2866 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

parathyroidectomy, as it leads to rapid diminution of serum calcium

and magnesium levels, causing dissolution and shedding of crystal.

Chronic CPP crystal arthritis has several patterns; the most common form is a polyarticular arthritis resembling osteoarthritis (pseudoosteoarthritis). The clinical picture mimics that of progressive

osteoarthritis, characterized by unusually severe joint damage in

atypical joints for osteoarthritis, such as metacarpophalangeal, wrist,

elbow, shoulder, or ankle joints. Other less common forms include

chronic symmetric synovitis that is clinically similar to rheumatoid

arthritis, severe destructive disease that may radiographically mimic

neuropathic arthritis, intervertebral disk and ligament calcification

with restriction of spine mobility, the crowned dens syndrome, spinal

stenosis (most commonly seen in the elderly), and rarely, tumoral

deposits of CPP crystals in soft tissues.

If radiographs or ultrasound reveal punctate and/or linear radiodense deposits within fibrocartilaginous joint menisci or articular

hyaline cartilage (chondrocalcinosis), the diagnostic likelihood of CPPD

disease is further increased. Definitive diagnosis requires demonstration of typical rhomboid or rodlike crystals (generally weakly positively

birefringent or nonbirefringent with polarized light) in synovial fluid

or articular tissue (Fig. 372-2). In the absence of joint effusion or indications to obtain a synovial biopsy, chondrocalcinosis is presumptive

of CPPD. One exception is chondrocalcinosis due to CaOx in some

patients with chronic renal failure.

In as many as 50% of cases, episodes of CPP crystal-induced inflammation are associated with low-grade fever and, on occasion, temperatures as high as 40°C (104°F). In such cases, synovial fluid analysis with

microbial cultures is essential to rule out the possibility of infection.

In fact, infection in a joint with any microcrystalline deposition process can lead to crystal shedding and subsequent synovitis from both

crystals and microorganisms. The leukocyte count in synovial fluid in

acute CPPD can range from several thousand cells to 100,000 cells/μL,

with the mean being ~24,000 cells/μL and the predominant cell being

the neutrophil. CPP crystals may be seen inside tissue fragments and

fibrin clots and in neutrophils (Fig. 372-2). CPP crystals may coexist

with MSU and apatite in some cases.

TREATMENT

CPPD Disease

Anti-inflammatory treatment for acute CPP crystal arthritis is

largely adapted from that for gout flares, including ice pack applications with rest, joint fluid aspiration and glucocorticoid injection, oral colchicine, NSAIDs, and systemic glucocorticoids. Severe

polyarticular attacks can also be treated with the IL-1β antagonist

anakinra. For patients with frequent recurrent attacks, prophylactic

treatment with daily colchicine can be helpful. For chronic CPP

crystal arthritis, there is no effective way to remove CPP crystal deposits from cartilage and synovium (unlike urate-lowering

agents in gout). Limited studies suggest that NSAIDs (with a gastric

protective agent if required), colchicine, low-dose glucocorticoids,

hydroxychloroquine, or methotrexate may be helpful for chronic

synovitis. Patients with progressive destructive large-joint arthropathy may require joint replacement.

CALCIUM APATITE DEPOSITION DISEASE

■ PATHOGENESIS

Apatite is the primary mineral of normal bone and teeth. Abnormal accumulation of basic calcium phosphates, largely carbonate

substituted apatite, can occur in areas of tissue damage (dystrophic

calcification), hypercalcemic or hyperparathyroid states (metastatic

calcification), connective tissue diseases (calcinosis), and other conditions (Table 372-3). In chronic renal failure, hyperphosphatemia can

contribute to extensive apatite deposition both in and around joints

(tumoral calcinosis, calciphylaxis). Familial aggregation is rarely seen.

Synovial lining cell or fibroblast cultures exposed to apatite (or CPP)

crystals can undergo mitosis and markedly increase the release of

prostaglandin E2

, various cytokines, and collagenases and neutral proteases, underscoring the destructive potential of abnormally stimulated

synovial lining cells.

Although the true incidence of apatite arthritis is not known,

30–50% of patients with osteoarthritis have apatite microcrystals in

their synovial fluid. Such crystals frequently can be identified in clinically stable osteoarthritic joints, but they are more likely to come to

attention in persons experiencing acute or subacute worsening of joint

pain and swelling.

■ CLINICAL MANIFESTATIONS

Periarticular or articular deposits can present with acute reversible

inflammation and/or chronic damage to the joint capsule, tendons,

bursa, or articular surfaces (Table 372-3). The most common sites of

apatite deposition include bursae and tendons in and/or around the

knees, shoulders, hips, and fingers. These deposits can also be asymptomatic radiographic abnormalities.

Apatite aggregates are often present in synovial fluid in an extremely

destructive chronic arthropathy of the elderly that occurs most often in

the shoulders (Milwaukee shoulder) and in a similar process in hips,

knees, and erosive osteoarthritis of fingers (Table 372-3). Joint destruction is associated with damage to cartilage and supporting structures,

leading to instability and deformity. Progression tends to be indolent.

Symptoms range from minimal to severe pain and disability that may

lead to joint replacement surgery.

■ DIAGNOSIS

Intra- and/or periarticular calcifications with or without erosive, destructive, or hypertrophic changes may be seen on radiographs (Fig. 372-3).

They should be distinguished from the linear calcificationstypical ofCPPD.

The synovial fluid leukocyte count in apatite arthritis is usually low

(<2000/μL) despite dramatic symptoms, with predominance of mononuclear cells. Definitive diagnosis of apatite arthropathy, also called

basic calcium phosphate disease, depends on identification of crystals

from synovial fluid or tissue (Fig. 372-3). Individual crystals are very

small and can be seen only by electron microscopy. Clumps of crystals

may appear as 1- to 20-μm shiny intra- or extracellular nonbirefringent

globules or aggregates that stain purplish with Wright’s stain and bright

red with alizarin red S. Absolute identification depends on electron

microscopy with energy-dispersive elemental analysis, x-ray diffraction, infrared spectroscopy, or Raman microspectroscopy, but these

techniques usually are not required in clinical diagnosis.

