2854 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

FIGURE 370-7 Dual-energy computed tomography (DECT) scan from a 45-year-old woman with right ankle swelling around the lateral malleolus. Three-dimensional

volume-rendered coronal reformatted DECT image shows that the mass is composed of monosodium urate (red) in keeping with tophus (arrow). (Reprinted from S Nicolaou

et al: Dual-energy CT as a potential new diagnostic tool in the management of gout in the acute setting. AJR Am J Roentgenol 194:1072, 2010.)

FIGURE 370-8 Superior sensitivity of magnetic resonance imaging (MRI) in the

diagnosis of osteonecrosis of the femoral head. A 45-year-old woman receiving

high-dose glucocorticoids developed right hip pain. Conventional x-rays (top)

demonstrated only mild sclerosis of the right femoral head. T1-weighted MRI

(bottom) demonstrated low-density signal in the right femoral head, diagnostic of

osteonecrosis.

Acknowledgment

The author acknowledges the insightful contributions of Dr. Peter E. Lipsky

to this chapter in previous editions.

■ FURTHER READING

Ali Y: Rheumatologic tests: A primer for family physicians. Am Fam

Physician 98:164, 2018.

Cush JJ et al: Evaluation of musculoskeletal complaints. Available

from http://www.rheumaknowledgy.com/evaluation-of-musculoskeletalcomplaints. Accessed April 6, 2017.

Hubbard MJ et al: Common soft tissue musculoskeletal pain disorders.

Prim Care 45:289, 2018.

Olsen NJ, Karp DR: Finding lupus in the ANA haystack. Lupus Sci

Med 7:e000384, 2020.

Rudwaleit M et al: How to diagnose axial spondyloarthritis early. Ann

Rheum Dis 63:535, 2004.

Simpfendorfer CS: Radiologic approach to musculoskeletal infections. Infect Dis Clin North Am 31:299, 2017.

Osteoarthritis (OA) is the most common type of arthritis. Its high

prevalence, especially in the elderly, and its negative impact on physical

function make it a leading cause of disability in the elderly. Because

of the aging of Western populations and because obesity, a major risk

factor, is increasing in prevalence, the occurrence of OA is on the rise.

OA affects certain joints, yet spares others (Fig. 371-1). Commonly

affected joints include the hip, knee, and first metatarsal phalangeal

371 Osteoarthritis

David T. Felson, Tuhina Neogi

Osteoarthritis

2855CHAPTER 371

OA is rare in China and in immigrants from China to the United States.

However, OA in the knees is at least as common, if not more so, in

Chinese as in whites from the United States, and knee OA represents a

major cause of disability in China, especially in rural areas. Anatomic

differences between Chinese and white hips may account for much of the

difference in hip OA prevalence, with white hips having a higher prevalence of anatomic predispositions to the development of OA.

DEFINITION

OA is joint failure, a disease in which all structures of the joint have

undergone pathologic change, often in concert. The pathologic sine

qua non of disease is hyaline articular cartilage loss, present in a focal

and, initially, nonuniform manner. This is accompanied by increasing

thickness and sclerosis of the subchondral bony plate, by outgrowth of

osteophytes at the joint margin, by stretching of the articular capsule,

by variable degrees of synovitis, and by weakness of muscles bridging

the joint. In knees, meniscal degeneration is part of the disease. There

are numerous pathways that lead to joint failure, but the initial step is

often joint injury in the setting of a failure of protective mechanisms.

JOINT PROTECTIVE MECHANISMS

AND THEIR FAILURE

Joint protectors include joint capsule and ligaments, muscle, sensory

afferents, and underlying bone. Joint capsule and ligaments serve as

joint protectors by providing a limit to excursion, thereby fixing the

range of joint motion.

Synovial fluid reduces friction between articulating cartilage surfaces, thereby serving as a protector against friction-induced cartilage

wear. This lubrication function depends on hyaluronic acid and on

lubricin, a mucinous glycoprotein secreted by synovial fibroblasts

whose concentration diminishes after joint injury and in the face of

synovial inflammation.

The ligaments, along with overlying skin and tendons, contain

mechanoreceptor sensory nerves. These mechanoreceptors fire at

different frequencies throughout a joint’s range of motion, providing

feedback by way of the spinal cord to muscles and tendons. As a consequence, these muscles and tendons can assume the right tension at

appropriate points in joint excursion to act as optimal joint protectors,

anticipating joint loading.

Muscles and tendons that bridge the joint are key joint protectors.

Focal stress across the joint is minimized by muscle contraction that

decelerates the joint before impact and assures that when joint impact

arrives, it is distributed broadly across the joint surface.

Failure of these joint protectors increases the risk of joint injury and

OA. For example, in animals, OA develops rapidly when a sensory nerve

to the joint is sectioned and joint injury induced. Similarly, in humans,

Charcot’s arthropathy, a severe and rapidly progressive OA, develops

when minor joint injury occurs in the presence of posterior column

Cervical

vertebrae

First

carpometacarpal

Lower

lumbar

vertebrae

Hip

Knee

First metatarsophalangeal

Distal and proximal

interphalangeal

FIGURE 371-1 Joints commonly affected by osteoarthritis.

FIGURE 371-2 Severe osteoarthritis of the hands affecting the distal interphalangeal

joints (Heberden’s nodes) and the proximal interphalangeal joints (Bouchard’s

nodes). There is no clear bony enlargement of the other common site in the hands,

the thumb base.

joint (MTP) and cervical and lumbosacral spine. In the hands, the

distal and proximal interphalangeal joints and the base of the thumb

are often affected. Usually spared are the wrist, elbow, and ankle. Our

joints were designed, in an evolutionary sense, for brachiating apes,

animals that still walked on four limbs. We thus develop OA in joints

that were ill designed for human tasks such as pincer grip (OA in the

thumb base) and walking upright (OA in knees and hips). Some joints,

like the ankles, may be spared because their articular cartilage may be

uniquely resistant to loading stresses.

OA can be diagnosed based on structural abnormalities or on the

symptoms these abnormalities evoke. According to cadaveric studies, by elderly years, structural changes of OA are nearly universal.

These include cartilage loss (seen as joint space loss on x-rays) and

osteophytes. Many persons with x-ray evidence of OA have no joint

symptoms, and although the prevalence of structural abnormalities

is of interest in understanding disease pathogenesis, what matters

more from a clinical perspective is the prevalence of symptomatic OA.

Symptoms, usually joint pain, determine disability, visits to clinicians,

and disease costs.

Symptomatic OA of the knee (pain on most days of a recent month

plus x-ray evidence of OA in that knee) occurs in ~12% of persons age

≥60 in the United States and 6% of all adults age ≥30. Symptomatic hip

OA is roughly one-third as common as disease in the knee. Although

radiographic hand OA and the appearance of bony enlargement in

affected hand joints (Fig. 371-2) are extremely common in older persons, most affected persons have no pain. Even so, painful hand OA

occurs in ~10% of elderly individuals and often produces measurable

limitation in function.

The prevalence of OA rises strikingly with age, being uncommon

in adults aged <40 and highly prevalent in those aged >60. It is also a

disease that, at least in middle-aged and elderly persons, is much more

common in women than in men.

X-ray evidence of OA is common in the lower back and neck, but

back pain and neck pain have not been tied to findings of OA on x-ray.

Thus, back pain and neck pain are treated separately (Chap. 17).

■ GLOBAL CONSIDERATIONS

With the aging of the populations, both the prevalence of OA and the

amount of disability worldwide related to OA have been increasing,

especially in developed countries where many are living into old age. Hip

2856 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

peripheral neuropathy. Another example of joint protectorfailure isrupture of ligaments, a well-known cause of the early development of OA.

■ CARTILAGE AND ITS ROLE IN JOINT FAILURE

In addition to being a primary target tissue for disease, cartilage also

functions as a joint protector. A thin rim of tissue at the ends of two

opposing bones, cartilage is lubricated by synovial fluid to provide an

almost frictionless surface across which these two bones move. The

compressible stiffness of cartilage compared to bone provides the joint

with impact-absorbing capacity.

