Sjögren’s Syndrome

2789CHAPTER 361

TABLE 361-2 Differential Diagnosis of Sicca Symptoms

XEROSTOMIA DRY EYE

BILATERAL PAROTID

GLAND ENLARGEMENT

Viral infections (HCV, HIV)

Drugs

Psychotherapeutic

Parasympatholytic

Antihypertensive

Psychogenic origin

Irradiation

Diabetes mellitus

Trauma

Sjögren’s syndrome

Amyloidosis

Autoimmune thyroid

disease

Inflammation

 Stevens-Johnson

syndrome

Pemphigoid

Chronic conjunctivitis

Chronic blepharitis

Sjögren’s syndrome

Toxicity

Burns

Drugs

Neurologic conditions

 Impaired lacrimal

gland function

 Impaired eyelid

function

Miscellaneous

Trauma

Hypovitaminosis A

Blink abnormality

Anesthetic cornea

Lid scarring

Epithelial irregularity

 Autoimmune thyroid

disease

Viral infections

Mumps

Influenza

Epstein-Barr virus

Coxsackievirus A

Cytomegalovirus

HIV, HCV

Sarcoidosis, tuberculosis

IgG4 syndrome

Sjögren’s syndrome

Metabolic disorders

Diabetes mellitus

 Hyperlipoproteinemias

(types IV and V)

Chronic pancreatitis

Hepatic cirrhosis

Endocrine

Acromegaly

Gonadal hypofunction

Lymphoma

Abbreviation: HCV, hepatitis C virus.

TABLE 361-3 Differential Diagnosis of Sjögren’s Syndrome

HIV INFECTION AND

SICCA SYNDROME SJÖGREN’S SYNDROME SARCOIDOSIS

Predominant in young

males

Predominant in middleaged women

No age or sex preference

Lack of autoantibodies to

Ro and/or La

Presence of

autoantibodies

Lack of autoantibodies to

Ro and/or La

Lymphoid infiltrates of

salivary glands by CD8+ T

lymphocytes

Lymphoid infiltrates of

salivary glands by CD4+ T

lymphocytes

Granulomas in salivary

glands

Association with

HLA-DR5

Association with

HLA-DR3 and DRw52

Unknown

Positive serologic tests

for HIV

Negative serologic tests

for HIV

Negative serologic tests

for HIV

associated with mixed type II or III cryoglobulinemia. Central nervous

system involvement is rarely recognized. A few cases of myelitis associated with antibodies to aquaporin 4 have been described.

Sjögren’s syndrome is characterized by the highest risk for lymphoma development among all autoimmune diseases. Tongue atrophy, persistent parotid gland enlargement, purpura, mixed type II

cryoglobulinemia, low serum C4 complement levels, autoantibodies

(rheumatoid factor, anti-Ro52, anti-Ro60, anti-La), and extensive

lymphocytic infiltration in minor salivary glands are among the main

features predicting the development of lymphoma. Most lymphomas are extranodal, low-grade, marginal zone B cell and are usually

detected incidentally during evaluation of the labial minor salivary

gland biopsy. The affected lymph nodes are usually peripheral. Survival

rates are decreased in patients with B symptoms, lymph node mass

>7 cm in diameter, and high or intermediate histologic grade. Despite

that, pathogenesis of lymphoma in the setting of Sjögren’s syndrome

remains to be elucidated, and genetic alterations involved in chronic

inflammatory, B-cell activation and the type I interferon pathways,

as well as epigenetic abnormalities, have been shown to be significant

contributors.

Recent data reveal an increased risk for multiple myeloma as well

for Sjögren’s syndrome patients with anti-Ro52, anti-Ro60, or anti-La

autoantibodies. In line with observations in rheumatoid arthritis and

systemic lupus erythematosus, patients with Sjögren’s syndrome also

display an increased risk of cardiovascular disease.

Routine laboratory tests in Sjögren’s syndrome can reveal leukopenia and infrequently lymphopenia. In two-thirds of patients, elevated

erythrocyte sedimentation rate, hypergammaglobulinemia, antinuclear

antibodies, rheumatoid factors, and antibodies against Ro52/Ro60

and La autoantigens are detected. Anticentromere autoantibodies are

present in Sjögren’s patients with a clinical picture similar to that of

limited scleroderma (Chap. 360), while the presence of antimitochondrial antibodies may connote liver involvement in the form of autoimmune cholangitis (Chap. 346). Autoantibodies to 21-hydroxylase

are found in patients with a blunted adrenal response, while autoantibodies to citrullinated peptides are seen in Sjögren’s patients with

arthritis. Anticalponin-3 antibodies have been recently associated with

the occurrence of peripheral neuropathies.

■ DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Sjögren’s syndrome should be suspected if a patient presents with eye

and/or mouth dryness, major salivary gland enlargement, or systemic

manifestations such as Raynaud’s phenomenon, palpable purpura, or

symptomatology of renal tubular acidosis. A careful history of medications causing dryness should be obtained. Recently, cases of Sjögren’s

syndrome were triggered by PD-1/PD-L1 checkpoint inhibitors.