TABLE 372-3 Clinical Manifestations of Apatite Crystal Deposition

Periarticular

Calcific periarthritis (e.g., supraspinatus tendon apatite deposit rupture)

Bursitis and tendinitis

Hydroxyapatite pseudopodagra

Polyarticular involvement

Asymptomatic deposition

Articular

Hemorrhagic shoulder effusions in the elderly (Milwaukee shoulder)

Chronic destructive arthropathy

Chronic erosive monoarthritis (resembling erosive osteoarthritis)

Acute synovitis

Association with osteoarthritis

Secondary apatite crystal deposition

Tumoral calcinosis

Hyperparathyroidism

Calciphylaxis (renal failure/long-term dialysis)

Connective tissue diseases (e.g., systemic sclerosis, dermatomyositis)

 Heterotopic calcification after neurologic catastrophes (e.g., stroke, spinal

cord injury)

Fibrodysplasia ossificans progressiva

Gout and Other Crystal-Associated Arthropathies

2867CHAPTER 372

TREATMENT

Calcium Apatite Deposition Disease

Treatment of apatite arthritis or periarthritis is nonspecific. Acute

attacks of bursitis or synovitis may be self-limiting, resolving in

days to several weeks. Aspiration of effusions and the use of either

NSAIDs or oral colchicine for 2 weeks or intra- or periarticular

injection of a depot glucocorticoid appear to shorten the duration

and intensity of symptoms. Periarticular apatite deposits may be

resorbed with resolution of attacks. Agents to lower serum phosphate levels may lead to resorption of deposits in renal failure

patients receiving hemodialysis. In patients with underlying severe

destructive articular changes, response to medical therapy is usually

less rewarding.

FIGURE 372-3 A. Radiograph showing calcification due to apatite crystals

surrounding an eroded joint. B. An electron micrograph demonstrates dark needleshaped apatite crystals within a vacuole of a synovial fluid mononuclear cell

(30,000×).

CaOx DEPOSITION DISEASE

■ PATHOGENESIS

In chronic renal disease, CaOx deposits have long been recognized in

visceral organs, blood vessels, bones, and cartilage and are now known

to be one of the causes of arthritis in chronic renal failure. Thus far,

reported patients have been dependent on long-term hemodialysis

or peritoneal dialysis (Chap. 312), and many had received ascorbic

acid supplements. Ascorbic acid is metabolized to oxalate, which is

inadequately cleared in uremia and by dialysis. Such supplements and

foods high in oxalate content usually are avoided in dialysis programs

because of the risk of enhancing hyperoxalosis and its sequelae.

CaOx aggregates can be found in bone, articular cartilage, synovium,

and periarticular tissues. From these sites, crystals may be shed, causing

acute synovitis. Persistent aggregates of CaOx can, like apatite and CPP

crystals,stimulate synovial cell proliferation and enzyme release,resulting

in progressive articular destruction. Primary oxalosis is a rare hereditary

metabolic disorder (Chap. 420) that can lead to acute or chronic CaOx

arthritis, periarthritis, and bone disease during later years of illness.

■ CLINICAL MANIFESTATIONS AND DIAGNOSIS

Clinical features of acuteCaOx arthritis may not be distinguishable from

those due to MSU, CPP, or apatite. Deposits have been documented in

fingers, wrists, elbows, knees, ankles, and feet. Radiographs may reveal

chondrocalcinosis or soft tissue calcifications. CaOx-induced synovial

effusions are usually noninflammatory, with <2000 leukocytes/μL, or

mildly inflammatory. Neutrophils or mononuclear cells can predominate. CaOx crystals have a variable shape and variable birefringence to

polarized light. The most easily recognized forms are bipyramidal, have

strong birefringence (Fig. 372-4), and stain with alizarin red S.

TREATMENT

Calcium Oxalate Deposition Disease

Treatment of CaOx arthropathy with NSAIDs, colchicine, intraarticular glucocorticoids, and/or an increased frequency of dialysis has produced only slight improvement. In primary oxalosis,

liver transplantation has induced a significant reduction in crystal

deposits (Chap. 420).

Acknowledgment

The chapter is an updated version of the chapter on this subject written by

H. Ralph Schumacher and Lan X. Chen in previous editions of this textbook.

■ FURTHER READING

Choi HK et al: Pathogenesis of gout. Ann Intern Med 143:499, 2005.

Dalbeth N et al: Gout. Nat Rev Dis Primers 5:69, 2019.

Rosenthal AK, Ryan LM: Calcium pyrophosphate deposition disease. N Engl J Med 374:2575, 2016.

A

B

FIGURE 372-4 Bipyramidal and small polymorphic calcium oxalate crystals from

synovial fluid are a classic finding in calcium oxalate arthropathy (ordinary light

microscopy; 400×).

2868 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

■ DEFINITION

Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain and tenderness. Although FM is defined primarily as

a pain syndrome, patients also commonly report associated neuropsychological symptoms of fatigue, unrefreshing sleep, cognitive dysfunction, anxiety, and depression. Patients with FM have an increased

prevalence of other syndromes associated with pain and fatigue,

including myalgic encephalitis/chronic fatigue syndrome (Chap. 450),

temporomandibular disorder, chronic headaches, irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, and other pelvic

pain syndromes. Available evidence implicates the central nervous

system as key to maintaining pain and other core symptoms of FM and

related conditions. The presence of FM is associated with substantial

negative consequences for physical and social functioning.