The earliest changes of OA may occur in cartilage, and abnormalities there can accelerate disease development. The two major macromolecules in cartilage are type 2 collagen, which provides cartilage its

tensile strength, and aggrecan, a proteoglycan macromolecule linked

with hyaluronic acid, which consists of highly negatively charged

glycosaminoglycans. In normal cartilage, type 2 collagen is woven

tightly, constraining the aggrecan molecules in the interstices between

collagen strands, forcing these highly negatively charged molecules

into close proximity. The aggrecan molecule, through electrostatic

repulsion of its negative charges, gives cartilage its compressive stiffness. Chondrocytes, the cells within this avascular tissue, synthesize

all elements of the matrix and produce enzymes that break it down

(Fig. 371-3). Cartilage matrix synthesis and catabolism are in a

dynamic equilibrium influenced by the cytokine and growth factor

environment. Mechanical and osmotic stress on chondrocytes induces

these cells to alter gene expression and increase production of inflammatory cytokines and matrix-degrading enzymes. While chondrocytes

synthesize numerous enzymes, matrix metalloproteinases (MMPs;

especially collagenases and ADAMTS-5) are critical enzymes in the

breakdown of cartilage matrix.

Local inflammation accelerates the development and progression

of osteoarthritis and increases the likelihood that an osteoarthritic

joint will be painful. Some of this inflammation may be induced by

mechanical stimuli, so called mechanoinflammation. The synovium,

cartilage, and bone all influence disease development through cytokines, chemokines, and even complement activation (Fig. 371-3). These

act on chondrocyte cell-surface receptors and ultimately have transcriptional effects. Matrix fragments released from cartilage stimulate

synovitis. Inflammatory cytokines such as interleukin 1β (IL-1β) and

tumor necrosis factor α (TNF-α) induce chondrocytes to synthesize

prostaglandin E2 and nitric oxide. At early stages in the matrix response

to injury, the net effect of cytokine stimulation may be matrix synthesis, but ultimately, the combination of effects on chondrocytes triggers

matrix degradation. Enzymes in the matrix are held in check by activation inhibitors, including tissue inhibitor of metalloproteinase (TIMP).

Growth factors are also part of this complex network, with bone

morphogenetic protein 2 (BMP-2) and transforming growth factor β

(TGF-β) playing prominent roles in stimulating the development of

osteophytes. Whereas healthy articular cartilage is avascular in part due

to angiogenesis inhibitors present in cartilage, disease is characterized

by the invasion of blood vessels into cartilage from underlying bone.

This is influenced by vascular endothelial growth factor (VEGF) synthesis in the cartilage and bone. With these blood vessels come nerves

that may bring nociceptive innervation.

With aging, articular chondrocytes exhibit a decline in synthetic

capacity, but they produce proinflammatory mediators and matrixdegrading enzymes, findings characteristic of a senescent secretory

phenotype. These chondrocytes are unable to maintain tissue homeostasis (such as after insults of a mechanical or inflammatory nature).

Thus, with age, cartilage is easily damaged by minor sometimes unnoticed injuries, including those that are part of daily activities.

OA cartilage is characterized by gradual depletion of aggrecan, an

unfurling of the tightly woven collagen matrix, and loss of type 2 collagen. With these changes comes increasing vulnerability of cartilage,

which loses its compressive stiffness.

RISK FACTORS

Joint vulnerability and joint loading are the two major factors contributing to the development of OA. On the one hand, a vulnerable joint

whose protectors are dysfunctional can develop OA with minimal levels of loading, perhaps even levels encountered during everyday activities. On the other hand, in a young joint with competent protectors, a

major acute injury or long-term overloading is necessary to precipitate

disease. Risk factors for OA can be understood in terms of their effect

either on joint vulnerability or on loading (Fig. 371-4).

■ SYSTEMIC RISK FACTORS THAT

AFFECT JOINT VULNERABILITY

Age is the most potent risk factor for OA. Radiographic evidence of

OA is rare in individuals aged <40; however, in some joints, such as the

hands, OA occurs in >50% of persons aged >70. Aging increases joint

vulnerability through several mechanisms. Whereas dynamic loading

of joints stimulates matrix synthesis by chondrocytes in young cartilage, aged cartilage is less responsive to these stimuli. Partly because of

this failure to synthesize matrix with loading, cartilage thins with age,

and thinner cartilage experiences higher shear stress and is at greater

risk of cartilage damage. Also, joint protectors fail more often with age.

Muscles that bridge the joint become weaker with age and respond

less quickly to oncoming impulses. Sensory nerve input slows with

age, retarding the feedback loop of mechanoreceptors to muscles and

Hyaline

cartilage

(non-calcified)

RANKL,

OPG, uPA

MMPs, IL-5,

IL-8

Osteocyte VEGF

Sclerostin

Vascular

invasion

Matrix fragments

Osteophyte

formation

Calcified

cartilage

VEGF

BONE REMODELING

Cell surface receptors on chondrocytes SYNOVITIS

activated by complement attack complex,

DAMPS, cytokines and chemokines, WNTs

(frizzled), fibronectin fragments and others

SYNOVITIS

ments

BONE R EMODELING

tin invasion

Osteophyte

Hyaline formation

cartilage

(non-calcified)

S100 proteins (alarmins),

DAMPs, complements,

IL-1β, TNFα, IL-15,

CCL 19, MCP-1, MIP-1β

RANKL,

OPG, uPA

MMPs, IL-5,

IL-8

TGF-β

BMP-2

Osteocyte VEGF

Sclerostin

Vascular

invasion

Matrix fragments

Osteophyte

Calcified formation

cartilage

VEGF

BONE REMODELING

SYNOVITIS

Ost

TGF-β

BMP-2

ost

BO

teo

clero

ocyte

Sc

VE Vascular

invasion

GF

GF

EGF

VEG

EG

TGF-β

BMP-2

x fr

m age

ag

T

B

Vascular

Matrix f M

Cell surface receptors on chondrocytes

activated by

DAMPS, cyt

(frizzled), fib

receptors on chondrocytes

y

t

b

p y

complement attack complex,

okines and chemokines, WNTs

bronectin fragments and o thers

Cell surface receptors on chondrocytes

activated by complement attack complex,

DAMPS, cytokines and chemokines, WNTs

(frizzled), fibronectin fragments, and others

FIGURE 371-3 Selected factors involved in the osteoarthritic process including chondrocytes, bone, and synovium. Synovitis causes release of cytokines, alarmins,

damage-associated molecular pattern (DAMP) molecules, and complement, which activate chondrocytes through cell-surface receptors. Chondrocytes produce matrix

molecules (collagen type 2, aggrecan) and the enzymes responsible for the degradation of the matrix (e.g., ADAMTS-5 and matrix metalloproteinases [MMPs]). Bone

invasion occurs through the calcified cartilage, triggered by vascular endothelial growth factor (VEGF) and other molecules. IL, interleukin; TGF, transforming growth factor;

TNF, tumor necrosis factor. (Reproduced with permission from RF Loeser et al: Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum 64:1697, 2012.)

Osteoarthritis

2857CHAPTER 371

tendons related to their tension and position. Ligaments stretch with

age, making them less able to absorb impulses. These factors work in

concert to increase the vulnerability of older joints to OA.

Older women are at high risk of OA in all joints, a risk that increases

as women reach their sixth decade. Although hormone loss with menopause may contribute to this risk, there is little understanding of the

unique vulnerability of older women versus men.

■ HERITABILITY AND GENETICS AND THEIR

RELATION TO JOINT VULNERABILITY

OA is a highly heritable disease, but its heritability is joint specific. Fifty percent of the hand and hip OA in the community is

attributable to inheritance, that is, to disease present in other

members of the family. However, the heritable proportion of knee OA

is at most 30%, with some studies suggesting no heritability at all.

Whereas many people with OA have disease in multiple joints, this

“generalized OA” phenotype is rarely inherited and is more often a

consequence of aging.

Emerging evidence has identified genetic mutations that confer

a high risk of OA. The best replicated is a polymorphism within the

growth differentiation factor 5 (GDF5) gene whose effect is to diminish

the quantity of GDF5. GDF5 affects joint shape, which is likely to be the

mechanism by which genes predisposing to OA increase risk of disease.

Minor abnormalities in joint shape can make a joint vulnerable to damage if focal stresses across the joint increase.

■ RISK FACTORS IN THE JOINT ENVIRONMENT

Some risk factors increase vulnerability of the joint through local

effects on the joint environment. With changes in joint anatomy, for

example, load across the joint is no longer distributed evenly across the

joint surface, but rather shows an increase in focal stress. In the hip,

three uncommon developmental abnormalities occurring in utero or

in childhood—congenital dysplasia, Legg-Perthes disease, and slipped

capital femoral epiphysis—leave a child with distortions of hip joint

anatomy that often lead to OA later in life. Girls are predominantly

affected by acetabular dysplasia, a mild form of congenital dislocation,

whereas the other abnormalities more often affect boys. Depending

on the severity of the anatomic abnormalities, hip OA occurs either

in young adulthood (severe abnormalities) or middle age (mild

abnormalities). Femoroacetabular impingement can develop during

adolescence. It is a clinical syndrome in which an outgrowth of bone

at the femur’s head/neck junction thought to develop during closure of

Intrinsic joint

vulnerabilities (local

environment)

Previous damage (e.g.,

meniscectomy)

Bridging muscle weakness

Increasing bone density

Malalignment

Proprioceptive deficiences

Use (loading) factors

acting on joints

Osteoarthritis

or its

progression

Susceptibility

to OA

Obesity

Injurious physical

activities

Systemic factors

affecting joint

vulnerability

Increased age

Female gender

Racial/ethnic factors

Genetic susceptibility

Nutritional factors

FIGURE 371-4 Risk factors for osteoarthritis (OA) either contribute to the

susceptibility of the joint (systemic factors or factors in the local joint environment)

or increase risk by the load they put on the joint. Usually, a combination of loading

and susceptibility factors is required to cause disease or its progression.

