, termed circinate balanitis,

consist of vesicles that quickly rupture to form painless superficial

erosions, which in circumcised individuals can form crusts similar to

those of keratoderma blennorrhagica. Nail changes are common and

consist of onycholysis, distal yellowish discoloration, and/or heaped-up

hyperkeratosis.

Less frequent or rare manifestations of ReA include cardiac conduction defects, aortic insufficiency, central or peripheral nervous system

lesions, and pleuropulmonary infiltrates.

In resolving cases, arthritis typically lasts for 3–5 months. Chronic

joint symptoms persist in about 15% of patients, and in up to 60% of

patients in hospital-based series. The chronic symptoms tend to be less

severe than in the acute stage, but work disability or forced change in

occupation is common. Chronic heel pain is often particularly distressing. Low-back pain, sacroiliitis, or even overt AS are common sequelae.

Recurrences of the acute syndrome may occur. In most studies, HLAB27–positive patients showed a worse outcome than B27-negative

patients. Patients with Yersinia- or Salmonella-induced arthritis have

less chronic disease than those whose initial episode follows epidemic

shigellosis.

■ LABORATORY AND RADIOGRAPHIC FINDINGS

The ESR and acute-phase reactants are usually elevated during the

acute phase of the disease, often markedly. Mild anemia may be

present. Synovial fluid is nonspecifically inflammatory. In most ethnic groups, 30–50% of the patients are B27-positive. The triggering

infection usually does not persist at the site of primary mucosal

infection through the time of onset of the reactive disease, but it

may be possible to culture the organism, for example, in the case of

Yersinia- or Chlamydia-induced disease. Serologic evidence of exposure to a causative organism is nonspecific and of questionable utility.

Polymerase chain reaction (PCR) for chlamydial DNA in first-voided

urine specimens may have high sensitivity in the acute stage but is less

useful with chronic disease.

In early or mild disease, radiographic changes may be absent or

confined to juxtaarticular osteoporosis. With long-standing disease,

radiographic features share those of PsA; marginal erosions and loss

of joint space can be seen in affected joints. Periostitis with reactive

new bone formation is characteristic, as in all the SpAs. Spurs at the

insertion of the plantar fascia are common. Sacroiliitis and spondylitis

may be seen as late sequelae. Sacroiliitis is more commonly asymmetric than in AS, and spondylitis can begin anywhere along the lumbar

spine. The syndesmophytes are described as nonmarginal; they are

coarse, asymmetric, and “comma”-shaped, arising from the middle of a

vertebral body, a pattern less commonly seen in primary AS. Progression to spinal fusion is uncommon.

■ DIAGNOSIS

ReA is a clinical diagnosis with no definitively diagnostic laboratory

test or radiologic finding. The diagnosis should be entertained in any

patient with an acute inflammatory, asymmetric, additive arthritis or

tendinitis. The evaluation should include thorough but tactful questioning regarding possible triggering events. On physical examination,

attention must be paid to the distribution of the joint and tendon

involvement and to possible sites of extraarticular involvement, including the eyes, mucous membranes, skin, nails, and genitalia. Synovial

fluid analysis is usually necessary to exclude septic or crystal-induced

arthritis. Culture, serology, or molecular methods may help identify a

triggering infection, but they cannot be relied upon.

Although typing for B27 has low negative predictive value in ReA, it

may have prognostic significance in terms of severity, chronicity, and

the propensity for spondylitis and uveitis. Furthermore, if positive,

it can be helpful diagnostically in atypical cases. HIV testing is often

indicated and may be necessary in selecting therapy.

Both ReA and disseminated gonococcal disease (Chap. 156) can

be venereally acquired and associated with urethritis. Unlike ReA,

gonococcal arthritis and tenosynovitis tend to involve both upper and

lower extremities equally, spare the axial skeleton, and be associated

with characteristic vesicular skin lesions. A positive gonococcal culture

from the urethra or cervix does not exclude ReA; however, culturing

gonococci from blood, skin lesion, or synovium establishes the diagnosis of disseminated gonococcal disease. PCR assay for Neisseria

gonorrhoeae and C. trachomatis may be helpful. Occasionally, only a

therapeutic trial of antibiotics can distinguish ReA from disseminated

gonococcal disease.

ReA shares many features with PsA. However, PsA is usually gradual

in onset; the arthritis tends to affect primarily the upper extremities;

and there are usually no associated mouth ulcers, urethritis, or bowel

symptoms.

TREATMENT

Reactive Arthritis

Most patients with ReA benefit to some degree from high-dose

NSAIDs, although acute symptoms are rarely completely ameliorated, and some patients fail to respond at all.