■ EPIDEMIOLOGY

Worldwide prevalence is ~2%, with a prevalence of ~4% in women and

<1% in men. There is some variability depending on the method of

ascertainment; however, the prevalence data are similar across world

regions and socioeconomic classes. Cultural factors may play a role in

determining whether patients with FM symptoms seek medical attention; however, even in cultures in which secondary gain is not expected

to play a significant role, the prevalence of FM remains in this range. In

clinical settings, a diagnosis of FM is far more common in women than

in men, with a ratio of ~9:1.

■ CLINICAL MANIFESTATIONS

Pain and Tenderness At presentation, patients with FM most

commonly report “pain all over.” These patients have pain that is typically both above and below the waist on both sides of the body and

involves the axial skeleton (neck, back, or chest). The pain attributable

to FM is poorly localized, difficult to ignore, severe in its intensity, and

associated with a reduced functional capacity. For a diagnosis of FM,

373 Fibromyalgia

Leslie J. Crofford

pain should have been present most of the day on most days for at least

3 months.

The pain of FM is associated with tenderness and increased evoked

pain sensitivity. In clinical practice, this elevated sensitivity may be

identified by pain induced by the pressure of a blood pressure cuff

or skin roll tenderness. More formally, an examiner may complete a

tender-point examination in which the examiner uses the thumbnail

to exert pressure of ~4 kg/m2 (or the amount of pressure leading to

blanching of the tip of the thumbnail) on well-defined musculotendinous sites (Fig. 373-1). Previously, the classification criteria of the

American College of Rheumatology required that 11 of 18 sites be

perceived as painful for a diagnosis of FM. In practice, tenderness is

a continuous variable, and strict application of a categorical threshold

for diagnostic specifics is not necessary. Newer criteria eliminate the

need for identification of tender points and focus instead on clinical

symptoms of widespread or multisite pain and neuropsychological

symptoms. The newer criteria perform well in a clinical setting in

comparison to the older, tender-point criteria. However, it appears

that when the new criteria are applied to populations, the result is

an increase in prevalence of FM and a change in the sex ratio (see

“Epidemiology,” earlier).

Patients with FM often have peripheral pain generators that are

thought to serve as triggers for the more widespread pain attributed

to central nervous system factors. Potential pain generators such as

arthritis, bursitis, tendinitis, neuropathies, and other inflammatory or

degenerative conditions should be identified by history and physical

examination. More subtle pain generators may include joint hypermobility and scoliosis. In addition, patients may have chronic myalgias

triggered by infectious, metabolic, or psychiatric conditions that can

serve as triggers for the development of FM. These conditions are often

identified in the differential diagnosis of patients with FM, and a major

challenge is to distinguish the ongoing activity of a triggering condition

from FM that is occurring as a consequence of a comorbid condition

and that should itself be treated.

Neuropsychological Symptoms In addition to widespread pain,

FM patients typically report fatigue, stiffness, sleep disturbance,

cognitive dysfunction, anxiety, and depression. These symptoms are

present to varying degrees in most FM patients but are not present

in every patient or at all times in a given patient. Relative to pain,

Occiput:

suboccipital

muscle

insertions

Trapezius:

midpoint of the

upper border

Supraspinatus:

above the medial

border of the

scapular spine

Gluteal:

upper outer

quadrants of

buttocks

Greater trochanter:

posterior to the

trochanteric

prominence

Low cervical:

anterior aspects

of the intertransverse

spaces at C5-C7

Second rib:

second

costochondral

junctions

Lateral epicondyle:

2 cm distal to the

epicondyles

Knee:

medial fat pad

proximal to the

joint line

FIGURE 373-1 Tender-point assessment in patients with fibromyalgia. (Figure created using data from F Wolfe et al: Arthritis Care Res 62:600, 2010.)

Fibromyalgia

2869CHAPTER 373

such symptoms may, however, have an equal or even greater impact

on function and quality of life. Fatigue is highly prevalent in patients

under primary care who ultimately are diagnosed with FM. Pain,

stiffness, and fatigue often are worsened by exercise or unaccustomed

activity. The sleep complaints include difficulty falling asleep, difficulty staying asleep, and early-morning awakening. Regardless of the

specific complaint, patients awake feeling unrefreshed. Patients with

FM may meet criteria for restless legs syndrome and sleep-disordered

breathing; frank sleep apnea can also be documented. Cognitive issues

are characterized as difficulties with attention or concentration, problems with word retrieval, and short-term memory loss. Studies have

demonstrated altered cognitive function in these domains in patients

with FM, although speed of processing is age appropriate. Symptoms

of anxiety and depression are common, and the lifetime prevalence

of mood disorders in patients with FM approaches 80%. Although

depression is neither necessary nor sufficient for the diagnosis of FM,

it is important to screen for major depressive disorders by querying

for depressed mood and anhedonia. Analysis of genetic factors that

are likely to predispose to FM reveals shared neurobiologic pathways

with mood disorders, providing the basis for comorbidity (see later in

this chapter).

Overlapping Syndromes FM is considered as part of a group of

conditions called “chronic overlapping pain syndromes” because of the

propensity to coexist with other syndromes that may share underlying

mechanisms. Review of systems often reveals headaches, facial/jaw

pain, regional myofascial pain particularly involving the neck or back,

and arthritis. Visceral pain involving the gastrointestinal tract, bladder,

and pelvic or perineal region is often present as well. It is important for

patients to understand that shared pathways may mediate symptoms

and treatment strategies effective for one condition may help with

global symptom management.

Comorbid Conditions FM is often comorbid with chronic musculoskeletal, infectious, metabolic, or psychiatric conditions. Whereas

FM affects only ~2% of the general population, it occurs in ~10–30%

of patients with degenerative or inflammatory rheumatic disorders,

likely because these conditions serve as peripheral pain generators to

alter central pain-processing pathways. Similarly, chronic infectious,

metabolic, or psychiatric diseases associated with musculoskeletal pain

can mimic FM and/or serve as a trigger for the development of FM.