Normal Varus Knock knees (valgus)

FIGURE 371-5 The two types of limb malalignment in the frontal plane: varus, in

which the stress is placed across the medial compartment of the knee joint, and

valgus, which places excess stress across the lateral compartment of the knee.

the growth plate results in abnormal contact between the femur and

acetabulum, especially during hip flexion and rotation. This leads to

cartilage and labral damage, to hip pain, and ultimately in later life, to

an increased risk of hip OA.

Major injuries to a joint also can produce anatomic abnormalities

that leave the joint susceptible to OA. For example, a fracture through

the joint surface often causes OA in joints in which the disease is otherwise rare such as the ankle and the wrist. Avascular necrosis can lead

to collapse of dead bone at the articular surface, producing anatomic

irregularities and subsequent OA.

Tears of ligamentous and fibrocartilaginous structures that protect

the joints, such as the meniscus in the knee and the labrum in the hip,

can lead to premature OA. Meniscal tears increase with age and when

chronic are often asymptomatic but lead to adjacent cartilage damage

and accelerated OA. Even injuries in which the affected person never

received a diagnosis may increase risk of OA. For example, in the

Framingham Study subjects, men with a history of major knee injury,

but no surgery, had a 3.5-fold increased risk for subsequent knee OA.

Another source of anatomic abnormality is malalignment across the

joint (Fig. 371-5). This factor has been best studied in the knee. Varus

(bowlegged) knees with OA are at exceedingly high risk of cartilage

loss in the medial or inner compartment of the knee, whereas valgus

(knock-kneed) malalignment predisposes to rapid cartilage loss in the

lateral compartment. Malalignment causes this effect by increasing

stress on a focal area of cartilage, which then breaks down; it also

causes damage to bone underlying the cartilage, producing bone marrow lesions seen on magnetic resonance imaging (MRI). Malalignment

in the knee often produces such a substantial increase in focal stress

within the knee (as evidenced by its destructive effects on subchondral

bone) that severely malaligned knees may be destined to progress

regardless of the status of other risk factors.

Weakness in the quadriceps muscles bridging the knee increases the

risk of the development of painful OA in the knee.

The role of bone in serving as a shock absorber for impact load is

not well understood, but persons with increased bone density are at

high risk of OA. Those with high bone density have an increased risk

of osteophytes at the joint margin.

■ LOADING FACTORS

Obesity Three to six times body weight is transmitted across the

knee during single-leg stance. Any increase in weight may be multiplied

by this factor to reveal the excess force across the knee in overweight

persons during walking. Obesity is a well-recognized and potent risk

factor for the development of knee OA and, less so, for hip OA. Obesity

precedes the development of disease and is not just a consequence of

the inactivity present in those with disease. It is a stronger risk factor

for disease in women than in men, and for women, the relationship of

weight to the risk of disease is linear, so that with each pound increase

in weight, there is a commensurate increase in risk. Weight loss in

women lowers the risk of developing symptomatic disease. Not only is

2858 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

obesity a risk factor for OA in weight-bearing joints, but obese persons

have more worse pain from the disease.

Obesity’s effect on the development and progression of disease is

mediated mostly through the increased loading in weight-bearing

joints that occurs in overweight persons and more severe joint pain in

obese persons.

Repeated Use of Joint and Exercise There are two categories of

repetitive joint use: occupational use and leisure time physical activities. Workers performing repetitive tasks as part of their occupations

for many years are at high risk of developing OA in the joints they

use repeatedly. For example, farmers are at high risk for hip OA, and

miners have high rates of OA in knees and spine. Workers whose jobs

require regular knee bending or lifting or carrying heavy loads have

a high rate of knee OA. One reason why workers may get disease is

that during long days at work, their muscles may gradually become

exhausted, no longer serving as effective joint protectors.

It is widely recommended for people to adopt an exercise-filled

lifestyle, and long-term studies of exercise suggest no consistent association of exercise with OA risk in most persons. However, persons who

already have injured joints may put themselves at greater risk by engaging in certain types of exercise. For example, persons who have already

sustained major knee injuries are at increased risk of progressive knee

OA as a consequence of running. In addition, compared to nonrunners, elite runners (professional runners and those on Olympic teams)

have high risks of both knee and hip OA. Lastly, although recreational

runners are not at increased risk of knee OA, studies suggest that they

have a modest increased risk of disease in the hip.

PATHOLOGY

The pathology of OA provides evidence of the involvement of many

joint structures in disease. Cartilage initially shows surface fibrillation

and irregularity. As disease progresses, focal erosions develop there,

and these eventually extend to the subjacent bone. With further progression, cartilage erosion down to bone expands to involve a larger

proportion of the joint surface, even though OA remains a focal disease

with nonuniform loss of cartilage.

After an injury to cartilage, chondrocytes undergo mitosis and clustering. Although the metabolic activity of these chondrocyte clusters is

high, the net effect of this activity is to promote proteoglycan depletion

in the matrix surrounding the chondrocytes. This is because the catabolic activity is greater than the synthetic activity. As disease develops,

collagen matrix becomes damaged, the negative charges of proteoglycans get exposed, and cartilage swells from ionic attraction to water

molecules. Because in damaged cartilage proteoglycans are no longer

forced into close proximity, cartilage does not bounce back after loading as it did when healthy, and cartilage becomes vulnerable to further

injury. Chondrocytes at the basal level of cartilage undergo apoptosis.

With loss of cartilage comes alteration in subchondral bone. Stimulated by growth factors and cytokines, osteoclasts and osteoblasts in

the bony plate just underneath cartilage become activated. Bone formation produces a thickening of the subchondral plate that occurs even

before cartilage ulcerates. Trauma to bone during joint loading may

be the primary factor driving this bone response, with healing from

injury (including microcracks) inducing remodeling. Small areas of

osteonecrosis usually exist in joints with advanced disease. Bone death

may also be caused by bone trauma with shearing of microvasculature,

leading to a cutoff of vascular supply to some bone areas.

At the margin of the joint, near areas of cartilage loss, osteophytes

form. These start as outgrowths of new cartilage, and with neurovascular invasion from the bone, this cartilage ossifies. Osteophytes are an

important radiographic hallmark of OA.

The synovium produces lubricating fluids that minimize shear stress

during motion. In healthy joints, the synovium consists of a single discontinuous layer filled with fat and containing two types of cells, macrophages and fibroblasts, but in OA, it can sometimes become edematous

and inflamed. There is a migration of macrophages from the periphery

into the tissue, and cells lining the synovium proliferate. Inflammatory

cytokines and alarmins secreted by the synovium activate chondrocytes

to produce enzymes that accelerate destruction of matrix.

Additional pathologic changes occur in the capsule, which stretches,

becomes edematous, and can become fibrotic.

The pathology of OA is not identical across joints. In hand joints

with severe OA, for example, there are often cartilage erosions in the

center of the joint probably produced by bony pressure from the opposite side of the joint.

Basic calcium phosphate and calcium pyrophosphate dihydrate

crystals are present microscopically in most joints with end-stage OA.

Their role in osteoarthritic cartilage is unclear, but their release from

cartilage into the joint space and joint fluid likely triggers synovial

inflammation, which can, in turn, produce release of cytokines and

trigger nociceptive stimulation.

SOURCES OF PAIN

Because healthy cartilage is aneural, cartilage loss alone in a joint is not

accompanied by pain. Thus, pain in OA likely arises from structures

outside the cartilage. Innervated structures in the joint include the

synovium, ligaments, joint capsule, muscles, and subchondral bone.

Most of these are not visualized by x-ray, and the severity of x-ray

changes in OA correlates poorly with pain severity. However, in later

stages of OA, loss of cartilage integrity accompanied by neurovascular

invasion may contribute to pain.