Prompt, appropriate antibiotic treatment of acute chlamydial

urethritis or enteric infection may prevent the emergence of ReA

but is not universally successful. Data regarding the potential

benefit of antibiotic therapy initiated after onset of arthritis are

conflicting; however, a systematic review and meta-analysis of 10

controlled trials suggested no benefit. One of these trials reported

that a majority of patients with chronic ReA associated with

C. trachomatis or C. pneumoniae benefited significantly from a

6-month course of rifampin plus either azithromycin or doxycycline. This 2010 study still awaits confirmation.

Multicenter trials have suggested that sulfasalazine, up to

3 g/d in divided doses, may be beneficial to patients with persistent

ReA.1 Patients with persistent disease may respond to azathioprine,

1–2 mg/kg per day, or to methotrexate, up to 20 mg per week; however, these regimens have never formally been studied. Anecdotal

evidence from 30 patients supports the use of anti-TNF in severe

chronic cases, and there are isolated reports of responses to anti-IL17A or anti-IL-6 receptor therapy.1

Tendinitis and other enthesitic lesions may benefit from intralesional glucocorticoids. Uveitis may require aggressive treatment

to prevent serious sequelae. Skin lesions ordinarily require only

symptomatic topical treatment. In patients with HIV infection and

ReA, many of whom have severe skin lesions, the skin lesions in

particular respond to antiretroviral therapy. Cardiac complications

are managed conventionally; management of neurologic complications is symptomatic.

Comprehensive management includes counseling patients to

avoid sexually transmitted disease and exposure to enteropathogens, as well as appropriate use of physical therapy, vocational

counseling, and continued surveillance for long-term complications

such as AS. Patients with a history of ReA are at increased risk for

recurrent attacks following repeat exposure.

1

Azathioprine, methotrexate, sulfasalazine, pamidronate, anti-TNFα agents, anti-IL17A agents, and anti-IL-6 receptor agents have not been approved for this purpose

by the FDA at the time of publication.

PSORIATIC ARTHRITIS

Psoriatic arthritis refers to an inflammatory musculoskeletal disease

that has both autoimmune and autoinflammatory features characteristically occurring in individuals with psoriasis.

■ HISTORIC BACKGROUND

The association between arthritis and psoriasis was noted in the nineteenth century. In the 1960s, it became clear that unlike RA, arthritis

associated with psoriasis was usually seronegative, often involved the

Spondyloarthritis

2799CHAPTER 362

distal interphalangeal (DIP) joints of the fingers and the spine and

sacroiliac joints, had distinctive radiographic features, and showed

considerable familial aggregation. In the 1970s, PsA was included in

the broader category of spondyloarthritis because of features similar to

those of AS and ReA.

■ EPIDEMIOLOGY

The prevalence of PsA appears to be increasing in parallel with disease

awareness. Recent data suggest that up to 30% of patients with psoriasis

develop PsA. Longer duration and greater severity of psoriasis increase

the likelihood of developing PsA. In white populations, psoriasis is estimated to have a prevalence of 1–3%. In other races, psoriasis and PsA

are less common in the absence of HIV infection, and the prevalence

of PsA in individuals with psoriasis may be less common. First-degree

relatives of PsA patients have an elevated risk for psoriasis, for PsA, and

for other forms of SpA. Of patients with psoriasis, up to 30% have an

affected first-degree relative. In monozygotic twins, the reported concordance for psoriasis varies from 35–72%, and for PsA from 10–30%.

A variety of HLA associations have been found. HLA-C6 is directly

associated with psoriasis, particularly familial juvenile-onset (type I)

psoriasis. HLA-B27 is associated with psoriatic spondylitis (see below).

HLA-DR7, -DQ3, and -B57 are associated with PsA because of linkage

disequilibrium with C6. A recent study found additive associations of

PsA with haplotypes containing HLA-B8, -C6, -B27, -B38, and -B39. A

correlation was also found between different haplotype combinations

and entheseal, synovial, or axial predominant phenotypes. Genomewide analyses have identified associations of PsA with polymorphisms

in the IL-23 receptor (IL23R), molecules involved in nuclear factor κB

gene expression (TNIP1, TRAF3IP2) and signaling (TNFAIP3, TYK2),

and cytokines TNF, IL12A, and IL12B. A specific IL23R SNP is associated with PsA distinct from psoriasis without arthritis. Overall genetic

sharing of AS with psoriasis is 0.28, lower than with IBD (see below).

Polymorphisms in IL-23A are associated with psoriasis and with PsA,

but not with AS.