The workup should include eye tests that might reveal keratoconjunctivitis sicca, salivary flow tests or ultrasonography, and serum evaluation

for specific autoantibodies. Testing for chronic viral infections (hepatitis

C virus, HIV), chest x-ray to rule out sarcoidosis, protein electrophoresis, IgG4 serum levels, and autoantibodies to thyroid antigens can be also

offered. Labial biopsy is valuable to rule out conditions that may cause

dry mouth, dry eyes, or parotid gland enlargement (Tables 361-2 and

361-3). Classification criteria are not valuable for everyday practice but

are of paramount importance for research. A diagnostic algorithm based

on recent classification criteria is presented (Fig. 361-1).

TREATMENT

Sjögren’s Syndrome

Treatment of Sjögren’s syndrome aims to relieve symptoms and

limit the damage from chronic xerostomia and keratoconjunctivitis

sicca through substitution or stimulation of impaired secretions.

To replace deficient tears, several ophthalmic preparations are

readily available (hydroxypropyl methylcellulose; polyvinyl alcohol; 0.5% methylcellulose; Hypo Tears). If corneal ulcerations are

present, eye patching and boric acid ointments are recommended,

as well as cyclosporine eye drops. Certain drugs that may decrease

lacrimal and salivary secretions, such as diuretics, antihypertensive

drugs, anticholinergics, and antidepressants, should be avoided.

For xerostomia, the best replacement is water. Propionic acid gels

may be used to treat vaginal dryness. To stimulate secretions, orally

administered pilocarpine (5 mg thrice daily) or cevimeline (30 mg

thrice daily) appears to improve sicca manifestations, and both are

well tolerated. Hydroxychloroquine (200 mg daily) is helpful for

arthralgias and mild arthritis.

Patients with renal tubular acidosis should receive sodium bicarbonate by mouth (0.5–2 mmol/kg in four divided doses). Glucocorticoids and monoclonal antibody to CD20 (rituximab) appear to be

effective in patients with systemic disease, particularly in those with

purpura and arthritis. Novel monoclonal antibodies targeting the

CD40L/CD40 costimulatory pathway or the BAFF receptor seem to

be promising therapeutic strategies for the management of Sjögren’s

syndrome patients with systemic manifestations. Treatment of lymphoma in the setting of Sjögren’s syndrome follows the general

guidelines for lymphoma management in the general population.

2790 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

Dry eyes and/or dry mouth1

And/or

Major salivary gland enlargement, fatigue, Raynaud’s phenomenon, arthralgias/arthritis

(particularly small hand joints), palpable purpura/urticarial lesions, renal

tubular acidosis/membranoproliferative glomerulonephritis, ILD/small airways

disease, autoimmune cholangitis, peripheral neuropathy, MS-like lesions

Unstimulated

whole saliva flow

rate ≤0.1 mL/min

Schirmer’s test

≤5 mm/5 min on

at least one eye

If any of those present If any of those present

+

Sjögren’s syndrome

Ocular staining

score ≥5 (or van

Bijsterveld’s

score ≥4) on at

least one eye2

+ Serum

antibodies

against Ro

antigen

+ Minor salivary

gland biopsy3

Exclude

History of head and neck radiation

treatment

Active hepatitis C infection

Acquired immunodeficiency

syndrome

Sarcoidosis

Amyloidosis

Graft-versus-host disease

IgG4-related disease

FIGURE 361-1 Diagnostic algorithm for Sjögren’s syndrome. 1

Defined as a positive response to at least one of the following questions: (a) Have you had daily, persistent,

troublesome dry eyes for more than 3 months? (b) Do you have a recurrent sensation of sand or gravel in the eyes? (c) Do you use tear substitutes more than three times a

day? (d) Have you had a daily feeling of dry mouth for more than 3 months? (e) Do you frequently drink liquids to aid in swallowing dry food? 2

Ocular staining score described

in Whitcher et al. van Bijsterveld score described in van Bijsterveld et al. 3

Focus score count ≥1 (based on the number of foci per 4 mm of salivary gland tissue) following a

protocol described in Daniels et al. ILD, interstitial lung disease; MS, multiple sclerosis.

Spondyloarthritis (SpA) refers to a group of overlapping disorders that

share clinical features, genetic associations, and pathogenic mechanisms. The classic designations include ankylosing spondylitis (AS),

reactive arthritis (ReA), psoriatic arthritis (PsA), arthritis associated

with inflammatory bowel disease (IBD), juvenile spondyloarthritis

(JSpA), and undifferentiated SpA. These disorders are broadly classified

362 Spondyloarthritis

Joel D. Taurog, Lianne S. Gensler,

Nigil Haroon

■ FURTHER READING

Daniels TE et al: Associations between salivary gland histopathologic

diagnoses and phenotypic features of Sjögren’s syndrome among

1,726 registry participants. Arthritis Rheum 63:2021, 2011.

Mavragani CP, Moutsopoulos HM: Sjögren’s syndrome. CMAJ

186:579, 2014.

Mavragani CP, Moutsopoulos HM: Sjogren’s syndrome: Old and

new therapeutic targets. J Autoimmun 110:102364, 2020.

Moutsopoulos HM: Sjögren’s syndrome: A forty-year scientific journey. J Autoimmun 51:1, 2014.