It is particularly important for clinicians to be sensitive to pain management of these comorbid conditions so that when FM emerges—

characterized by pain outside the boundaries of what could reasonably

be explained by the triggering condition, development of neuropsychological symptoms, or tenderness on physical examination—treatment

of central pain processes will be undertaken as opposed to a continued

focus on treatment of peripheral or inflammatory causes of pain.

Psychosocial Considerations Symptoms of FM often have their

onset and are exacerbated during periods of perceived stress. This

pattern may reflect an interaction among central stress physiology,

vigilance or anxiety, and central pain-processing pathways. An understanding of current psychosocial stressors will aid in patient management, as many factors that exacerbate symptoms cannot be addressed

by pharmacologic approaches. Furthermore, there is a high prevalence

of exposure to previous interpersonal and other forms of violence

in patients with FM and related conditions. If posttraumatic stress

disorder is an issue, the clinician should be aware of it and consider

treatment options.

Functional Impairment It is crucial to evaluate the impact of FM

symptoms on function and role fulfillment. In defining the success of a

management strategy, improved function is a key measure. Functional

assessment should include physical, mental, and social domains. Recognition of the ways in which role functioning falls short will be helpful

in establishing treatment goals.

■ DIFFERENTIAL DIAGNOSIS

Because musculoskeletal pain is such a common complaint, the differential diagnosis of FM is broad. Table 373-1 lists some of the more

common conditions that should be considered. Patients with inflammatory causes for widespread pain should be identifiable on the basis

of specific history, physical findings, and laboratory or radiographic

tests.

■ LABORATORY OR RADIOGRAPHIC TESTING

Routine laboratory and radiographic tests yield normal results in FM

without comorbidities. Thus, diagnostic testing is focused on identification of other diagnoses and evaluation for pain generators or

comorbid conditions (Table 373-2). Most patients with new chronic

widespread pain should be assessed for the most common entities in

the differential diagnosis. Radiographic testing should be used very

sparingly and only for diagnosis of inflammatory arthritis. After the

patient has been evaluated thoroughly, repeat testing is discouraged

unless the symptom complex changes. Particularly to be discouraged

is magnetic resonance imaging (MRI) of the spine unless there are features suggesting inflammatory spine disease or neurologic symptoms.

TABLE 373-1 Common Conditions in the Differential Diagnosis

of Fibromyalgia

Inflammatory

Polymyalgia rheumatica

Inflammatory arthritis: rheumatoid arthritis, spondyloarthritides

Connective tissue diseases: systemic lupus erythematosus, Sjögren’s syndrome

Infectious

Hepatitis C

HIV infection

Lyme disease

Parvovirus B19 infection

Epstein-Barr virus infection

Noninflammatory

Degenerative joint/spine/disk disease

Myofascial pain syndromes

Bursitis, tendinitis, repetitive strain injuries

Endocrine

Hypo- or hyperthyroidism

Hyperparathyroidism

Neurologic Diseases

Multiple sclerosis

Neuropathic pain syndromes

Psychiatric Disease

Major depressive disorder

Drugs

Statins

Aromatase inhibitors

TABLE 373-2 Laboratory and Radiographic Testing in Patients with

Fibromyalgia Symptoms

Routine

Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)

Complete blood count (CBC)

Thyroid-stimulating hormone (TSH)

Guided by History and Physical Examination

Complete metabolic panel

Antinuclear antibody (ANA)

Anti-SSA (anti–Sjögren’s syndrome A) and anti-SSB

Rheumatoid factor and anti–cyclic citrullinated peptide (anti-CCP)

Creatine phosphokinase (CPK)

Viral (e.g., hepatitis C, HIV) and bacterial (e.g., Lyme) serologies

Spine and joint radiographs

Source: LM Arnold et al: J Women’s Health 21:231, 2012; MA Fitzcharles et al:

J Rheumatol 40:1388, 2013.

2870 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

■ GENETICS AND PHYSIOLOGY

As in most complex diseases, it is likely that a number of genes

contribute to vulnerability to the development of FM. To date,

these genes appear to be in pathways controlling pain and stress

responses. Some of the genetic underpinnings of FM are shared across

other chronic pain conditions. Genes associated with metabolism,

transport, and receptors of serotonin and other monoamines have been

implicated in FM and overlapping conditions. Genes associated with

other pathways involved in pain transmission have also been described

as vulnerability factors for FM. Taken together, the pathways in which

polymorphisms have been identified in FM patients further implicate

central factors in mediation of the physiology that leads to the clinical

manifestations of FM.

Psychophysical testing of patients with FM has demonstrated altered

sensory afferent pain processing and impaired descending noxious

inhibitory control leading to hyperalgesia and allodynia. Functional

MRI and other research imaging procedures clearly demonstrate

activation of the brain regions involved in the experience of pain in

response to stimuli that are innocuous in study participants without

FM. Pain perception in FM patients is influenced by the emotional

and cognitive dimensions, such as catastrophizing and perceptions of

control, providing a solid basis for recommendations for cognitive and

behavioral treatment strategies.

Studies have indicated that some patients meeting criteria for FM

may have a small fiber neuropathy. Other studies have identified alterations in expressed gene or metabolic signatures in peripheral blood.

These early studies raise the possibility that confirmatory diagnostic

testing could be developed in the future to assist in the diagnosis of FM.

APPROACH TO THE PATIENT

Fibromyalgia

FM is common and has an extraordinary impact on the patient’s

function and health-related quality of life. Optimal management

requires prompt diagnosis and assessment of pain, function, and

psychosocial context. Physicians and other health professionals

can be helpful in managing some of the symptoms and impact of

FM. Developing a partnership with patients is essential for improving the outcome of FM, with a goal of understanding the factors

involved, implementing a treatment strategy, and choosing appropriate nonpharmacologic and pharmacologic treatments.