■ PATHOLOGY

The inflamed synovium in PsA resembles that of RA, although with

somewhat less hyperplasia and cellularity than in RA. As noted with

AS above, the synovial vascular pattern in PsA is generally greater and

more tortuous than in RA, independent of disease duration. Some

studies have indicated a higher tendency to synovial fibrosis in PsA.

Unlike RA, PsA shows prominent enthesitis, with histology similar to

other forms of SpA.

■ PATHOGENESIS

PsA presumably shares immunopathogenic mechanisms with psoriasis. PsA synovium is characterized by lining layer hyperplasia; diffuse

infiltrationwithTcells, B cells, macrophages, and NKreceptor–expressing

cells, with upregulation of leukocyte homing receptors; and neutrophil

proliferation with angiogenesis. Clonally expanded T-cell subpopulations are frequent and have been demonstrated both in the synovium

and the skin. Plasmacytoid dendritic cells are thought to play a key

role in psoriasis, and there is some evidence for their participation in

PsA. Interferon γ, TNF, and IL-1β, 2, 6, 8, 10, 12, 13, 15, and 17A, and

myeloid-related protein (S100A8/A9) are found in PsA synovium or

synovial fluid. IL-23/17 pathway cytokines are critical drivers of PsA

pathogenesis. Both TH17 cells and type 3 innate lymphocytes (ILC3)

have been identified in dermal extracts of psoriatic lesions and in synovial fluid of PsA patients. Consistent with the extensive bone remodeling in PsA, patients with PsA have been found to have a marked

increase in osteoclastic precursors in peripheral blood and upregulation of receptor activator of nuclear factor κB ligand (RANKL) in the

synovial lining layer. Increased serum levels of TNF, RANKL, leptin,

and omentin positively correlate with these osteoclastic precursors.

■ CLINICAL FEATURES

In 70% of cases, psoriasis precedes joint disease. In 15% of cases, the

two manifestations appear within 1 year of each other. In about 15%

of cases, the arthritis precedes the onset of psoriasis and can present

a diagnostic challenge. The frequency in men and women is almost

equal, although the frequency of disease patterns differs somewhat in

the two sexes. The disease can begin in childhood or late in life but typically begins in the fourth or fifth decade, at an average age of 37 years.

Many classification schemes have been proposed for the broad

spectrum of arthropathy in PsA. Wright and Moll described five patterns: (1) arthritis of the DIP joints; (2) asymmetric oligoarthritis; (3)

symmetric polyarthritis similar to RA; (4) axial involvement (spine and

sacroiliac joints); and (5) arthritis mutilans, a highly destructive form

of the disease. These patterns frequently coexist, and the pattern that

persists chronically often differs from that of the initial presentation.

A simpler scheme in recent use contains three patterns: oligoarthritis,

polyarthritis, and axial arthritis.

Nail changes in the fingers or toes occur in most patients with PsA,

compared with only a minority of psoriatic patients without arthritis,

and pustular psoriasis is said to be associated with more severe arthritis. Dactylitis and enthesitis are common in PsA and help to distinguish

it from other joint disorders. Dactylitis occurs in >30%; enthesitis and

tenosynovitis are probably present in most patients, although often not

appreciated on physical examination. Shortening of digits because of

underlying osteolysis is particularly characteristic of PsA, and there is a

much greater tendency than in RA for both fibrous and bony ankylosis

of small joints. Rapid ankylosis of one or more proximal interphalangeal (PIP) joints early in the course of disease is not uncommon. Joint

involvement tends to follow a “ray” distribution, with all of the joints

of one finger involved, while sparing adjacent fingers entirely. Back and

neck pain and stiffness are also common in PsA.

Arthropathy confined to the DIP joints occurs in ~5% of cases.

Accompanying nail changes in the affected digits are almost always

present. These joints are also often affected in the other patterns of

PsA. Approximately 30% of patients have asymmetric oligoarthritis.

This pattern commonly involves a knee or another large joint with a

few small joints in the fingers or toes, often with dactylitis. Symmetric

polyarthritis occurs in about 40% of PsA patients at presentation. It

may be indistinguishable from RA in terms of the joints involved, but

other features characteristic of PsA are usually also present. Almost

any peripheral joint can be involved. Axial arthritis without peripheral involvement is found in ~5% of PsA patients. It may be clinically

indistinguishable from idiopathic AS, although more neck involvement

and less thoracolumbar spinal involvement are characteristic, and nail

changes are not found in idiopathic AS. A small percentage of PsA

patients have arthritis mutilans, in which there can be widespread

shortening of digits (“telescoping”), sometimes coexisting with ankylosis and contractures in other digits.