Shiboski CH et al: 2016 American College of Rheumatology/

European LeagueAgainstRheumatism ClassificationCriteria for Primary

Sjögren’s Syndrome:Aconsensus and data-driven methodology involving

three international patient cohorts. Arthritis Rheumatol 69:35, 2017.

van Bijsterveld OP: Diagnostic tests in the Sicca syndrome. Arch

Ophthalmol 82:10, 1969.

Vivino FB et al: Sjogren’s syndrome: An update on disease pathogenesis, clinical manifestations and treatment. Clin Immunol 203:81, 2019.

Whitcher JP et al: A simplified quantitative method for assessing

keratoconjunctivitis sicca from the Sjögren’s Syndrome International

Registry. Am J Ophthalmol 149:405, 2010.

as predominantly axial SpA, affecting the spine, pelvis, and thoracic

cage, or predominantly peripheral SpA, affecting the extremities.

ANKYLOSING SPONDYLITIS AND AXIAL

SPONDYLOARTHRITIS

Axial spondyloarthritis (axSpA) is the current term used to describe

the most common inflammatory disorder affecting the axial skeleton,

with variable involvement of peripheral joints and extraarticular structures. AxSpA includes patients with significant radiographic damage

of the sacroiliac joints, classically termed AS and now considered

radiographic axial spondyloarthritis (r-axSpA), and those patients

with a similar clinical presentation but lacking significant radiographic

sacroiliitis. In this latter group, some eventually develop significant

radiographic sacroiliitis; however, many do not. The general concept

of axSpA is supported by classification criteria formulated in 2009

(Table 362-1). AxSpA patients with sacroiliitis on MRI without significant damage on x-ray are categorized as having nonradiographic axial

spondyloarthritis (nr-axSpA).

■ EPIDEMIOLOGY

The estimated adult prevalence of AS in 20 countries during the past

2 decades is ~0.17% (range 0.02–0.5%). In the few studies that have

addressed ax-SpA, prevalence is ~1.3- to 2-fold higher than that of AS.

AS shows a striking correlation with the histocompatibility antigen

HLA-B27 and occurs worldwide roughly in proportion to the prevalence of B27. In North American whites, the prevalence of B27 is 6%,

whereas it is 80–90% in patients with AS.

In population surveys, AS is found in 1–6% of adults inheriting B27,

whereas the prevalence is 10–30% among B27+ adult first-degree relatives of AS probands. The concordance rate in identical twins is about

65%. Susceptibility to AS is determined largely by genetic factors, with

B27 comprising ~20% of the genetic component. Single-nucleotide

polymorphism (SNP) analysis has identified 115 additional non-HLA

alleles that altogether contribute another ~7–8% of genetic susceptibility. The prevalence of HLA-B27 in nr-axSpA is somewhat lower

than in AS and the proportion of females is higher. Little information

is available about non-HLA susceptibility loci in nr-axSpA, which is

genetically more heterogeneous than AS.

Spondyloarthritis

2791CHAPTER 362

is associated with prominent edema of the adjacent bone marrow

and is often characterized by erosive lesions that eventually undergo

ossification.

Subclinical intestinal inflammation has been found in the colon

or distal ileum in most patients with SpA. The histology is described

below under “IBD-Associated Arthritis.”

■ PATHOGENESIS

AS is immune-mediated, and increasing evidence suggests more of an

autoinflammatory rather than antigen-specific autoimmune pathogenesis. Uncertainty remains regarding the primary site of disease initiation. The dramatic response of the disease to therapeutic blockade of

tumor necrosis factor (TNF) or IL-17A indicates that these cytokines

play a central immunopathogenic role. Genes related to TNF pathways

show association with AS, including TNFRSF1A, TNFAIP3, LTBR, and

TBKBP1. Genes in the IL-23/IL-17 pathway show association with

AS, including IL23R, PTER4, IL12B, CARD9, IL6R, TYK2, JAK2, and

STAT3. Of these 12 genes, 11 are also associated with IBD, and 6 with

psoriasis. Serum levels of IL-23 and IL-17 are elevated in AS patients.

In mice, tissue-resident thymus-dependent T cells expressing γ/δ T-cell

receptors and IL-23 receptors are found at entheses, in the aortic root,

and near the ciliary body in the eye. These cells express abundant IL-17

and IL-22 upon exposure to systemic IL-23. This finding suggests that

site-specific innate immune cells play a critical role in the anatomic

specificity of these lesions. IL-23 signals through the Janus kinase (Jak)

TYK2. TYK2 loss of function SNPs are protective against AS, and Tyk2

inhibition blocks IL-23-dependent immunity and SpA progression in

a mouse model.

High levels of circulating γδ T cells expressing IL-23 receptors and

producing IL-17 have been found in AS patients. Recent studies of

human spinal entheses identified IL-23-producing CD14+ myeloid

cells and IL-17A-producing γδ-T cells. One subset of these γδ-T cells

lacked IL-23 receptors. This population evidently produces IL-17A

independently of IL-23 and may explain the therapeutic failure in

ax-SpA of agents targeting IL-23, despite the positive response of

peripheral SpA to these agents and the dramatic response of both axial

and peripheral SpA to agents targeting IL-17A (see Fig. 362-3).