TREATMENT

Fibromyalgia

NONPHARMACOLOGIC TREATMENT

Patients with chronic pain, fatigue, and other neuropsychological

symptoms require a framework for understanding the symptoms

that have such an important impact on their function and quality

of life. Explaining the genetics, triggers, and physiology of FM

can be an important adjunct in relieving associated anxiety and

in reducing the overall cost of health care resources. In addition,

patients must be educated regarding expectations for treatment.

The physician should focus on improved function and quality of life

rather than elimination of pain. Illness behaviors, such as frequent

physician visits, should be discouraged and behaviors that focus on

improved function strongly encouraged.

Treatment strategies should include physical conditioning, with

encouragement to begin at low levels of aerobic exercise and to

proceed with slow but consistent advancement. Physical activity

and exercise are consistently found to be the most helpful strategies.

Patients who have been physically inactive may do best in supervised or water-based programs at the start. Strength training may be

recommended after patients reach their aerobic goals. Transcutaneous electric nerve stimulation (TENS) reduces movement-evoked

pain and fatigue. Meditative movement therapies, such as qigong,

yoga, or Tai Chi, may also be helpful. Other defined physical

therapies such as acupuncture or hydrotherapy may also be considered. Exercise programs are helpful in reducing tenderness and

enhancing self-efficacy. Cognitive-behavioral strategies to improve

sleep hygiene and reduce illness behaviors can also be helpful in

management.

PHARMACOLOGIC APPROACHES

It is essential for the clinician to treat any comorbid triggering

condition and to clearly delineate for the patient the treatment

goals for each medication. For example, glucocorticoids or nonsteroidal anti-inflammatory drugs may be useful for management

of inflammatory triggers but are not effective against FM-related

symptoms. At present, the treatment approaches that have proved

most successful in FM patients target afferent or descending pain

pathways. Table 373-3 lists the drugs with demonstrated effectiveness. It should be emphasized that strong opioid analgesics are to be

avoided in patients with FM. These agents have no demonstrated

efficacy in FM and are associated with adverse effects that can

worsen both symptoms and function. Tramadol, an opioid with

mild serotonin-noradrenaline reuptake inhibitor activity, has been

studied in this population with indication of efficacy. Use of single

agents to treat multiple symptom domains is strongly encouraged.

For example, if a patient’s symptom complex is dominated by pain

and sleep disturbance, use of an agent that exerts both analgesic and

sleep-promoting effects is desirable. These agents include cyclobenzaprine, sedating antidepressants such as amitriptyline, and alpha2-delta ligands such as gabapentin and pregabalin. For patients

whose pain is associated with fatigue, anxiety, or depression, drugs

that have both analgesic and antidepressant/anxiolytic effects, such

as duloxetine or milnacipran, may be the best first choice.

■ FURTHER READING

Clauw DJ: Fibromyalgia: A clinical review. JAMA 311:1547, 2014.

Macfarlane GJ et al: EULAR revised recommendations for the management of fibromyalgia. Ann Rheum Dis 76:318, 2017.

Wolf F et al: 2016 Revisions to the 2010/2011 fibromyalgia diagnostic

criteria. Semin Arthritis Rheum 46:319, 2016.

TABLE 373-3 Pharmacologic Agents Effective for Treatment

of Fibromyalgia

Muscle relaxant

Cyclobenzaprine

Antidepressants: balanced serotonin–norepinephrine reuptake inhibitors

Amitryptilinea

Duloxetineb,c

Milnacipranb,c

Anticonvulsants: ligand of the alpha-2-delta subunit of voltage-gated calcium

channels

Pregabalinb

Analgesic

Tramadol

a

RA Moore et al: Cochrane Database Syst Rev 12:CD008242, 2012. b

Approved by the

U.S. Food and Drug Administration. c

W Hauser et al: Cochrane Database Syst Rev 1:

CD010292, 2013.

Source: GJ Macfarlane et al: EULAR revised recommendations for the management

of fibromyalgia. Ann Rheum Dis 76:318, 2017.

Arthritis Associated with Systemic Disease, and Other Arthritides

2871CHAPTER 374

ARTHRITIS ASSOCIATED

WITH SYSTEMIC DISEASE

■ ARTHROPATHY OF ACROMEGALY

Acromegaly is the result of excessive production of growth hormone

by an adenoma in the anterior pituitary gland (Chap. 383). The excess

of growth hormone along with insulin-like growth factor I stimulates

proliferation of cartilage, periarticular connective tissue, and bone,

resulting in several musculoskeletal problems, including osteoarthritis,

back pain, muscle weakness, and carpal tunnel syndrome.

Osteoarthritis is a common feature, most often affecting the knees,

shoulders, hips, and hands. Single or multiple joints may be affected.

Hypertrophy of cartilage initially produces radiographic widening of

the joint space. The newly synthesized cartilage is abnormally susceptible to fissuring, ulceration, and destruction. Ligamental laxity of

joints further contributes to the development of articular discomfort

and osteoarthritis. Cartilage degrades, the joint space narrows, and

subchondral sclerosis and osteophytes may develop. Joint examination

reveals crepitus and laxity. Joint fluid is noninflammatory. Calcium

pyrophosphate dihydrate crystals are found in the cartilage in some

cases of acromegaly arthropathy and, when shed into the joint, can

elicit attacks of pseudogout (calcium pyrophosphate arthropathy).

Chondrocalcinosis may be observed on radiographs. Back pain is

extremely common, perhaps as a result of spine hypermobility. Spine

radiographs show normal or widened intervertebral disk spaces,

hypertrophic anterior osteophytes, and ligamental calcification. The

latter changes are similar to those observed in patients with diffuse

idiopathic skeletal hyperostosis. Dorsal kyphosis in conjunction with

elongation of the ribs contributes to the development of the barrel chest

seen in acromegalic patients. The hands and feet become enlarged as

a result of soft tissue proliferation. The fingers are thickened and have

spadelike distal tufts. One-third of patients have a thickened heel pad.