Six patterns of nail involvement are identified: pitting, horizontal

ridging, onycholysis, yellowish discoloration of the nail margins, dystrophic hyperkeratosis, and combinations of these findings. Extraarticular and extradermal manifestations are common. Eye involvement,

either conjunctivitis or uveitis, is reported in 7–33% of PsA patients.

Unlike uveitis associated with AS, the uveitis in PsA is more often

insidious in onset, bilateral, chronic, and/or nonanterior. The prevalences of aortic valve insufficiency and heart block are apparently

similar to those in AS.

Widely varying estimates of clinical outcome have been reported in

PsA. At its worst, severe PsA with arthritis mutilans is potentially at

least as crippling and ultimately fatal as severe untreated RA. Unlike

RA, however, many patients with PsA experience temporary remissions. Overall, erosive disease develops in the majority of patients,

progressive disease with deformity and disability is common, and in

some large series, mortality was found to be significantly increased

compared with the general population.

The psoriasis and associated arthropathy seen with HIV infection

both tend to be severe and can occur in populations with low prevalence of psoriasis. Severe enthesitis, dactylitis, and rapidly progressive

joint destruction are seen, but axial involvement is very rare. This

condition is prevented by or responds well to antiretroviral therapy.

■ LABORATORY AND RADIOGRAPHIC FINDINGS

There are no laboratory tests diagnostic of PsA. ESR and CRP are

elevated in only 30% of patients. A small percentage of patients may

2800 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

have low titers of rheumatoid factor or ANAs. About 10% of patients

have anti-CCP antibodies. Uric acid may be elevated in the presence of

extensive psoriasis. HLA-B27 is found in 50–70% of patients with axial

disease but in ≤20% of patients with only peripheral joint involvement.

Peripheral and axial arthritis in PsA show several radiographic

features that distinguish them from RA and AS, respectively. Characteristics of peripheral PsA include DIP involvement, including the

classic “pencil-in-cup” deformity; marginal erosions with adjacent

bony proliferation (“whiskering”); small-joint ankylosis; osteolysis of

phalangeal and metacarpal bone, with telescoping of digits; periostitis

and proliferative new bone at sites of enthesitis; and a “ray” distribution

of lesions. Characteristics of axial PsA that differ from idiopathic AS

include asymmetric sacroiliitis; less facet joint arthritis; nonmarginal,

bulky, “comma”-shaped syndesmophytes that tend to be fewer, less

symmetric, and less delicate than the marginal syndesmophytes of AS;

fluffy hyperperiostosis on anterior vertebral bodies; severe cervical

spine involvement, with a tendency to atlantoaxial subluxation but relative sparing of the thoracolumbar spine; and paravertebral ossification.

Ultrasound and MRI both readily demonstrate enthesitis and tendon

sheath effusions that can be difficult to assess on physical examination.

A recent MRI study of 68 PsA patients found sacroiliitis in 35%, unrelated to B27 but correlated with restricted spinal movement.

■ DIAGNOSIS

Classification criteria for PsA were published in 2006 (Classification

of Psoriatic Arthritis [CASPAR] criteria) (Table 362-2). The sensitivity and specificity of these criteria exceed 90%, and they are useful

in clinical practice as a guide for early diagnosis. Diagnosis can be

challenging when the arthritis precedes psoriasis, the psoriasis is

undiagnosed or obscure, or the joint involvement closely resembles

another form of arthritis. A high index of suspicion is needed in any

patient with an undiagnosed inflammatory arthritis. The history

should include inquiry about psoriasis in the patient and family

members. Patients should be examined disrobed, and psoriasiform

lesions should be sought in the scalp, ears, umbilicus, and gluteal

folds in addition to more accessible sites; the fingernails and toenails

should also be carefully examined. Axial symptoms or signs, dactylitis, enthesitis, ankylosis, the pattern of joint involvement, and characteristic radiographic changes can be helpful clues. The differential

diagnosis includes all other forms of arthritis, which can occur coincidentally in individuals with psoriasis. The differential diagnosis of

isolated DIP involvement is short. Osteoarthritis (Heberden’s nodes)

is usually not inflammatory; gout involving more than one DIP joint

often involves other sites and may be accompanied by tophi; the very

rare entity multicentric reticulohistiocytosis involves other joints

and has characteristic small pearly periungual skin nodules; and the

uncommon entity, inflammatory osteoarthritis, like the others, lacks

the nail changes of PsA. Radiography can be helpful in all these cases,

TABLE 362-2 The CASPAR (Classification Criteria for Psoriatic

Arthritis) Criteriaa

To meet the CASPAR criteria, a patient must have inflammatory articular

disease (joint, spine, or entheseal) with ≥3 points from any of the following five

categories:

1. Evidence of current psoriasis,b,c a personal history of psoriasis, or a family

history of psoriasisd

2. Typical psoriatic nail dystrophye

 observed on current physical examination

3. A negative test result for rheumatoid factor

4. Either current dactylitisf

 or a history of dactylitis recorded by a rheumatologist

5. Radiographic evidence of juxtaarticular new bone formationg

 in the hand or

foot

a

Specificity of 99% and sensitivity of 91%. b

Current psoriasis is assigned 2 points;

all other features are assigned 1 point. c

Psoriatic skin or scalp disease present

at the time of examination, as judged by a rheumatologist or dermatologist.

d

History of psoriasis in a first- or second-degree relative. e

Onycholysis, pitting,

or hyperkeratosis. f

Swelling of an entire digit. g

Ill-defined ossification near joint

margins, excluding osteophyte formation.

Source: Reproduced with permission from W Taylor et al: Classification criteria

for psoriatic arthritis: development of new criteria from a large international study.

Arthritis Rheum 54:2665, 2006.

and in distinguishing between psoriatic spondylitis and idiopathic

AS. A history of trauma to an affected joint preceding the onset of

arthritis may occur more frequently in PsA than in other types of

arthritis, perhaps reflecting the Koebner phenomenon in which psoriatic skin lesions arise at sites of skin trauma.

TREATMENT

Psoriatic Arthritis

Ideally, coordinated therapy is directed at both the skin and joints in

PsA, and biologic agents have dramatically facilitated this goal. This

was first observed with anti-TNF agents, with prompt and dramatic

resolution of both arthritis and skin lesions observed in large, randomized controlled trials of all five agents. Many of the responding

patients had long-standing disease that was resistant to all previous

therapy, as well as extensive skin disease. The clinical response is

often more dramatic than in RA, and delay of disease progression

has been demonstrated radiographically. The potential additive

effect of methotrexate to anti-TNF agents in PsA remains uncertain.

As noted above, anti-TNF therapy, paradoxically, has been reported

to trigger exacerbation or de novo appearance of psoriasis, typically

the palmoplantar pustular variety. In some cases, the therapy can

nevertheless be continued.

Antagonists of the IL-23/IL-17 pathway show efficacy at least

comparable to that of anti-TNF for PsA and in some cases superior

for psoriasis. Approved agents include secukinumab and ixekizumab, monoclonal antibodies to IL-17A; and ustekinumab, a

monoclonal antibody to the shared IL-23/IL-12p40 subunit. Three

monoclonal antibodies to IL-23 (p19 subunit) that are approved for

plaque psoriasis—guselkumab, risankizumab, and tildrakizumab—

showed efficacy in PsA in clinical trials (Fig. 362-3).

Apremilast, an oral phosphodiesterase-4 inhibitor, is approved

for both psoriasis and PsA. Although not quite as effective for PsA

as the biologics, apremilast has a more favorable safety profile. It is

not indicated in patients with radiographically evident joint damage

or axial involvement.

The oral JAK inhibitor, tofacitinib, is approved for treatment of

PsA. When directly compared, its efficacy was comparable to the

anti-TNF agent adalimumab. At least five other JAK inhibitors are

currently being studied in PsA clinical trials.

Oldertreatmentsfor PsAhave been based on drugsthat have efficacy

in RA and/or in psoriasis. Methotrexate in doses of 15–25 mg/week

has moderate efficacy for psoriasis, and expert opinion favors its

use in PsA not requiring biologics. Agents with efficacy in psoriasis

reported to benefit PsA are cyclosporine, retinoic acid derivatives,

and psoralens plus ultraviolet A light (PUVA). The pyrimidine

synthetase inhibitor leflunomide has been shown to be beneficial in

PsA, with modest benefit for psoriasis.

All these treatments require careful monitoring. Immunosuppressive therapy may be used cautiously in HIV-associated PsA if

the HIV infection is well controlled.

UNDIFFERENTIATED AND JUVENILE

SPONDYLOARTHRITIS

Many patients present with one or more SpA features but lack sufficient findings for one of the preceding diagnoses. These patients were

formerly said to have undifferentiated spondyloarthritis, or simply spondyloarthritis, as defined by the 1991 European Spondyloarthropathy

Study Group criteria. Some of these patients may have ReA in which

the triggering infection remains clinically silent. In other cases, the

patient may subsequently develop IBD or psoriasis. The diagnosis of

undifferentiated SpA was commonly applied to patients with peripheral arthritis and/or enthesitis, and to patients with IBP and other SpA

features who did meet radiographic criteria for AS. Many of these latter

patients would now be classified as nr-axSpA (Table 362-1).