Other associated genes encode other cytokines or cytokine receptors

(IL1R1, IL1R2, IL7R, IL27), transcription factors involved in the differentiation of immune cells (RUNX3, EOMES, BACH2, NKX2-3, TBX21),

or other molecules involved in activation or regulation of immune or

inflammatory responses (FCGR2A, ZMIZ1, NOS2, ICOSLG).

The inflamed sacroiliac joint is infiltrated with CD4+ and CD8+

T cells and macrophages and shows high levels of TNF, particularly

early in the disease. Abundant transforming growth factor β (TGF-β)

is found in more advanced lesions. Peripheral synovitis in SpA is characterized by neutrophils, macrophages expressing CD68 and CD163,

CD4+ and CD8+ T cells, and B cells. There is prominent staining for

intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion

molecule 1 (VCAM-1), matrix metalloproteinase 3 (MMP-3), and

myeloid-related proteins 8 and 14 (MRP-8 and MRP-14).

Gut microbiota dysbiosis is consistently found in SpA patients and

animal models, and in both may be influenced by HLA genotype,

including HLA-B27. Bacteria species with mucolytic properties are

expanded in patients, suggesting a pathogenic role for degradation of

intestinal mucus. Overlapping features with ReA and IBD and involvement of the IL-23/IL-17 pathway, which is fundamentally associated

with host defense at mucosal sites, provide additional support for

the importance of the microbiome in SpA pathogenesis. It has been

hypothesized that systemic inflammation, dysbiosis, and increased

intestinal permeability form an amplification loop driving sustained

inflammation in SpA.

HLA-B27 plays a direct role in AS pathogenesis, but its precise

molecular role remains unresolved. Rats transgenic for HLA-B27

develop arthritis and spondylitis, and this is unaffected by the absence

of CD8. It thus appears that classical peptide antigen presentation to

CD8+ T cells may not be the primary disease mechanism. However, the

association of AS with ERAP1 and ERAP2, which strongly influence

the MHC class I peptide repertoire, suggests that peptide binding to

TABLE 362-1 ASAS Criteria for Classification of Axial

Spondyloarthritis (to be applied for patients with back pain ≥3 months

and age of onset <45 years)a

SACROILIITIS ON IMAGING

PLUS ≥1 SpA FEATURE OR

HLA-B27 PLUS ≥2 OTHER SpA

FEATURES

Sacroiliitis on imaging

• Active (acute) inflammation

on MRI highly suggestive of

SpA-associated sacroiliitisb

and/or

• Definite radiographic

sacroiliitis according to

modified New York criteriac

SpA features

• Inflammatory back paind

• Arthritise

• Enthesitis (heel)f

• Anterior uveitisg

• Dactylitise

• Psoriasise

• Crohn’s disease or ulcerative

colitise

• Good response to NSAIDsh

• Family history of SpAi

• HLA-B27

• Elevated CRPj

a

Sensitivity 83%, specificity 84%. The imaging arm (sacroiliitis) alone has a

sensitivity of 66% and a specificity of 97%. b

Bone marrow edema and/or osteitis on

short tau inversion recovery (STIR) or gadolinium-enhanced T1 image. c

Bilateral

grade ≥2 or unilateral grade 3 or 4. d

See text for criteria. e

Past or present, diagnosed

by a physician. f

Past or present pain or tenderness on examination at calcaneus

insertion of Achilles tendon or plantar fascia. g

Past or present, confirmed by an

ophthalmologist. h

Substantial relief of back pain at 24–48 h after a full dose of

NSAID. i

First- or second-degree relatives with ankylosing spondylitis (AS), psoriasis,

uveitis, reactive arthritis (ReA), or inflammatory bowel disease (IBD). j

After

exclusion of other causes of elevated CRP.

Abbreviations: ASAS, Assessment of Spondyloarthritis international Society; CRP,

C-reactive protein; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal antiinflammatory drugs; SpA, spondyloarthritis.

Source: Adapted from M Rudwaleit et al: The development of assessment

of spondylo arthritis international society classification criteria for axial

spondyloarthritis (part II): Validation and final selection. Ann Rheum Dis 68:777, 2009.

■ PATHOLOGY

Sacroiliitis is typically an early manifestation of axSpA, whether or

not it is evident radiographically. In biopsy and autopsy studies of

sacroiliac joints, covering a range of disease durations, synovitis and

myxoid marrow represent the earliest changes, followed by pannus

and subchondral granulation tissue. Marrow edema, enthesitis, and

chondroid differentiation are also found. Macrophages, T cells, plasma

cells, and osteoclasts are prevalent. If the process progresses, eventually

the eroded joint margins are replaced by fibrocartilage regeneration

and then by ossification.

In the spine, inflammatory granulation tissue is seen in the paravertebral connective tissue at the junction of annulus fibrosus and

vertebral bone, or even along the entire outer annulus. The outer

annular fibers are eroded and eventually replaced by bone, forming an

early syndesmophyte, which then grows by endochondral ossification,

ultimately bridging the adjacent vertebral bodies (Fig. 362-1F, G).

Progression of this process can lead to “bamboo spine.” Other spinal

lesions include osteoporosis (loss of trabecular bone despite accretion

of periosteal bone), erosion of vertebral bodies at the disk margin, and

inflammation and destruction of the disk-bone border. Inflammatory

arthritis of the facet joints is common, with erosion of joint cartilage by

pannus often followed by bony ankylosis. This may precede formation

of syndesmophytes bridging the adjacent disks. Bone mineral density is

diminished in the spine and proximal femur early in the disease course.