Based on MRI studies in osteoarthritic knees comparing those with

and without pain and on studies mapping tenderness in unanesthetized

joints, likely sources of pain include synovial inflammation, joint effusions, and bone marrow edema. Modest synovitis develops in many but

not all osteoarthritic joints. The presence of synovitis on MRI is correlated with the presence and severity of knee pain, and potentially with

pain sensitization. Capsular stretching from fluid in the joint stimulates

nociceptive fibers there, inducing pain. Increased focal loading as part

of the disease not only damages cartilage but probably also injures the

underlying bone. As a consequence, bone marrow edema appears on

the MRI; histologically, this edema signals the presence of microcracks

and scar, which are the consequences of trauma. These lesions may

stimulate bone nociceptive fibers. Pain may arise from outside the joint

also, including bursae near the joints. Common sources of pain near

the knee are anserine bursitis and iliotibial band syndrome.

Much of the pain experienced in OA occurs when nociceptors in

the joint are stimulated during weight-bearing activities. However, the

pain may eventually become more constant and present at rest, and

this suggests other mechanisms contribute to the pain experience. The

pathologic changes of OA may lead to alterations in nervous system

signaling (Chap. 17). Specifically, peripheral nociceptors can become

more responsive to sensory input, known as peripheral sensitization,

and there can also be an increase in facilitated central ascending nociceptive signaling, known as central sensitization. Individuals with OA

may also have insufficient descending inhibitory modulation. Some

individuals may be genetically predisposed to becoming sensitized;

however, regardless of the etiology, these nervous system alterations are

associated with more severe pain severity, contribute to the presence of

allodynia and hyperalgesia in patients with OA, and may predispose to

development of chronic pain. Obesity increases the severity of joint pain.

This is probably because adipose tissue produces adipokines and other

hormones which act on the nervous system to enhance pain sensitivity.

CLINICAL FEATURES

Joint pain from OA is primarily activity-related in the early stages of

the disease. Pain comes on either during or just after joint use and then

gradually resolves. Examples include knee or hip pain with going up or

down stairs, pain in weight-bearing joints when walking, and, for hand

OA, pain when cooking. Early in disease, pain is episodic, triggered

often by overactive use of a diseased joint, such as a person with knee

OA taking a long run and noticing a few days of pain thereafter. As

disease progresses, the pain becomes continuous and even begins to be

bothersome at night. Stiffness of the affected joint may be prominent,

but morning stiffness is usually brief (<30 min).

In knees, buckling may occur, in part, from weakness of muscles

crossing the joint. Mechanical symptoms, such as buckling, catching,

or locking, could also signify internal derangement, like an anterior

cruciate ligament or meniscal tear; however, these symptoms, which

Osteoarthritis

2859CHAPTER 371

are common in persons with knee OA, need to be further evaluated

only if they develop after an acute knee injury. In the knee, pain with

activities requiring knee flexion, such as stair climbing and arising

from a chair, often emanates from the patellofemoral compartment

of the knee, which does not actively articulate until the knee is bent

~35°.

OA is the most common cause of chronic knee pain in persons aged

>45, but the differential diagnosis is long. Inflammatory arthritis is

likely if there is prolonged morning stiffness and many other joints are

affected. Bursitis occurs commonly around knees and hips. A physical

examination should focus on whether tenderness is over the joint line

(at the junction of the two bones around which the joint is articulating)

or outside of it. Anserine bursitis, medial and distal to the knee, is an

extremely common cause of chronic knee pain that may respond to

a glucocorticoid injection. Prominent nocturnal pain in the absence

of end-stage OA merits a distinct workup. For hip pain, OA can be

detected by loss of internal rotation on passive movement, and pain

isolated to an area lateral to the hip joint usually reflects the presence

of trochanteric bursitis.

No blood tests are routinely indicated for workup of patients with

OA unless symptoms and signs suggest inflammatory arthritis. Examination of the synovial fluid is often more helpful diagnostically than

an x-ray. If the synovial fluid white count is >1000/μL, inflammatory

arthritis or gout or pseudogout is likely, the latter two being also identified by the presence of crystals.

Neither x-rays nor magnetic resonance imaging are indicated in the

workup of OA. They should be ordered only when joint pain and physical findings are not typical of OA or if pain persists after inauguration

of treatment effective for OA. In OA, imaging findings (Fig. 371-6)

correlate poorly with the presence and severity of pain. Further, in both

FIGURE 371-6 X-ray and MRI of knee with medial osteoarthritis. X-ray shows osteophytes at the medial and lateral tibia and femur and joint space narrowing of the medial

tibiofemoral joint. Coronal intermediate-weighted fat-suppressed MRI confirms the presence of medial and lateral osteophytes and the medial tibiofemoral joint space

narrowing. There is diffuse denuded area with no cartilage remaining at the weight-bearing medial tibiofemoral joint (arrows). There is also a severe medial meniscus

extrusion (arrowhead). Bone marrow lesions, which provide evidence of bone injury, are present at medial tibia, medial femur, and intraspinous tibial region. Cartilage focal

defects are also seen at the lateral weight-bearing femur and tibia.

2860 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

knees and hips, radiographs may be normal in early disease as they are

insensitive to cartilage loss and other early findings.

Although MRI may reveal the extent of pathology in an osteoarthritic joint, it is not indicated as part of the diagnostic workup.

Findings such as meniscal tears and cartilage and bone lesions occur

not only in most patients with OA in the knee, but also in most older

persons without joint pain. MRI findings almost never warrant a

change in therapy.

TREATMENT

Osteoarthritis

The goals of the treatment of OA are to alleviate pain and minimize

loss of physical function. To the extent that pain and loss of function

are consequences of inflammation, of weakness across the joint, and

of laxity and instability, the treatment of OA involves addressing

each of these impairments. Comprehensive therapy consists of a

multimodality approach including physical modalities and pharmacologic elements.

Patients with mild and intermittent symptoms may need only

symptomatic management and/or treatments aimed at weight loss,

physical activity, exercise, and self-management strategies. Patients

with ongoing, disabling pain are likely to need both physical modalities and pharmacotherapy.

Treatments for knee OA have been more completely evaluated

than those for hip and hand OA or for disease in other joints. Thus,

although the principles of treatment are identical for OA in all

joints, we shall focus below on the treatment of knee OA, noting

specific recommendations for disease in other joints, especially

when they differ from those for the knee.

PHYSICAL MANAGEMENT MODALITIES

Because OA is a mechanically driven disease, the mainstay of

treatment involves altering loading across the painful joint and

improving the function of joint protectors, so they can better distribute load across the joint. Ways of lessening focal load across the

joint include:

1. Avoiding painful activities as these are usually activities that

overload the joint

2. Improving the strength and conditioning of muscles that bridge

the joint to optimize their function

3. Unloading the joint, either by redistributing load within the joint

with a brace or a splint or by unloading the joint during weight

bearing with a cane or a crutch

The simplest treatment for many patients is to avoid activities

that precipitate pain. For example, for the middle-aged patient

whose long-distance running brings on symptoms of knee OA, a

less demanding form of weight-bearing activity may alleviate all

symptoms. For an older person whose daily walks up and down

hills bring on knee pain, routing these away from hills might eliminate symptoms.

Weight loss is a central strategy, particularly for knee OA. Each

pound of weight loss may have a multiplier effect, unloading both

knees and hips and probably relieving pain in those joints.

In hand joints affected by OA, splinting, by limiting motion,

often minimizes pain for patients with involvement especially in

the base of the thumb. Weight-bearing joints such as knees and hips

can be unloaded by using a cane in the hand opposite the affected

joint for partial weight bearing. A physical therapist can help teach

the patient how to use the cane optimally, including ensuring that

its height is optimal for unloading. Crutches or walkers can serve a

similar beneficial function.

Exercise Osteoarthritic pain in knees or hips during weight bearing results in lack of activity and poor mobility, and because OA is so

common, the inactivity that results increases the risk of cardiovascular disease and obesity. Aerobic capacity is poor in most elders with

symptomatic knee OA, worse than others of the same age.

Weakness in muscles that bridge osteoarthritic joints is multifactorial in etiology. First, there is a decline in strength with

age. Second, with limited mobility comes disuse muscle atrophy.

Third, patients with painful knee or hip OA alter their gait to

lessen loading across the affected joint, and this further diminishes

muscle use. Fourth, “arthrogenous inhibition” may occur, whereby

contraction of muscles bridging the joint is inhibited by a nerve

afferent feedback loop emanating in a swollen and stretched joint

capsule; this prevents attainment of voluntary maximal strength.