Approximately 25% of patients exhibit Raynaud’s phenomenon. Carpal

tunnel syndrome occurs in about half of patients. The median nerve

may become compressed by excess connective tissue in the carpal tunnel. Patients with acromegaly may develop proximal muscle weakness,

which is thought to be caused by the effect of growth hormone on

muscle. Serum muscle enzyme levels and electromyographic findings

are normal. Muscle biopsy specimens contain muscle fibers of varying

size without inflammation.

■ ARTHROPATHY OF HEMOCHROMATOSIS

Hemochromatosis is a disorder of iron storage. Absorption of excessive

amounts of iron from the intestine leads to iron deposition in parenchymal cells, which results in impairment of organ function (Chap. 414).

Symptoms of hemochromatosis usually begin between the ages of 40

and 60 but can appear earlier. Arthropathy, which occurs in 20–40% of

patients, usually begins after the age of 50 and may be the first clinical

feature of hemochromatosis. The arthropathy is an osteoarthritis-like

disorder affecting the small joints of the hands and later the larger

joints, such as knees, ankles, shoulders, and hips. The second and third

metacarpophalangeal joints of both hands are often the first and most

prominent joints affected; this clinical picture may provide an important clue to the possibility of hemochromatosis because these joints are

not predominantly affected by primary osteoarthritis. Patients experience some morning stiffness and pain with use of involved joints. The

affected joints are enlarged and mildly tender. Hand pain in patients

with hemochromatosis generally is milder, starts at an earlier age,

and causes less disability than in patients with primary osteoarthritis.

374 Arthritis Associated

with Systemic Disease,

and Other Arthritides

Carol A. Langford, Brian F. Mandell

Radiographs show narrowing of the joint space, subchondral sclerosis,

subchondral cysts, and juxtaarticular proliferation of bone. Hooklike osteophytes are seen in up to 20% of patients; although they are

regarded as a characteristic feature of hemochromatosis, they are not

disease specific. However, dominant radiographic and clinical findings

in the second and third metacarpophalangeal joints, even if modest

in degree, warrants evaluation of ferritin and iron/total iron-binding

capacity levels. The more typical radiographic changes of primary osteoarthritis in the proximal interphalangeal, distal interphalangeal, and

first carpometacarpal joint are often not present. The synovial fluid is

noninflammatory. The synovium shows mild to moderate proliferation

of iron-containing lining cells, fibrosis, and some mononuclear cell

infiltration. In approximately half of patients, there is evidence of calcium pyrophosphate deposition disease, and some patients late in the

course of disease experience episodes of acute calcium pyrophosphate

arthritis (Chap. 372). An early diagnosis is suggested by high serum

transferrin saturation, which is more sensitive than ferritin elevation.

Iron may damage the articular cartilage in several ways. Iron catalyzes superoxide-dependent lipid peroxidation, which may play a

role in joint damage. In animal models, ferric iron has been shown to

interfere with collagen formation and increase the release of lysosomal

enzymes from cells in the synovial membrane. Iron inhibits synovial

tissue pyrophosphatase in vitro and therefore may inhibit pyrophosphatase in vivo, resulting in chondrocalcinosis.

TREATMENT

Arthropathy of Hemochromatosis

The treatment of hemochromatosis is repeated phlebotomy. Unfortunately, this treatment has little effect on established arthritis,

which, along with chondrocalcinosis, may progress. Symptombased treatment of the arthritis consists of administration of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs),

as tolerated. Acute calcium pyrophosphate arthropathy flares are

treated with high doses of an NSAID or a short course of glucocorticoids. Low-dose colchicine may have efficacy in limiting the

number of flares. Hip or knee total joint replacement has been

successful in advanced disease.

■ HEMOPHILIC ARTHROPATHY

Hemophilia is a sex-linked recessive genetic disorder characterized by

the absence or deficiency of factor VIII (hemophilia A, or classic hemophilia) or factor IX (hemophilia B, or Christmas disease) (Chap. 116).

Hemophilia A constitutes 85% of cases. Spontaneous hemarthrosis is

a common problem with both types of hemophilia and can lead to a

deforming arthritis. The frequency and severity of hemarthrosis are

related to the degree of clotting factor deficiency. Hemarthrosis is not

common in other disorders of coagulation such as von Willebrand

disease, factor V deficiency, warfarin therapy, or thrombocytopenia.

Hemarthrosis occurs after 1 year of age, when a child begins to walk

and run. In order of frequency, the joints most commonly affected are

the knees, ankles, elbows, shoulders, and hips. Small joints of the hands

and feet are occasionally involved.

In the initial stage of arthropathy, hemarthrosis produces a warm,

tensely swollen, and painful joint. The patient holds the affected joint

in flexion and guards against any movement. Blood in the joint remains

liquid because of the absence of intrinsic clotting factors and the

absence of tissue thromboplastin in the synovium. The synovial blood

is resorbed over a period of ≥1 week, with the precise interval depending on the size of the hemarthrosis. Joint function usually returns to

normal or baseline in ~2 weeks. Low-grade temperature elevation

may accompany hemarthrosis, but a fever >38.3°C (101°F) warrants

concern about infection.

Recurrent hemarthrosis may result in chronic, noninflammatory,

fibrotic arthropathy. The involved joints remain swollen, and flexion

deformities impacting function develop. Restricted joint motion or

laxity with subluxation is a feature of end-stage disease.

2872 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

Bleeding into muscle and soft tissue also causes musculoskeletal

dysfunction. When bleeding into the iliopsoas muscle occurs, the hip

is held in flexion because of the pain, resulting in a hip flexion contracture. Rotation of the hip is preserved, which distinguishes this problem

from hemarthrosis or other causes of hip synovitis. Expansion of the

hematoma may place pressure on the femoral nerve, resulting in femoral neuropathy. Hemorrhage into a closed compartment space, such as

the calf or the volar compartment in the forearm, can result in muscle

necrosis, neuropathy, and flexion deformities of the ankles, wrists,

and fingers. When bleeding involves periosteum or bone, a painful

pseudotumor forms. These pseudotumors occur distal to the elbows

or knees in children and improve with treatment of hemophilia. Surgical removal is indicated if the pseudotumor continues to enlarge. In

adults, pseudotumors develop in the femur and pelvis and are usually

refractory to treatment. When bleeding occurs in muscle, cysts may

develop within the muscle. Needle aspiration of a cyst is contraindicated because this procedure can induce further bleeding; however,

if the cyst becomes secondarily infected, drainage may be necessary

(after factor repletion).