Peripheral synovitis in AS shows marked vascularity, evident as tortuous macrovascularity seen during arthroscopy. Lining layer hyperplasia, lymphoid infiltration, and pannus formation are also found.

Central cartilaginous erosions from proliferation of subchondral granulation tissue are common. The characteristics of peripheral arthritis in

AS are shared by other forms of SpA and are distinct from those of RA.

Extensive investigation has implicated the enthesis, the fibrocartilaginous region where a tendon, ligament, or joint capsule attaches to

bone, as a primary site of pathology in AS and other SpAs, at both axial

and peripheral sites. Entheses transduce mechanical forces from muscles to bones and hence are widely distributed anatomically. Enthesitis

2792 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

B27 is nonetheless important. CD8+ T cells are decreased in peripheral blood and increased in synovial fluid in AS patients, but their

role in AS pathogenesis remains unclear. The B27 heavy chain has an

unusual tendency to misfold, a process that can be proinflammatory.

Genetic and functional studies in humans have suggested a role for

natural killer (NK) cells in AS, possibly through interaction with B27

heavy chain homodimers. SpA-prone B27 rats show defective dendritic cell function and share with AS patients a characteristic “reverse

interferon” gene expression signature in antigen-presenting cells. A

recent study provided evidence for an interaction between HLA-B27

and activin receptor-like kinase-2, a bone morphogenic protein family

member, mutations of which are associated with fibrodysplasia ossificans progressiva, a disease of uncontrolled bone formation.

Enthesitis can arise in healthy individuals from repetitive mechanical strain at a particular anatomic site. In SpA, it is thought that the

threshold for strain-induced entheseal inflammation is lowered by

genetic factors and/or microbial products, resulting in widespread,

chronic lesions arising at entheseal sites subjected only to normal use.

Supporting this concept, mice transgenic for constitutive TNF production develop peripheral enthesitis and arthritis mediated by innate

immunity, and nonweightbearing reduces inflammation and new bone

formation at these sites.

New bone formation in AS appears to be largely based on enchondral bone formation and occurs only in the periosteal compartment. It

correlates with lack of regulation of the Wnt signaling pathway, which

controls the differentiation of mesenchymal cells into osteophytes, by

the inhibitors DKK-1 and sclerostin. Indirect evidence and data from

animal models also implicate bone morphogenic proteins, hedgehog

proteins, and prostaglandin E2

. Patients with high inflammatory markers and inflammation at vertebral corners on MRI are the ones most

likely to develop syndesmophytes. Mounting evidence suggests that

early and prolonged anti-TNF therapy may decrease spinal fusion. Vertebral inflammatory lesions that undergo metaplasia to fat (increased

T1-weighted signal) are a preferential site of subsequent syndesmophyte formation despite anti-TNF therapy, whereas early acute inflammatory lesions resolve, reinforcing the importance of early treatment

to resolve inflammation.

■ CLINICAL MANIFESTATIONS

The initial AS symptoms are usually first noticed in late adolescence or

early adulthood, at a median age in the mid-twenties. In 5% of patients,

symptoms begin after age 40. The initial symptom is pain that can be

either sharp or dull, insidious in onset, felt deep in the lower lumbar

or gluteal region, and accompanied by low-back morning stiffness of

up to a few hours’ duration that improves with activity and returns

following inactivity. Within a few months, the pain usually becomes

persistent and bilateral. Nocturnal exacerbation of pain often forces the

patient to rise and move around.

In some patients, bony tenderness (presumably reflecting enthesitis

or osteitis) accompanies back pain or stiffness, whereas in others it may

A B C

D

E F G

FIGURE 362-1 Imaging in nonradiographic axial spondyloarthritis (nr-axSpA) and in ankylosing spondylitis (radiographic axial spondyloarthritis).

A. Anterior posterior (AP) pelvis radiograph in a patient with nr-axSpA, showing insignificant sacroiliac (SI) joint changes. There is minimal right-sided SI joint sclerosis

(blue arrow).

B. T1-weighted MRI of the sacrum from the patient shown in A. The yellow arrow indicates cortical erosion of the right SI joint and the white arrow indicates subchondral fat.

C. Short tau inversion recovery (STIR) sequence MRI from the same patient shows bone marrow edema on both sides of the SI joint (blue arrows).

D. AP pelvis radiograph in a patient with AS. Blue arrows indicate advanced bilateral radiographic sacroiliitis (sclerosis, partial fusion, erosions). There is severe bilateral

hip disease with autofusion on the left (yellow arrow), and diffuse osteoporosis.

E. Lateral lumbar spine radiograph in a patient with AS. Blue arrows indicate Romanus lesions (shiny corners).

F. AP lumbar spine radiograph in a patient with AS. Blue arrows indicate bridging syndesmophytes.

G. Lateral cervical spine radiograph in a patient with AS. There is complete ankylosis of the facet joints (blue arrow) and bridging syndesmophytes throughout (yellow arrow).