Because adequate muscle strength and conditioning are critical to

joint protection, weakness in a muscle that bridges a diseased joint

makes the joint more susceptible to further damage and pain. The

degree of weakness correlates strongly with the severity of joint pain

and the degree of physical limitation. One of the cardinal elements

of the treatment of OA is to improve the functioning of muscles

surrounding the joint.

Trials in knee and hip OA have shown that exercise lessens pain

and improves physical function. Most effective exercise regimens

consist of aerobic and/or resistance training, the latter of which

focuses on strengthening muscles across the joint. Exercises are

likely to be effective especially if they train muscles for the activities

a person performs daily. Activities that increase pain in the joint

should be avoided, and the exercise regimen needs to be individualized to optimize effectiveness. Range-of-motion exercises, which

do not strengthen muscles, and isometric exercises that strengthen

muscles, but not through range of motion, are unlikely to be effective by themselves. Low-impact exercises, including water aerobics

and water resistance training, are often better tolerated by patients

than exercises involving impact loading, such as running or treadmill exercises. A patient should be referred to an exercise class or to

a therapist who can create an individualized regimen. In addition

to conventional exercise regimens, tai chi may be effective for knee

OA. However, there is no strong evidence that patients with hand

OA benefit from therapeutic exercise.

Adherence over the long term is the major challenge to an exercise prescription. In trials involving patients with knee OA who

were engaged in exercise treatment, from a third to over half of

patients stopped exercising by 6 months. Less than 50% continued

regular exercise at 1 year. The strongest predictor of a patient’s continued exercise is a previous personal history of successful exercise.

Physicians should reinforce the exercise prescription at each clinic

visit, help the patient recognize barriers to ongoing exercise, and

identify convenient times for exercise to be done routinely. Mobile

health and wearable technologies are increasingly being used to

encourage adherence to exercise. The combination of exercise with

calorie restriction and weight loss is especially effective in lessening

pain.

Correction of Malalignment Malalignment in the frontal plane

(varus-valgus) markedly increases the stress across the joint,

which can lead to progression of disease and to pain and disability

(Fig. 371-5). Correcting varus-valgus malalignment, either surgically

or with bracing, may relieve pain in persons whose knees are

malaligned. However, correcting malalignment is often very challenging. Fitted braces that straighten varus knees by putting valgus

stress across the knee can be effective. Unfortunately, many patients

are unwilling to wear a realigning knee brace; in addition, in

patients with obese legs, braces may slip with usage and lose their

realigning effect. Braces are indicated for willing patients who can

learn to put them on correctly and on whom they do not slip. Shoes

modified with rubber hemispheres on the sole that alter alignment

of the proximal knee have shown efficacy in trials especially if used

over several months.

Pain from the patellofemoral compartment of the knee can be

caused by tilting of the patella or patellar malalignment with the

patella riding laterally in the femoral trochlear groove. Using a

patellar brace to realign the patella, or tape to pull the patella back

into the trochlear sulcus or reduce its tilt, has been shown in controlled trials to lessen patellofemoral pain. However, patients may

Osteoarthritis

2861CHAPTER 371

find it difficult to apply tape, and skin irritation from the tape is

common, and like realigning braces, patellar braces may slip.

Although their effect on malalignment is questionable, neoprene

sleeves pulled up to cover the knee lessen pain and are easy to use

and popular among patients. The explanation for their therapeutic

effect on pain is unclear.

In patients with knee OA, acupuncture produces modest pain

relief compared to placebo needles and may be an adjunctive treatment, though placebo effect is likely high. In patients with refractory joint pain from OA, radiofrequency ablation of the nerves

innervating the joint has been shown to provide prolonged pain

relief, although long-term safety is unknown.

PHARMACOTHERAPY

Although approaches involving physical modalities constitute its

mainstay, pharmacotherapy serves an important adjunctive role

in OA treatment for symptom management. Available drugs are

administered using oral, topical, and intraarticular routes. To date,

there are no available drugs that alter the disease process itself.

Acetaminophen, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs),

and Cyclooxygenase-2 (COX-2) Inhibitors NSAIDs are the most

popular drugs to treat osteoarthritic pain. They can be administered either topically or orally. In clinical trials, oral NSAIDs

produce ~30% greater improvement in pain than high-dose acetaminophen. Occasional patients treated with NSAIDs experience

dramatic pain relief, whereas others experience little improvement.

Initially, NSAIDs should be administered topically or taken orally

on an “as-needed” basis because side effects are less frequent with

low intermittent doses. If occasional medication use is insufficiently effective, then daily treatment may be indicated, with an

anti-inflammatory dose selected (Table 371-1). Patients should be

reminded to take low-dose aspirin and ibuprofen or naproxen at

different times to eliminate a drug interaction.

NSAIDs taken orally have substantial and frequent side effects,

the most common of which is upper gastrointestinal (GI) toxicity,

including dyspepsia, nausea, bloating, GI bleeding, and ulcer disease. Thirty to forty percent of patients experience upper GI side

effects so severe as to require discontinuation of medication. To

minimize the risk of nonsteroidal-related GI side effects, patients

should take NSAIDs after food; if risk is high, patients should take

a gastroprotective agent, such as a proton pump inhibitor. Certain

oral agents are safer to the stomach than others, including nonacetylated salicylates and nabumetone. Major NSAID-related GI

side effects can occur in patients who do not complain of upper GI

symptoms. In one study of patients hospitalized for GI bleeding,

81% had no premonitory symptoms.

Because of the increased rates of cardiovascular events associated

with conventional NSAIDs such as diclofenac, many of these drugs

are not appropriate long-term treatment choices for older persons

with OA, especially those at high risk of heart disease or stroke. The

American Heart Association has identified COX-2 inhibitors as

putting patients at high risk, although low doses of celecoxib (≤200

mg/d) are not associated with an elevation of risk. The only conventional NSAIDs that appear safe from a cardiovascular perspective

are naproxen and low-dose celecoxib, but they do have GI toxicity.

There are other common side effects of NSAIDs, including the

tendency to develop edema because of prostaglandin inhibition of

afferent blood supply to glomeruli in the kidneys and, for similar

reasons, a predilection toward reversible renal insufficiency. Blood

pressure may increase modestly in some NSAID-treated patients.

Oral NSAIDs should not be used in patients with stage IV or V renal

disease and should be used with caution in those with stage III disease.

NSAIDs can be placed into a gel or topical solution with another

chemical modality that enhances penetration of the skin barrier creating a topical NSAID. When absorbed through the skin, plasma

concentrations are an order of magnitude lower than with the same

amount of drug administered orally or parenterally. However, when

these drugs are administered topically in proximity to a superficial joint

TABLE 371-1 Pharmacologic Treatment for Osteoarthritis

TREATMENT DOSAGE COMMENTS

Oral NSAIDs and

COX-2 inhibitors

Naproxen

Salsalate

Ibuprofen

Celecoxib

375–500 mg

bid

1500 mg bid

600–800 mg

3–4 times a

day

100–200 mg qd

Take with food. Increased risk of myocardial

infarction and stroke for some NSAIDs.

High rates of gastrointestinal side effects,

including ulcers and bleeding, occur.

Patients at high risk for gastrointestinal

side effects should also take either a proton

pump inhibitor or misoprostol.a

 There is an

increase in gastrointestinal side effects or

bleeding when taken with acetylsalicylic

acid. Can also cause edema and renal

insufficiency.

Topical NSAIDs Rub onto joint. Few systemic side effects.

Skin irritation common.

 Diclofenac Na

1% gel

4 g qid (for

knees, hands)

Acetaminophen Up to 1 g tid Of limited efficacy and only conditionally

recommended

Opiates Various Common side effects include dizziness,

sedation, nausea or vomiting, dry mouth,

constipation, urinary retention, and pruritus.

Addiction risk. Less efficacious than oral

NSAIDs

Capsaicin 0.025–0.075%

cream 3–4

times a day

Can irritate mucous membranes.

Intraarticular

injections

Steroids

Hyaluronans Varies from

3 to 5 weekly

injections

depending on

preparation

Mild to moderate pain at injection site.

Controversy exists regarding efficacy.

a

Patients at high risk include those with previous gastrointestinal events, persons

≥60 years, and persons taking glucocorticoids. Trials have shown the efficacy

of proton pump inhibitors and misoprostol in the prevention of ulcers and

bleeding. Misoprostol is associated with a high rate of diarrhea and cramping;

therefore, proton pump inhibitors are more widely used to reduce NSAID-related

gastrointestinal symptoms.

Abbreviations: COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs.

Source: From DT Felson: Osteoarthritis of the Knee. N Engl J Med 354:841, 2006.

Copyright © 2006 Massachusetts Medical Society. Reprinted with permission from

Massachusetts Medical Society.