Comparable to the classification criteria for axial SpA, the ASAS

has formulated criteria for peripheral SpA. This is intended to exclude

patients with axial symptoms and thus to divide the universe of patients

Spondyloarthritis

2801CHAPTER 362

with SpA into predominantly axial and predominantly peripheral subsets. These criteria are shown in Table 362-3.

In juvenile SpA, which usually begins between ages 7 and 16 years, an

asymmetric, predominantly lower-extremity oligoarthritis and enthesitis without extraarticular features is the typical mode of presentation.

This condition is termed the seronegative enthesitis and arthritis (SEA)

syndrome. There is male predominance (60–80%), and the prevalence

of B27 is ~80%. Despite the absence of axial symptoms, active sacroiliitis by MRI has commonly been found at diagnosis. Many, but not all,

of these patients go on to develop AS in late adolescence or adulthood.

Management of peripheral SpA is similar to that of the other spondyloarthritides. Biologic therapy is indicated in severe, persistent cases

not responsive to other treatment.

Current pediatric literature should be consulted for information on

management of juvenile SpA.

IBD-ASSOCIATED ARTHRITIS

■ HISTORIC BACKGROUND

The relationship between arthritis and IBD, first observed in the 1930s,

was further defined by epidemiologic studies in the 1950s and 1960s,

and included in the concept of the spondyloarthritides in the 1970s.

■ EPIDEMIOLOGY

Both common forms of IBD, ulcerative colitis (UC) and Crohn’s disease

(CD) (Chap. 326), are associated with SpA. UC and CD both have an

estimated prevalence of 0.1–0.2%, and the incidence of each is thought

to have increased in recent decades. Both axial and peripheral SpA are

associated with UC and CD. Wide variations have been reported in the

estimated frequencies of these associations. In recent series, AS was

diagnosed in 1–10%, and peripheral arthritis in 10–50% of patients

with IBD. IBP and enthesitis are common, and many patients have

sacroiliitis on imaging studies.

The prevalence of UC or CD in patients with AS is thought to be

5–10%, and a recent meta-analysis found the prevalence in patients

with nr-axSpA to be 6.4%. However, investigation of unselected SpA

patients by ileocolonoscopy has revealed that up to two-thirds of

patients with AS have subclinical intestinal inflammation that is evident either macroscopically or histologically. These lesions have also

been found in patients with undifferentiated SpA or ReA (both enterically and urogenitally acquired).

Both UC and CD show familial aggregation, more so for CD. HLA

associations have been weak and inconsistent. HLA-B27 is found in

up to 70% of patients with IBD and AS, but in ≤15% of patients with

IBD and peripheral arthritis or IBD alone. Three alleles of the NOD2/

TABLE 362-3 ASAS Criteria for Peripheral Spondyloarthritisa

ARTHRITISb OR ENTHESITIS OR DACTYLITIS

PLUS EITHER

One or more of the following SpA features:

• Psoriasis

• Crohn’s disease or ulcerative colitis

• Preceding infection

• Uveitis

• HLA-B27

• Sacroiliitis on imaging (radiographs or MRI)

OR two or more of the following SpA features:

• Arthritis

• Enthesitis

• Dactylitis

• Inflammatory back pain ever

• Family history for SpA

a

Sensitivity 78%, specificity 82%. b

Peripheral arthritis, usually predominantly lower

limb and/or asymmetric. The various SpA features are as defined in Table 362-1.

Preceding infection refers to preceding gastrointestinal or urogenital infection.

Source: M Rudawaleit et al: Ann Rheum Dis 70:25, 2011.

CARD15 gene have been found in approximately one-half of patients

with CD. These alleles are not associated with SpA per se. In addition,

more than 200 other genes have been found to be associated with CD,

UC, or both. Many of the SNPs associated with AS are also associated

with IBD, almost all with the same direction of association. Overall, the

genetic correlation of AS is 0.49 with CD and 0.47 with UC.

■ PATHOLOGY

Available data for IBD-associated peripheral arthritis suggest a synovial

histology similar to other forms of SpA. Association with arthritis does

not affect the gut histology of UC or CD (Chap. 326). The subclinical

inflammatory lesions in the colon and distal ileum associated with SpA

are classified as either acute or chronic. The former resembles acute

bacterial enteritis, with largely intact architecture and neutrophilic

infiltration in the lamina propria. The latter resemble the lesions of CD,

with distortion of villi and crypts, aphthoid ulceration, and mononuclear cell infiltration in the lamina propria.