Spondyloarthritis

2793CHAPTER 362

be the predominant complaint. Common sites include the costosternal

junctions, spinous processes, iliac crests, greater trochanters, ischial

tuberosities, tibial tubercles, and heels. Hip and shoulder (“root” joint)

arthritis is considered part of axial disease. Hip arthritis occurs in

25–35% of patients. Severe isolated hip arthritis or bony chest pain may

be the presenting complaint, and symptomatic hip disease can dominate the clinical picture, especially in those with juvenile-onset disease.

Arthritis of peripheral joints is usually asymmetric and may occur at

any point in the disease course. Neck pain and stiffness from cervical

spine involvement may be later manifestations but are occasionally

dominant symptoms. Chest pain is common at any stage of ax-SpA and

if not accurately diagnosed can be confused with cardiovascular disease.

In juvenile spondyloarthritis, peripheral arthritis and enthesitis

predominate, with axial symptoms supervening in late adolescence.

Initially, axial physical findings mirror the inflammatory process.

The most specific findings involve loss of spinal mobility, with limitation of anterior and lateral flexion and extension of the lumbar spine

and of chest expansion. Limitation of motion is usually out of proportion to the degree of bony ankylosis and may reflect muscle spasm

secondary to pain and inflammation. Pain in the sacroiliac joints may

be elicited either with direct pressure or with stress on the joints. In

addition, there is commonly tenderness upon palpation of the posterior spinous processes and other sites of symptomatic bony tenderness.

The modified Schober test is a useful measure of lumbar spine flexion. The patient stands erect, with heels together, and marks are made

on the spine at the lumbosacral junction (identified by a horizontal line

between the posterosuperior iliac spines) and 10 cm above. The patient

then bends forward maximally with knees fully extended, and the

distance between the two marks is measured. This distance increases

by ≥2 cm with normal mobility. Chest expansion is measured as the

difference between maximal inspiration and maximal forced expiration

at the levels of either the fourth intercostal space or the xiphisternum,

with the patient’s hands resting on or just behind the head. Normal

chest expansion is ≥2.5 cm. Lateral bending measures the distance

the patient’s middle finger travels down the leg with maximal lateral

bending. Normal is >10 cm.

Limitation or pain with motion of the hips or shoulders is usually

present if these joints are involved. It should be emphasized that in

early, mild, or atypical cases, the symptoms and/or physical findings

may be subtle and/or nonspecific.

The course of ax-SpA is extremely variable, ranging from the individual with mild stiffness and normal radiographs to the patient with

a totally fused spine and severe bilateral hip arthritis, severe peripheral

arthritis, and extraarticular manifestations. Available data on natural history pertain predominantly to AS, although the prevalence of

peripheral arthritis, enthesitis, psoriasis, and IBD appears to be similar

in nr-axSpA and AS. Pain tends to be persistent early in the disease

and intermittent later, with alternating exacerbations and quiescent

periods. In a typical severe untreated case with progression to syndesmophyte formation, the posture undergoes characteristic changes,

with obliterated lumbar lordosis, buttock atrophy, and accentuated

thoracic kyphosis. There may be a forward stoop of the neck or flexion

contractures at the hips, compensated by flexion at the knees. Disease

progression can be estimated clinically from loss of height, limitation

of chest expansion and spinal flexion, and increasing occiput-to-wall

distance. Occasional individuals are encountered with advanced deformities who deny ever having significant symptoms.

The factors most predictive of radiographic progression (see below)

are the presence of existing syndesmophytes, high inflammatory markers, and smoking. In some but not all studies, onset of AS in adolescence and early hip involvement correlate with a worse prognosis. In

women, AS tends to progress less frequently to total spinal ankylosis,

although there may be an increased prevalence of peripheral arthritis.

Peripheral arthritis occurs in up to 30% of patients. Pregnancy has

no consistent effect on AS, with symptoms improving, remaining the

same, or deteriorating in one-third of pregnant patients, respectively.

However, those requiring biologic therapy before pregnancy are quite

likely to flare during the second and third trimester if the medication

is discontinued during pregnancy.

The most serious complication of advanced spinal disease is spinal

fracture, which can occur with even minor trauma to the rigid, osteoporotic spine. The lower cervical spine is most commonly involved. These

fractures are often displaced, causing spinal cord injury. A recent survey

suggested a >10% lifetime risk of fracture. Occasionally, fracture through

a diskovertebral junction and adjacent neural arch, termed pseudoarthrosis, most common in the thoracolumbar spine, can be an unrecognized source of persistent localized pain and/or neurologic dysfunction.

Wedging of thoracic vertebrae can lead to accentuated kyphosis.

The most common extraarticular manifestation is acute anterior

uveitis, which occurs in up to 50% of patients and can antedate the

spondylitis. Attacks are typically unilateral, causing pain, photophobia,

and pain with accommodation. These may recur, often in the opposite eye. Cataracts and secondary glaucoma may ensue. Up to 60% of

patients with AS have inflammation in the colon or ileum. This is usually asymptomatic, but overt IBD occurs in 5–10% of patients with AS

(see “IBD-Associated Arthritis,” below). About 10% of patients meeting

criteria for AS have psoriasis (see “Psoriatic Arthritis,” below). Occasional patients are seen with AS in association with skin manifestations

seen in SAPHO syndrome (see below), such as acne fulminans or

hidradenitis suppurativa. There is an apparently increased risk of ischemic heart disease. Aortic insufficiency occurs in a small percentage of

patients, usually after longstanding disease. Third-degree heart block

may occur alone or together with aortic insufficiency, and association

with lesser degrees of heart block has been described. Cauda equina

syndrome and upper pulmonary lobe fibrosis are rare late complications. Prostatitis has been reported to have an increased prevalence.