(knees, hands, but not hips), the drug can be found in joint tissuessuch

as the synovium and cartilage. Trial results have varied but generally

have found that topical NSAIDs are slightly less efficacious than oral

agents, but have far fewer GI and systemic side effects. Unfortunately,

topical NSAIDs often cause local skin irritation where the medication

is applied, inducing redness, burning, or itching (see Table 371-1).

The treatment effect of acetaminophen (paracetamol) in OA is

small and not considered clinically meaningful (Table 371-1). However, for a minority of patients, it is adequate to control symptoms,

in which case more toxic drugs such as NSAIDs can be avoided.

Intraarticular Injections: Glucocorticoids and Hyaluronic

Acid Because synovial inflammation is likely to be a major cause

of pain in patients with OA, local anti-inflammatory treatments

administered intraarticularly may be effective in ameliorating pain,

for up to 3 months. Glucocorticoid injections provide such efficacy,

but response is variable. While some patients having little relief

of pain, most experience pain relief lasting up to several months.

Synovitis, a major cause of joint pain in OA, may abate after an

injection, and this correlates with the reduction in knee pain severity. Glucocorticoid injections are useful to get patients over acute

flares of pain. Repeated injections may cause minor amounts of

cartilage loss with probably unimportant clinical consequences.

Hyaluronic acid injections can be given for treatment of symptoms in knee and hip OA, but most evidence suggests no efficacy

versus placebo (Table 371-1).

2862 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

The use of polarizing light microscopy during synovial fluid analysis

in 1961 by McCarty and Hollander and the subsequent application of

other crystallographic techniques, such as electron microscopy, energydispersive elemental analysis, and x-ray diffraction, have allowed

investigators to identify the pathogenic roles of different microcrystals,

including monosodium urate (MSU), calcium pyrophosphate (CPP),

calcium apatite (apatite), and calcium oxalate (CaOx), in inducing

acute or chronic arthritis or periarthritis (Table 372-1). The clinical

manifestations that result from these crystals have substantial similarities but also have notable differences. Given their therapeutic

implications, the need to perform synovial fluid analysis to distinguish

the type of crystal involved should be emphasized. Polarized light

microscopy alone can identify most typical crystals, except for apatite.

Aspiration and analysis of effusions are also important to assess the

possibility of infection. Crystal shedding from inert deposits triggered

by certain factors is considered a key process behind episodic manifestation of acute inflammation (gout or pseudogout) involving activation

of inflammasome and potent proinflammatory cytokines such as

interleukin (IL) 1β. Furthermore, physical, inflammatory, and catalytic

effects (involving metalloproteinase, collagenase, or prostaglandin E2

)

of crystal deposits on the cartilage and other joint structures can lead

to chronic erosive or destructive changes in the articular structures.

GOUT

■ PATHOGENESIS

Gout is a hyperuricemic metabolic condition, typically manifested by

episodic inflammatory arthritis with disabling pain, among middle-aged

to elderly men and postmenopausal women. It stems from an increased

372 Gout and Other

Crystal-Associated

Arthropathies

Hyon K. Choi

TABLE 372-1 Musculoskeletal Manifestations of

Crystal-Induced Arthritis

Acute arthritis (episodic)

Mono-, oligo-, or polyarthritis

Periarticular inflammation

Bursitis

Tendinitis

Enthesitis

Tophaceous deposits

Chronic arthropathy

Destructive arthropathies

Chronic inflammatory arthritis

Peculiar type of osteoarthritis

Spinal arthritis

Carpal tunnel syndrome

Other Classes of Drugs and Nutraceuticals Opioids have only

modest short-term efficacy in treating pain in hip or knee OA

with unclear benefit over the long-term and, given concerns about

opioid dependency, should be avoided. If NSAIDs are ineffective,

one option is the use of duloxetine, which has modest efficacy in

OA and may be efficacious especially when knee pain is part of a

syndrome of widespread pain.

Recent guidelines recommend against the use of glucosamine or

chondroitin for OA. Large publicly supported trials have failed to

show that, compared with placebo, these compounds relieve pain

in persons with disease.

Optimal pharmacologic therapy for OA is often achieved by

trial and error, with each patient having idiosyncratic responses

to specific treatments. Placebo (or contextual) effects may account

for 50% of more of treatment effects in OA, and certain modes of

treatment delivery including intraarticular injections have greater

contextual effects than others such as pills. When medical therapies

have failed and the patient has an unacceptable reduction in their

quality of life and ongoing pain and disability, then at least for knee

and hip OA, total joint arthroplasty is indicated.

SURGERY

Based on data from randomized trials, the efficacy of arthroscopic

debridement and lavage in persons with OA is no greater than that

of sham surgery for relief of pain or disability. Further, if a meniscal

tear is present, as is often the case in persons with knee OA, trials

have shown that arthroscopic meniscectomies do not relieve knee

pain or improve function long-term nor do they reduce catching or

locking symptoms.

On the other hand, for patients with knee OA isolated to the

medial compartment, operations to realign the knee to lessen

medial loading can relieve pain. These include a high tibial osteotomy, in which the tibia is broken just below the tibial plateau

and realigned to load the lateral, nondiseased compartment, or a

unicompartmental replacement with realignment. Each surgery

may provide the patient with years of pain relief before a total knee

replacement is required.

Ultimately, when the patient with knee or hip OA has failed

nonsurgical treatments with limitations of pain or function that

compromise their quality of life, patients with reasonable expectations and readiness for surgery should be referred for total knee

or hip arthroplasty. These are highly efficacious operations that

relieve pain and improve function in the vast majority of patients,

although pain elimination occurs in almost all patients getting a hip

replacement but only ~80% of those undergoing knee replacement.

Currently, failure rates from loosening or infection for both are ~1%

per year, with higher rates in obese patients. The chance of surgical

success is greater in centers where at least 25 such operations are

performed yearly or with surgeons who perform multiple operations annually. The timing of knee or hip replacement is critical.

If the patient suffers for many years until their functional status

has declined substantially, with considerable muscle weakness,

postoperative functional status may not improve to a level achieved

by others who underwent operation earlier in their disease course.

Cartilage Regeneration Chondrocyte transplantation has not

been found to be efficacious in OA, perhaps because OA includes

pathology of joint mechanics, which is not corrected by chondrocyte transplants. Similarly, abrasion arthroplasty (chondroplasty)

has not been well studied for efficacy in OA, but it produces

fibrocartilage in place of damaged hyaline cartilage. Both surgical

attempts to regenerate and reconstitute articular cartilage are more

likely to be efficacious early in disease when joint malalignment and

many of the other noncartilage abnormalities that characterize OA

have not yet developed.

■ FURTHER READING

Felson D: Safety of nonsteroidal antiinflammatory drugs. N Engl J

Med 375:2595, 2016.

Glyn-Jones S et al: Osteoarthritis. Lancet 386:376, 2015.

Kolasinski SL et al: 2019AmericanCollege of Rheumatology/Arthritis

Foundation Guideline for the management of osteoarthritis of the

hand, hip, and knee. Arthritis Rheumatol 72:220, 2020.

Mc Alindon TE et al: Effect of intra-articular triamcinolone vs saline

on knee cartilage volume and pain in patients with knee osteoarthritis: A randomized clinical trial. JAMA 317:1967, 2017.

Gout and Other Crystal-Associated Arthropathies

2863CHAPTER 372

of cellulitis (pseudocellulitis). Typical flares tend to subside spontaneously within 1–2 weeks, and most patients have intervals of varying

length with no residual symptoms until the next episode (intercritical

gout). Triggers of gout flares include purine-rich food, alcohol, diuretic

use, initial introduction of urate-lowering therapy, local trauma, and

medical illnesses such as congestive heart failure and respiratory

hypoxic conditions (Fig. 372-1).

Usually after years of gout flares without treatment, chronic gouty

arthritis can develop, often associated with ongoing synovitis, subcutaneous tophi, deformity, and bony destruction. Less commonly,

chronic gouty arthritis will be the only manifestation, and more rarely,

gout can manifest only as tophi. Women represent only 5–20% of all

patients with gout. Most women with gout are postmenopausal and

elderly; tend to have osteoarthritis, hypertension, or mild renal insufficiency; and usually are receiving diuretics. Premenopausal gout is

rare, although kindreds of precocious gout in young women caused

by decreased renal urate clearance and renal insufficiency have been

described.