■ PATHOGENESIS

Both IBD and SpA are immune-mediated, and the shared genetics

presumably reflect shared pathogenic mechanisms, but the specific

connection between them remains obscure. Rodent models showing

various immune perturbations manifest both IBD and arthritis. Resident innate immune cells and intestinal dysbiosis have been implicated

in both conditions. Several lines of evidence indicate trafficking of

leukocytes between the gut and the joint. Mucosal leukocytes from

IBD patients have been shown to bind avidly to synovial vasculature

through several different adhesion molecules. Macrophages expressing

CD163 are prominent in the inflammatory lesions of both gut and

synovium in the spondyloarthritides.

■ CLINICAL FEATURES

AS associated with IBD is clinically indistinguishable from idiopathic

AS. It runs a course independent of the bowel disease, and in some

patients, it precedes the onset of IBD. Peripheral arthritis may also

begin before onset of overt bowel disease. The spectrum of peripheral

arthritis includes acute self-limited attacks of oligoarthritis that often

coincide with relapses of IBD, and more chronic and symmetric polyarticular arthritis that runs an independent course. The patterns of

joint involvement are similar in UC and CD. In general, erosions and

deformities are infrequent in IBD-associated peripheral arthritis. Isolated destructive hip arthritis is a rare complication of CD, apparently

distinct from osteonecrosis and septic arthritis. Dactylitis and enthesopathy are occasionally found. In addition to the ~20% of IBD patients

with SpA, a comparable percentage have arthralgias or fibromyalgia

symptoms.

Other extraintestinal manifestations of IBD are seen in addition to

arthritis, including uveitis, psoriasis, pyoderma gangrenosum, erythema nodosum, pulmonary nodules, and clubbing, all somewhat more

commonly in CD than UC. The uveitis shares the features described

above for PsA-associated uveitis.

■ LABORATORY AND RADIOGRAPHIC FINDINGS

Laboratory findings reflect the inflammatory and metabolic manifestations of IBD. Joint fluid is usually at least mildly inflammatory. Of

patients with AS and IBD, 30–70% carry HLA-B27, compared with

80–90% of patients with AS alone and 50–70% of those with AS and

psoriasis. Hence, definite or probable AS in a B27-negative individual

in the absence of psoriasis should raise concern for occult IBD. Radiographic changes in the axial skeleton are the same as in uncomplicated

AS. Erosions are uncommon in peripheral arthritis but may occur,

particularly in the metatarsophalangeal joints.

■ DIAGNOSIS

Diarrhea and arthritis are both common conditions that can coexist for

a variety of reasons. When etiopathogenically related, ReA and IBDassociated arthritis are the most common causes. Rare causes include

celiac disease and Whipple’s disease. Behcet’s disease can mimic CD

and cause arthritis. In most cases, diagnosis depends on investigation

of the bowel disease.

2802 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

DEFINITION

Vasculitis is a clinicopathologic process characterized by inflammation

of and damage to blood vessels. The vessel lumen is usually compromised, and this is associated with ischemia of the tissues supplied by

the involved vessel. A broad and heterogeneous group of syndromes

may result from this process, since any type, size, and location of blood

vessel may be involved. Vasculitis and its consequences may be the primary or sole manifestation of a disease; alternatively, vasculitis may be

a secondary component of another disease. Vasculitis may be confined

to a single organ, such as the skin, or it may simultaneously involve

several organ systems.

CLASSIFICATION

A major feature of the vasculitic syndromes as a group is the fact that

there is a great deal of heterogeneity at the same time as there is considerable overlap among them. Table 363-1 lists the major vasculitis

363 The Vasculitis Syndromes

Carol A. Langford, Anthony S. Fauci

TABLE 363-1 Vasculitis Syndromes

PRIMARY VASCULITIS SYNDROMES

SECONDARY VASCULITIS

SYNDROMES

Granulomatosis with polyangiitis

Microscopic polyangiitis

Eosinophilic granulomatosis with

polyangiitis (Churg-Strauss)

IgA vasculitis (Henoch-Schönlein)

Cryoglobulinemic vasculitis

Polyarteritis nodosa

Kawasaki disease

Giant cell arteritis

Takayasu arteritis

Behçet’s disease

Cogan’s syndrome

Single-organ vasculitis

Cutaneous leukocytoclastic angiitis

Cutaneous arteritis

 Primary central nervous system

vasculitis

Isolated aortitis

Vasculitis associated with probable

etiology

Drug-induced vasculitis

 Hepatitis C virus–associated

cryoglobulinemic vasculitis

 Hepatitis B virus–associated

vasculitis

Cancer-associated vasculitis

Vasculitis associated with systemic

disease

Lupus vasculitis

Rheumatoid vasculitis

Sarcoid vasculitis

Source: Adapted from JC Jennette et al: Arthritis Rheum 65:1, 2013.