Amyloidosis is rare (Chap. 112).

Several validated measures of disease activity and functional outcome are in widespread use in the study and management of ax-SpA,

particularly the Bath Ankylosing Spondylitis Disease Activity Index

(BASDAI) and the Ankylosing Spondylitis Disease Activity Score

(ASDAS), both measures of disease activity; the Bath Ankylosing Spondylitis Functional Index (BASFI), a measure of limitation in activities

of daily living; and several measures of radiographic changes. The new

Assessment of Spondyloarthritis international Society (ASAS) Health

Index is a spondyloarthritis-specfic tool for assessing impairment of

function and health. Despite persistence of the disease, most patients

remain gainfully employed. Some but not all studies of survival in AS

have suggested that AS shortens life span, compared with the general

population. Mortality attributable to AS is largely the result of spinal

trauma, aortic insufficiency, respiratory failure, amyloid nephropathy,

or complications of therapy such as upper gastrointestinal hemorrhage.

The impact of biologic therapy on outcome and mortality is not yet

known, except for significantly improved work productivity.

■ LABORATORY FINDINGS

No laboratory test is diagnostic of AS. In most ethnic groups, HLA-B27

is present in 75–90% of patients. Erythrocyte sedimentation rate (ESR)

and C-reactive protein (CRP) are often, but not always, elevated. Mild

anemia may be present. Patients with severe disease may show elevated

alkaline phosphatase. Elevated serum IgA is common. Rheumatoid factor, anti-cyclic citrullinated peptide (CCP), and antinuclear antibodies

(ANAs) are largely absent unless caused by a coexistent disease, although

ANAs may appear with anti-TNF therapy. Circulating levels of CD8+

T cells tend to be low, and serum matrix metalloproteinase 3 levels correlate with disease activity. Synovial fluid from peripheral joints is nonspecifically inflammatory. Restricted chest wall motion causes decreased

vital capacity, but ventilatory function is usually well maintained.

■ RADIOGRAPHIC FINDINGS (FIG. 362-1)

By definition, the diagnosis of AS is associated with advanced radiographically demonstrable sacroiliitis, usually symmetric. The earliest

changes by standard radiography are blurring of the cortical margins of

the subchondral bone, followed by erosions and sclerosis. Progression

of the erosions leads to “pseudowidening” of the joint space; as fibrous

and then bony ankylosis supervene, the joints may become obliterated.

In the lumbar spine, progression of the disease can lead to loss of

lordosis, and osteitis of the anterior corners of the vertebral bodies

2794 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

with subsequent erosion, and new bone formation causing “squaring”

or even “barreling” of one or more vertebral bodies. Progressive ossification leads to eventual formation of marginal syndesmophytes, visible

on plain films as bony bridges connecting successive vertebral bodies

anteriorly and laterally.

Only a minority of patients meeting criteria for nr-axSpA develop

radiographic sacroiliitis within a decade or more, and even fewer

develop spinal changes. MRI is thus much more useful for the timely

diagnosis of ax-SpA, provided that it is done correctly. It must be

emphasized that MRI protocols routinely used to evaluate low back

pain have low sensitivity for detecting inflammation and often give

false-negative results in ax-SpA. Active sacroiliitis is best visualized

by dynamic MRI on semicoronal slices with fat saturation, either

T2-weighted turbo spin-echo sequence or short tau inversion recovery

(STIR) with high resolution, or T1-weighted images with contrast

enhancement. These techniques identify early intraarticular inflammation, cartilage changes, and underlying bone marrow edema in sacroiliitis

(Fig. 362-1). These protocols are also sensitive for evaluation of acute

and chronic spinal changes. Bone marrow edema alone is not specific for

spondyloarthritis. The presence of erosions enhances specificity and is

best detected on conventional T1-weighted images. Optimal MRI results

require a high index of suspicion, an appropriate protocol, an experienced

radiologist, and close communication between radiologist and clinician.

Reduced bone mineral density can be detected by dual-energy x-ray

absorptiometry of the femoral neck and the lumbar spine. Employing

a lateral projection of the L3 vertebral body can prevent falsely elevated

readings related to spinal ossification.

■ DIAGNOSIS

It is important to recognize ax-SpA before the development of irreversible deformity. This goal is challenging for several reasons: (1) only

a minority of back pain patients have ax-SpA; (2) an early diagnosis

often relies on clinical grounds and/or an appropriate MRI protocol

requiring considerable expertise; (3) young individuals with symptoms

of ax-SpA often do not seek medical care; and (4) reliance on definite

radiographic sacroiliitis causes early or mild cases to be missed. The

classification criteria for ax-SpA proposed by ASAS are shown in Table

362-1. They were developed for research purposes only and should not

be strictly applied as diagnostic criteria but can be considered an aid to

diagnosis. They are applicable to individuals with ≥3 months of back

pain and age of onset <45 years. Active inflammation of the sacroiliac

joints as determined by MRI is considered equivalent to definite radiographic sacroiliitis (see below).