■ DIAGNOSIS

Laboratory Diagnosis Even if characteristic clinical features

strongly suggest gout, the presumptive diagnosis ideally should be

confirmed by needle aspiration of involved joints or tophaceous

deposits. Acute septic arthritis, other crystal-associated arthropathies,

palindromic rheumatism, and psoriatic arthritis can mimic clinical

presentations of gout. During acute gout flares, needle-shaped MSU

crystals typically are present both intracellularly and extracellularly

(Fig. 372-2). Under compensated polarized light, these crystals show

bright, negative birefringence. Synovial fluid appears cloudy due to the

increased numbers of leukocytes (e.g., from 5000–75,000/μL). Large

amounts of crystals occasionally produce a thick, pasty, chalky joint

fluid or drainage from distended tophus. Because bacterial infection

body pool of urate due to chronic hyperuricemia, leading to supersaturation and crystal formation and deposition of MSU within the

joints and connective tissue (Fig. 372-1). If left untreated, gout can

progress to chronic gouty arthritis, frequently with low-grade persistent synovitis and erosive deformities due to growing deposition

of MSU crystals. Humans are the only mammals known to develop

gout spontaneously as they often develop hyperuricemia with their

evolutionary species-wide loss of uricase, which converts urate into

the highly water-soluble compound allantoin. Although chronic hyperuricemia is a prerequisite for the development of gout, other factors

influence MSU deposition and pathogenic reactions to the crystals

(Fig. 372-1); a minority of hyperuricemic individuals develop gout during their lifetime. At physiologic pH, uric acid exists largely as urate,

the ionized form, given its weak acidic property (pKa, 5.8). Considered

as a part of the insulin resistance syndrome, hyperuricemia and gout

are associated with multiple cardiovascular-metabolic comorbidities,

including obesity, hypertension, type 2 diabetes, myocardial infarction,

stroke, and urate nephrolithiasis (Chap. 417); modifiable risk factors

include obesity, Western diet, alcohol, sedentary lifestyle, and diuretics

(Fig. 372-1).

■ CLINICAL MANIFESTATIONS

Early clinical manifestation of gout is characterized by acute recurrent

gout flares. Usually, only one joint is affected initially, although oligoand polyarticular gout flares can develop over time. The metatarsophalangeal joint of the first toe is involved in 70–90% of cases (podagra),

followed by tarsal joints, ankles, and knees. Finger, wrist, and elbow

joints can also be involved, although more often in elderly patients

or in advanced disease. The gout flares often begin at night to early

morning, constituting one of the most painful conditions experienced

by humans. The affected joints rapidly become warm, red, tender, and

substantially swollen with a clinical appearance that often mimics that

Risk factors

• Obesity and insulin resistance syndrome

• Metabolic factors (diet, alcohol)

• Genes

• Medications (diuretics, low-dose aspirin)

• Cardiovascular-renal conditions

Normal urate level

Chronic hyperuricemia

Increased urate pool

MSU crystallization,

crystal growth,

tissue deposition

Recurrent gout flares

Acute crystal-induced inflammation

Chronic gouty arthritis

Crystal burden sequalae

Anti-inflammatory therapy

(NSAlDs, colchicine, glucocorticoids)

Urate-lowering

therapy with SU

target <5–6 mg/dL

(allopurinol, febuxostat,

probenecid, uricase)

Dissolution

SU >~6.85 mg/dL

Pathophysiologic factors

• Urate levels >6.85 mg/dL

• Temperature

• pH

• Intra-articular dehydration

• Cation concentration

• Collagen, chondrotin sulfate

• Nonaggregating proteoglycans

Triggers

• Metabolic triggers (purine-rich food, alcohol)

• Diuresis

• Rapid changes in urate levels (ULT initiation)

• Local trauma

• Medical illness (e.g., heart failure, hypoxia)

FIGURE 372-1 Pathogenesis of gout and therapeutic targets. Metabolic and some genetic factors contribute to the development of chronic hyperuricemia. Gout stems from

an increased body pool of urate due to chronic hyperuricemia, leading to supersaturation and crystal formation and deposition of monosodium urate (MSU; tophi) within the

joints and connective tissue. Synovial tophi are usually walled off, but certain triggers may loosen them from the organic matrix, leading to crystal shedding and interaction

with synovial cell lining and residential inflammatory cells, initiating an acute gout flare. In some individuals, growing MSU crystal deposition leads to chronic gouty arthritis

with subcutaneous tophi. Anti-inflammatory therapy targets the downstream process of crystal-induced inflammation, whereas ultimate control of gout requires correction

of the underlying central cause, chronic hyperuricemia with increased urate pool. NSAIDs, nonsteroidal anti-inflammatory drugs; SU, sodium urate; ULT, urate-lowering

therapy.

2864 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

FIGURE 372-2 A. Extracellular and intracellular monosodium urate crystals, as

seen in a fresh preparation of synovial fluid, illustrate needle- and rod-shaped

crystals (400×). These crystals are strongly negative birefringent crystals under

compensated polarized light microscopy. (Inset 400×, provided by Eliseo Pascual.)

B. Intracellular and extracellular calcium pyrophosphate (CPP) crystals, as seen in a

fresh preparation of synovial fluid, illustrate rectangular, rod-shaped, and rhomboid

crystals (400×). These crystals are weakly positively or nonbirefringent crystals

under compensated polarized light microscopy (inset 600×). (Images provided by

Eliseo Pascual.)

A

B

can coexist with MSU crystals in synovial fluid, joint fluid is often

stained and cultured for potential septic arthritis. MSU crystals also

can often be demonstrated in the first metatarsophalangeal joint and

in knees not acutely involved with gout, making arthrocentesis of these

joints useful for the diagnosis of gout between flares.

While chronic hyperuricemia is a prerequisite in the pathogenesis of

gout, serum urate levels can be normal or low at the time of an acute

flare, as inflammatory cytokines’ uricosuric property (e.g., IL-6) can

lower the level by ~2 mg/dL. This tends to limit the value of serum

urate testing in the setting of an acute flare. Nevertheless, serum urate

levels are almost always elevated at some time in a gout patient’s lifetime, and thus, it is important to seek historical or postflare serum

urate values as a diagnostic clue or therapeutic target to urate-lowering

therapy. Serum creatinine, liver function tests, hemoglobin, white

blood cell (WBC) count, hemoglobin A1c, and serum lipids are usually

obtained at baseline to assess possible risk factor and comorbidities

requiring treatment or monitored for potential adverse effects of gout

treatments.

Radiographic Features In plain radiography, cystic changes,

well-defined erosions with sclerotic margins (often with overhanging bony edges), and soft tissue masses are characteristic features of

advanced gout with tophaceous deposits, although these findings are

typically absent in earlier stages of gout. Musculoskeletal ultrasound

can timely aid earlier diagnosis by revealing a double-contour sign

overlying the articular cartilage (signifying MSU deposition). Similarly,

dual-energy computed tomography (CT) that utilizes two different

energy beams and identifies MSU based on its chemical composition

can indicate specific presence of MSU crystals.

TREATMENT

Acute Gout Care

Although nonpharmacologic measures, such as ice pack application

and rest of the involved joints, can be helpful, the mainstay of acute

gout care is the administration of anti-inflammatory drugs such as

nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and

glucocorticoids (Fig. 372-1). The choice of these options largely

depends on the patients’ comorbidities, concurrent medications,

and previous response if recurrent flares. Early initiation of antiinflammatories helps abort or reduce the severity of flares. Thus,

for recurrent flares in established gout patients, patients can be

provided a supply of their medications ready to start at the first sign

of a flare. NSAIDs are used most often in individuals without complicating comorbidities; NSAIDs given in full anti-inflammatory

doses are effective in the vast majority of patients (e.g., indomethacin, 25–50 mg tid; naproxen, 500 mg bid; ibuprofen, 800 mg tid;

and celecoxib, 800 mg followed by 400 mg 12 h later, then 400 mg

bid). Oral colchicine is also effective, particularly if used early in a

gout flare. A low-dose regimen (1.2 mg with the first sign of a flare,

followed by 0.6 mg in 1 h and subsequent-day dosing depending on

response) is as effective as, and better tolerated than, the formerly

used higher-dose regimens. Colchicine is eliminated from the body

through P-glycoprotein (also known as MDR1) in the liver, small

intestine, and kidneys as well as via enteric and hepatic cytochrome

P450 3E4 (CYP3A4). As such, the dose, particularly for prolonged

use, is reduced among patients with renal disease or when used

with P-glycoprotein or CYP3A4 inhibitors such as clarithromycin

or tacrolimus; additional caution is warranted among patients with

hepatorenal impairment.

Glucocorticoids given as an intramuscular injection or orally

(e.g., prednisone, 30–50 mg/d as the initial dose and gradually

tapered with the resolution of the attack) can be effective even

in polyarticular gout. For a single joint or a few involved joints,

intraarticular glucocorticoid injection is effective and well tolerated.