TREATMENT

IBD-Associated Arthritis

Treatment of CD has been improved by anti-TNF agents. Infliximab,

adalimumab, and certolizumab pegol are effective for induction and

maintenance of clinical remission in CD, and infliximab is effective

in fistulizing CD. IBD-associated arthritis also responds to these

agents. Other biologics with efficacy in IBD that may have efficacy

for peripheral arthritis include ustekinumab (anti-IL12/23) and

risankizumab (anti-IL-23), but anti-IL-17 therapy is not indicated

(Fig. 362-3). Tofacitinib is approved for treatment of UC. Other

promising JAK inhibitors include upadacitinib and filgotinib. Other

treatments for IBD include sulfasalazine and related drugs as well

as systemic and local glucocorticoids. NSAIDs, especially COXselective formulations, are helpful for arthritis and generally well

tolerated, but they can precipitate IBD flares. As noted above for

psoriasis, rare cases of IBD, either CD or UC, have apparently been

precipitated by anti-TNF therapy. Vedolizumab is a gut-selective

integrin inhibitor approved for both CD and UC. It is not given

specifically for joint disease, but coexistent arthritis can improve

during treatment of the IBD. However, there are many reports of de

novo or flaring arthritis, either axial or peripheral, in IBD patients

treated with vedolizumab.

SAPHO SYNDROME

The syndrome of synovitis, acne, pustulosis, hyperostosis, and osteitis

(SAPHO) is characterized by a variety of skin and musculoskeletal

manifestations. Dermatologic manifestations include palmoplantar

pustulosis, acne conglobata, acne fulminans, and hidradenitis suppurativa. The main musculoskeletal findings are sternoclavicular and

spinal hyperostosis, chronic recurrent foci of sterile osteomyelitis, and

axial or peripheral arthritis. Cases with one or a few manifestations

are probably the rule. The ESR and/or CRP are usually mildly to

moderately elevated, occasionally dramatically. Bacteria, most often

Propionibacterium acnes, have been cultured from bone biopsy specimens and occasionally other sites. IBD was coexistent in 8% of patients

in one large series. No gene associations have been found, despite the

resemblance to autoinflammatory syndromes. Radionuclide bone scan

is very helpful diagnostically, often showing the classic “bull’s head”

sign involving the sternoclavicular joints and clavicles. High-dose

NSAIDs may provide relief from bone pain. Uncontrolled series and

case reports describe successful therapy with pamidronate or other

bisphosphonates. Anecdotal benefit from biologic agents has been

reported, including anti-TNF, anti-IL-17A, anti-IL-12/23, anti-IL-6,

and anti-IL-1 agents. Successful prolonged antibiotic therapy has also

been reported.

■ FURTHER READING

Bravo A, Kavanaugh A: Bedside to bench: defining the immunopathogenesis of psoriatic arthritis. Nat Rev Rheumatol 15:645, 2019.

Breban M et al: The microbiome in spondyloarthritis. Best Pract Res

Clin Rheumatol 33:101495, 2019.

Bridgewood C et al: Interleukin-23 pathway at the enthesis: The

emerging story of enthesitis in spondyloarthropathy. Immunol Rev

294:27, 2020.

Ellinghaus D et al: Analysis of five chronic inflammatory diseases

identifies 27 new associations and highlights disease-specific patterns

at shared loci. Nat Genet 48:510, 2016.

Gladman DD: Editorial: What is peripheral spondyloarthritis? Arthritis Rheumatol 67:865, 2015.

Gmuca S, Weiss PF: Juvenile spondyloarthritis. Curr Opin Rheumatol

27:364, 2015.

Gracey E et al: TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis. J Clin Invest

130:1863, 2020.

Kiltz U et al: Development of a health index in patients with ankylosing spondylitis (ASAS HI): Final result of a global initiative based on

the ICF guided by ASAS. Ann Rheum Dis 74:830, 2015.

Maksymowych WP et al: MRI lesions in the sacroiliac joints of

patients with spondyloarthritis: An update of definitions and validation by the ASAS MRI working group. Ann Rheum Dis 78:1550,

2019.

Manasson J et al: Gut microbiota perturbations in reactive arthritis

and postinfectious spondyloarthritis. Arthritis Rheumatol 70:242,

2018.

Mease P, Khan MA (eds): Axial Spondyloarthritis. Elsevier, 2019.

Ranganathan V et al: Pathogenesis of ankylosing spondylitis—recent

advances and future directions. Nat Rev Rheumatol 13:359, 2017.

Ward MM et al: 2019 update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research

and Treatment Network recommendations for the treatment of

ankylosing spondylitis and nonradiographic axial spondyloarthritis.

Arthritis Rheumatol 71:1519, 2019.