AxSpA must be differentiated from numerous other causes of lowback pain, some substantially more common than axSpA. Increased

specificity is obtained when the nature and pattern of the pain and

the age of the patient are considered. The most typical symptom is

inflammatory back pain (IBP), present in 70–80% of patients with

axSpA. In chronic (≥3 months) back pain, IBP has the following characteristic features: (1) age of onset <40 years; (2) insidious onset; (3)

improvement with exercise; (4) no improvement with rest; (5) pain

at night with improvement upon getting up; (6) morning stiffness

>30 min; (7) awakening from back pain during only the second half

of the night; and (8) alternating buttock pain. The presence of two

or more of these features should arouse suspicion for IBP, and four

or more can be considered presumptively diagnostic. The most common causes of back pain other than SpA are primarily mechanical or

degenerative rather than primarily inflammatory. These are less likely

to show clustering of SpA features, but IBP can be present in up to 30%

of patients with mechanical back pain.

Less-common causes of back pain must also be differentiated from

axSpA, including infectious spondylitis, spondylodiskitis, or sacroiliitis;

and primary or metastatic tumor. Ochronosis can produce a phenotype

similar to AS. Calcification and ossification of paraspinous ligaments

occur in diffuse idiopathic skeletal hyperostosis (DISH), which occurs in

middle age and above and is usually asymptomatic. Ligamentous calcification gives the appearance of “flowing wax” on the anterior bodies

of the vertebrae. Intervertebral disk spaces are preserved, and sacroiliac

and facet joints appear normal, helping to differentiate DISH from

spondylosis and from AS, respectively. Both primary and secondary

hyperparathyroidism can cause subchondral bone resorption around

the SI joints, with bilateral widened and ill-defined joints on radiographs, but without joint space narrowing.

An algorithm for making or excluding the diagnosis of ax-SpA in

patients with chronic back pain is shown in Fig. 362-2.

TREATMENT

Axial Spondyloarthritis

All management of ax-SpA should include an exercise program

to maintain posture and range of motion. Exercise videos are

available from the Spondylitis Association of America (https://

spondylitis.org/resources-support/educational-materials-resources/

back-in-action-again/.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first

line of pharmacologic therapy. They reduce pain and tenderness and

increase mobility in many patients. Continuous high-dose NSAID

therapy may slow radiographic progression, particularly in patients

who are at higher risk for progression. However, many patients

have persistent symptoms despite NSAID therapy and may benefit

from biologic therapy. Patients with AS treated with the anti-TNF

agents infliximab (chimeric human/mouse anti-TNF monoclonal

antibody), etanercept (soluble p75 TNF receptor–IgG fusion protein), adalimumab or golimumab (human anti-TNF monoclonal

antibodies), or certolizumab pegol (humanized mouse anti-TNF

monoclonal antibody) have shown rapid, profound, and sustained

reductions in all clinical and laboratory measures of disease activity. In a good response, there is significant improvement in both

objective and subjective indicators of disease activity and function,

including morning stiffness, pain, spinal mobility, peripheral joint

swelling, CRP, ESR, and bone mineral density. MRI studies indicate substantial resolution of bone marrow edema, enthesitis, and

joint effusions in the sacroiliac, facet, and peripheral joints. These

results have been obtained in large randomized controlled trials of

all five agents and many open-label studies. About one-half of the

patients achieve a ≥50% reduction in the BASDAI. The response

tends to persist over time and remission of symptoms is feasible in

a proportion of patients. Predictors of the best responses include

younger age, shorter disease duration, higher baseline inflammatory markers, and lower baseline functional disability. Nonetheless,

some patients with long-standing disease and even spinal ankylosis

obtain significant benefit. There is greater chance of slowing syndesmophyte formation with sustained therapy, especially if started

early. The response of patients with nr-axSpA to anti-TNF therapy

is generally similar to that of patients with AS.

Typically, infliximab is given intravenously, 5 mg/kg body

weight, and then repeated 2 weeks later, again 6 weeks later, and

then at 6- to 8-week intervals. Etanercept is given by subcutaneous

injection, 50 mg once weekly. Adalimumab is given by subcutaneous injection, 40 mg biweekly. Golimumab is given by subcutaneous

injection, 50 mg every 4 weeks. Certolizumab pegol is given by

subcutaneous injection, 200 mg biweekly or 400 mg every 4 weeks.

Dosage adjustments can be considered in selected cases.

These potent immunosuppressive agents are relatively safe, but

patients are at increased risk for serious infections, including disseminated tuberculosis. Hypersensitivity infusion or injection site

reactions are not uncommon. Cases of anti-TNF-induced psoriasis

have been increasingly recognized. Rare cases of systemic lupus

erythematosus (SLE)–related disease have been reported, as have

hematologic disorders such as pancytopenia, demyelinating disorders, exacerbation of congestive heart failure, and severe liver

disease. The overall incidence of malignancy is not increased in

AS patients treated with anti-TNF therapy, but isolated cases of

hematologic malignancy have occurred shortly after initiation of

treatment.

Because of the expense, potentially serious side effects, and

unknown long-term effects of these agents, their use should be