Septic arthritis is rare in hemophilia but is difficult to distinguish

from acute hemarthrosis on physical examination. If there is serious

suspicion of an infected joint, the joint should be aspirated immediately, the fluid cultured, and treatment with broad-spectrum antibiotics administered, with coverage for microorganisms including

Staphylococcus, until culture results become available. Clotting factor

deficiency should be corrected before arthrocentesis to minimize the

risk of traumatic bleeding. Notably, low-grade fever can occur in the

setting of acute hemarthrosis.

Radiographs of joints reflect the stage of disease. In early stages,

there is capsule distention; later, juxtaarticular osteopenia, marginal

erosions, and subchondral cysts develop. Late in the disease, the joint

space is narrowed, and there is bony overgrowth similar to that in

osteoarthritis.

TREATMENT

Hemarthrosis

The treatment of musculoskeletal bleeding is initiated with the

immediate infusion of factor VIII or IX at the first sign of joint or

muscle hemorrhage. Patients who have developed factor inhibitors

are at elevated risk for joint damage and may benefit from receiving

recombinant activated factor VII or activated prothrombin complex concentrate. The joint should be rested in a position of forced

extension, as tolerated, to avoid contracture. Analgesia should

be provided; nonselective NSAIDs, which can diminish platelet

function, should be avoided. Selective cyclooxygenase-2 inhibitors

do not interfere with platelet function, although cardiovascular

and gastrointestinal risks must still be weighed. Synovectomy—

open or arthroscopic—may be attempted in patients with chronic

symptomatic synovial proliferation and recurrent hemarthrosis,

although hypertrophied synovium is highly vascular and subject to

bleeding. Both types of synovectomy reduce the number of hemarthroses. Open surgical synovectomy, however, is associated with

some loss of range of motion. Both require aggressive prophylaxis

against bleeding. Radiosynovectomy with either yttrium-90 silicate

or phosphorus-31 colloid has been effective and may be attempted

when surgical synovectomy is not practical. Total joint replacement

is indicated for severe joint destruction and incapacitating pain.

■ ARTHROPATHIES ASSOCIATED WITH

HEMOGLOBINOPATHIES

Sickle Cell Disease Sickle cell disease (Chap. 98) is associated

with several musculoskeletal abnormalities (Table 374-1). Children

aged <5 years may develop diffuse swelling, tenderness, and warmth

of the hands and feet lasting 1–3 weeks. This condition, referred to as

sickle cell dactylitis or hand-foot syndrome, has also been observed in

sickle cell thalassemia. Dactylitis is believed to result from infarction

of the bone marrow and cortical bone leading to periostitis and soft

tissue swelling. Radiographs show periosteal elevation, subperiosteal

new bone formation, and areas of radiolucency and increased density

involving the metacarpals, metatarsals, and proximal phalanges. These

bone changes disappear after several months. The syndrome leaves little

or no residual damage. Because hematopoiesis ceases in the small bones

of the hands and feet with age, the syndrome is rarely seen after age 5.

Sickle cell crisis is associated with periarticular pain and occasionally with joint effusions. The joint and periarticular area are warm and

tender. Knees and elbows are most often affected, but other joints can

be involved. Joint effusions are usually noninflammatory. Acute synovial infarction can cause a sterile effusion with high neutrophil counts

in synovial fluid. Synovial biopsies have shown mild lining-cell proliferation and microvascular thrombosis with infarctions. Scintigraphic

studies have shown decreased marrow uptake adjacent to the involved

joint. The treatment for sickle cell crisis is detailed in Chap. 98.

Patients with sickle cell disease are predisposed to osteomyelitis,

which commonly involves the long tubular bones (Chap. 131); Salmonella is a particularly common cause (Chap. 165). Radiographs of

the involved site initially show periosteal elevation, with subsequent

disruption of the cortex. Treatment of the infection results in healing

of the bone lesion. In addition, bone infarction resulting from vasoocclusion secondary to the sickling of red cells can occur and is the cause

of the bone pain in sickle cell crisis. Bone infarction also occurs in

hemoglobin sickle cell disease and sickle cell thalassemia (Chap. 98).

In children, infarction of the epiphyseal growth plate interferes with

normal growth of the affected extremity. Radiographically, infarction

of the bone cortex results in periosteal elevation and irregular thickening of the bone cortex. Infarction in the bone marrow leads to lysis,

fibrosis, and new bone formation. Clinical distinction between osteomyelitis and bone infarctions can be difficult; imaging can be helpful.

Avascular necrosis of the head of the femur occurs in ~5% of

patients. It also occurs in the humeral head and less commonly in the

distal femur, tibial condyles, distal radius, vertebral bodies, and other

juxtaarticular sites. Irregularity of the femoral head and other articular surfaces often results in degenerative joint disease. Radiographs

may show patchy radiolucency and density followed by flattening of

the bone. MRI is a sensitive technique for detecting early avascular

necrosis as well as bone infarction elsewhere. Total hip replacement

and placement of prostheses in other joints may improve function and

relieve joint pain in these patients.