With the central role of the inflammasome and IL-1β in gout flares,

anakinra is a useful option when other treatments are contraindicated or have failed.

URATE-LOWERING THERAPY

Ultimate control of gout requires correction of the underlying chronic

hyperuricemia, the central cause for gout. Attempts to normalize

serum urate to a subsaturation point (typically, <300–360 μmol/L

[5.0–6.0 mg/dL]) to prevent recurrent gout flares and eliminate

tophi are critical and entail a commitment to urate-lowering regimens that are required usually for life (Fig. 372-1). Urate-lowering

drug therapy should be considered when, as in most patients, the

hyperuricemia cannot be corrected by risk factor interventions

(control of body weight, healthy diet, limitation of alcohol use,

decreased consumption of fructose-rich foods and beverages, and

avoidance of thiazide and loop diuretics). The decision to initiate

urate-lowering drug therapy usually is made considering the number of gout flares (urate lowering may be cost-effective with more

than two attacks yearly), severity and duration of flares, quality

of life, or the patient’s willingness to commit to lifelong therapy.

Urate-lowering therapy should be initiated in any patient who

already has subcutaneous tophi or chronic gouty arthritis or known

uric acid stones.

Gout and Other Crystal-Associated Arthropathies

2865CHAPTER 372

Allopurinol, a xanthine oxidase inhibitor, is the first-line

urate-lowering drug among gout patients. Allopurinol can be given

in a single morning dose, starting at 100 mg daily or less and

titrating up (to 800 mg daily) to achieve a target serum urate level

<5–6 mg/dL (i.e., a subsaturation point of MSU crystals). In patients

with chronic kidney disease (CKD), the starting allopurinol dose

should be lowered depending on the CKD levels; for example, with

an estimated glomerular filtration rate of 30–45 mL/min, one would

start at 50 mg daily and titrate up slowly. Starting at a low dose and

titrating up reduces the risk of severe cutaneous adverse reactions

(SCARs), including Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as the risk of gout flares associated with

rapid serum urate reduction due to introduction of urate-lowering

therapy (Fig. 372-1). Allopurinol is generally well tolerated, but

mild cutaneous reactions can develop in ~2% of users. SCARs to

allopurinol are rare but can be life-threatening, and thus, appropriate precaution is advised. Presence of CKD, higher allopurinol initial dosing (e.g., >100 mg daily in CKD patients), and HLA-B*

5801

carriage are important risk factors; older age and female sex are also

associated with a higher risk of SCARs. As the HLA-B*

5801 carriage

rate is substantially higher among Southeast Asians (except for

Japanese descendants), Pacific Islanders/Native Hawaiians, and

blacks than whites or Hispanics (leading to racial disparity in the

risk of SCARs), screening for HLA-B*

5801 should be performed

before starting allopurinol in those Asians and blacks. If patients

carry the HLA-B*

5801 allele, an alternative urate-lowering agent

should be administered. Febuxostat is a newer xanthine oxidase

inhibitor that is predominantly metabolized by glucuronide formation and oxidation in the liver and considered to not require dose

adjustment in moderate to severe chronic kidney disease. It has also

been used in patients who carry the HLA-B*

5801 allele.

Uricosuric agents such as probenecid are considered second-line

urate-lowering therapies for gout and can be used in patients with

good renal function either alone or in combination with xanthine

oxidase inhibitors such as allopurinol. Probenecid can be started

at a dose of 250 mg twice daily and increased gradually as needed

up to 3 g/d to achieve and maintain a target serum urate level.

Probenecid is generally not effective in patients with serum creatinine levels >177 μmol/L (2 mg/dL). Benzbromarone (not available in

the United States) is another uricosuric drug that is more effective

in patients with CKD. In contrast to thiazide and loop diuretics,

which increase serum urate levels and trigger gout attacks, other

drugs used to treat common comorbidities of gout can also help

lower serum urate levels, including losartan, amlodipine, fenofibrate, and sodium-glucose cotransporter-2 inhibitors. Pegloticase is

a pegylated uricase that is available for patients who do not tolerate

or fail full doses of other treatments.

Urate-lowering drugs are generally not initiated during active

ongoing gout flares, given the potential worsening of the flare by

acutely lowering serum urate levels. However, urate-lowering therapy can be started during the resolution phase of or after a gout

flare, together with anti-inflammatory prophylaxis (e.g., colchicine

0.6 mg one to two times daily or naproxen 250 mg twice daily) to

reduce the risk of the flares that often occur with the initiation of

urate-lowering therapy. These paradoxical flares are presumed to

be inflammatory reactions to MSU crystals shed from dissolution

of organized MSU deposits (synovial tophi) induced by rapid

serum urate reduction (Fig. 372-1). As such, faster urate reduction

has been associated with higher risk of flares in clinical trials of

urate-lowering drugs. Continuing concomitant anti-inflammatory

prophylaxis is usually recommended until the patient is normouricemic and without gouty attacks for 3–6 months or tophi disappear.

CALCIUM PYROPHOSPHATE

DEPOSITION DISEASE

CPP deposition (CPPD) predominately affects the elderly, with a

doubling prevalence of CPPD in articular tissues with each decade

>60 years of age (e.g., prevalence of nearly 50% for those >85 years old).

In most cases, this process is asymptomatic with uncertain underlying

etiology, although it is likely that biochemical changes in aging or

diseased cartilage favor CPP crystal nucleation. Increased levels of

inorganic pyrophosphate in cartilage matrix are thought to be a central pathogenic process in patients with CPPD arthritis, analogous to

hyperuricemia in gout. This pyrophosphate can combine with calcium

to form CPP crystals in cartilage matrix vesicles or on collagen fibers.

Most inorganic pyrophosphate in cartilage matrix originates from

breakdown of extracellular ATP. The ATP efflux (and thus the levels of

inorganic pyrophosphate) is tightly regulated by a multipass membrane

protein, ANKH. As such, mutations in the ANKH gene, as described

in both familial and sporadic cases, have been found to increase elaboration and extracellular transport of pyrophosphate. The increase in

pyrophosphate production is also related to enhanced activity of ATP

pyrophosphohydrolase and 5′-nucleotidase, which catalyze the reaction of ATP to adenosine and pyrophosphate. Decreased levels of cartilage glycosaminoglycans and increased activities of transglutaminase

enzymes may contribute to the deposition of CPP crystals.

Similar to MSU crystals, release of CPP crystals into the joint

space is followed by the phagocytosis of those crystals by monocytemacrophages and neutrophils, which respond by releasing chemotactic

and inflammatory substances and activating the inflammasome.

A minority of patients with CPPD arthropathy have metabolic

abnormalities or hereditary CPPD (Table 372-2). As such, the presence of CPPD arthritis in individuals aged <50 years should lead to

consideration of these metabolic disorders and inherited forms of disease, including those identified in a variety of ethnic groups. Included

among endocrine-metabolic conditions are hyperparathyroidism,

hemochromatosis, hypophosphatasia, and hypomagnesemia. These

associations suggest that a variety of different metabolic products may

enhance CPP crystal deposition either by directly altering cartilage or

by inhibiting inorganic pyrophosphatases. Investigation of younger

patients with CPPD should include inquiry for evidence of familial

aggregation and evaluation of serum calcium, phosphorus, alkaline

phosphatase, magnesium, iron, and transferrin.

■ CLINICAL MANIFESTATIONS

Acute CPP crystal arthritis, originally termed pseudogout by McCarty

and co-workers, often mimics acute gout flares with similar articular

findings of substantial inflammation. There are several clinical clues

that suggest CPP crystal arthritis. The knee is the joint most commonly

affected, followed by the wrist, while the first metatarsophalangeal joint

(podagra) is rarely affected. Other affected joints include the shoulder,

ankle, elbow, and hands. Also, initial episodes of acute attacks tend to

last longer than typical gout flares, even up to weeks to months. Acute

attacks present sometimes with systemic signs such as fever, chills,

and elevated acute-phase reactants. Acute CPP crystal arthritis may

be precipitated by trauma, severe medical illness, or surgery, especially

TABLE 372-2 Factors and Conditions Associated with Calcium

Pyrophosphate Crystal Deposition Disease

Aging

Osteoarthritis

Postmeniscectomy or joint trauma

Familial-genetic

Endocrine-metabolic conditions

Primary hyperparathyroidism

Hemochromatosis

Hypophosphatasia

Hypomagnesemia

 Certain drugs: thiazide and loop diuretics, potentially proton pump inhibitors

 Malabsorption

 Gitelman’s syndrome

Gout

X-linked hypophosphatemic rickets

Familial hypocalciuric hypercalcemia