Septic arthritis is occasionally encountered in sickle cell disease

(Chap. 130). Multiple joints may be infected. Joint infection may result

from bacteremia due to splenic dysfunction or from contiguous osteomyelitis. The more common microorganisms include Staphylococcus

aureus, Streptococcus, and Salmonella. Salmonella does not cause septic

arthritis as frequently as it causes osteomyelitis. Acute gouty arthritis is

uncommon in sickle cell disease, even though 40% of patients are hyperuricemic. However, it may occur in patients generally not expected

to get gout (young patients, female patients). Hyperuricemia is due to

overproduction of uric acid secondary to increased red cell turnover as

well as suboptimal renal excretion. Attacks may be polyarticular, and

diagnostic arthrocentesis should be performed to distinguish infection

from gout or synovial infarction.

The bone marrow hyperplasia in sickle cell disease results in widening of the medullary cavities, thinning of the cortices, and coarse trabeculations and central cupping of the vertebral bodies. These changes

are also seen to a lesser degree in hemoglobin sickle cell disease and

sickle cell thalassemia. In normal individuals, red marrow is located

TABLE 374-1 Musculoskeletal Abnormalities in Sickle Cell Disease

Sickle cell dactylitis Avascular necrosis

Joint effusions in sickle cell crises Bone changes secondary to marrow

hyperplasia

Osteomyelitis Septic arthritis

Infarction of bone Gouty arthritis

Infarction of bone marrow Synovial infarction

Arthritis Associated with Systemic Disease, and Other Arthritides

2873CHAPTER 374

mostly in the axial skeleton, but in sickle cell disease, red marrow is

found in the bones of the extremities and even in the tarsal and carpal

bones. Vertebral compression may lead to dorsal kyphosis, and softening of the bone in the acetabulum may result in protrusio acetabuli.

Thalassemia A congenital disorder of hemoglobin synthesis,

β thalassemia is characterized by impaired production of β chains

(Chap. 98). Bone and joint abnormalities occur in β thalassemia,

being most common in the major and intermedia groups. In one study,

~50% of patients with β thalassemia had evidence of symmetric ankle

arthropathy with onset in the second or third decade of life. The degree

of ankle pain in these patients varied. Some patients experienced

self-limited ankle pain that occurred only after strenuous physical

activity and lasted several days or weeks, while others had chronic

ankle pain that became worse with walking. Compression of the ankle,

calcaneus, or forefoot was painful in some patients. Synovial fluid from

two patients was noninflammatory. Radiographs of the ankle showed

osteopenia, widened medullary spaces, thin cortices, and coarse trabeculations as a result of bone marrow expansion. The joint space was

preserved. Specimens of bone from three patients revealed osteomalacia, osteopenia, and microfractures. Increased numbers of osteoblasts

as well as increased foci of bone resorption were present on the bone

surface. Iron staining was found in the bone trabeculae, in osteoid, and

in the cement line. Synovium showed hyperplasia of lining cells, which

contained deposits of hemosiderin. This arthropathy was considered to

be related to the underlying bone pathology. The role of iron overload

or abnormal bone metabolism in the pathogenesis of this arthropathy

is not known. The arthropathy was treated with analgesics and splints.

Patients also received transfusions to decrease hematopoiesis and bone

marrow expansion.

In patients with β-thalassemia major and β-thalassemia intermedia,

other joints are also involved, including the knees, hips, and shoulders.

Acquired hemochromatosis with arthropathy has been described in a

patient with thalassemia. Gouty arthritis and septic arthritis can occur.

Avascular necrosis is not a feature of thalassemia because there is no

sickling of red cells leading to thrombosis and infarction.

β Thalassemia minor (also known as β thalassemia trait) is likewise

associated with joint manifestations. Chronic seronegative oligoarthritis affecting predominantly ankles, wrists, and elbows has been

described; the affected patients had mild persistent synovitis without

large effusions or joint erosions. Recurrent episodes of acute asymmetric arthritis have also been reported; episodes last <1 week and

may affect the knees, ankles, shoulders, elbows, wrists, and metacarpophalangeal joints. The mechanism underlying this arthropathy is

unknown. Treatment with NSAIDs is not particularly effective.

■ MUSCULOSKELETAL DISORDERS ASSOCIATED

WITH HYPERLIPIDEMIA

(See also Chap. 407) Musculoskeletal or cutaneous manifestations

may be the first clinical indication of a specific hereditary disorder of

lipoprotein metabolism. Patients with familial hypercholesterolemia

(previously referred to as type II hyperlipoproteinemia) may have

recurrent migratory polyarthritis involving the knees and other large

peripheral joints and, to a lesser degree, peripheral small joints. Pain

ranges from moderate to incapacitating. The involved joints can be

warm, erythematous, swollen, and tender. Arthritis usually has a

sudden onset, lasts from a few days to 2 weeks, and does not cause

joint damage. Synovial fluid from involved joints is not inflammatory

and contains few white cells and no crystals. Joint involvement may

actually represent inflammatory periarthritis or peritendinitis and

not true arthritis. The recurrent, transient nature of the arthritis may

suggest acute gout or rheumatic fever, especially because patients with

hyperlipoproteinemia may have an elevated erythrocyte sedimentation

rate and elevated antistreptolysin O titers (the latter being quite common). Attacks of tendinitis, including the large Achilles and patellar

tendons, may come on gradually and last only a few days or may be

acute, as described above. Patients may be asymptomatic between

attacks. Achilles tendinitis and other joint manifestations often precede

the appearance of xanthomas and may be the first clinical indication

of hyperlipoproteinemia. Attacks of tendinitis may follow treatment

with a lipid-lowering drug. Over time, patients may develop tendinous

xanthomas in the Achilles, patellar, and extensor tendons of the hands

and feet. Xanthomas have also been reported in the peroneal tendon,

the plantar aponeurosis, and the periosteum overlying the distal tibia

where they are located within tendon fibers. Tuberous xanthomas

are soft subcutaneous masses located over the extensor surfaces of

the elbows, knees, and hands as well as on the buttocks. They appear

during childhood in homozygous patients and after the age of 30 in

heterozygous patients. Patients with elevated plasma levels of verylow-density lipoprotein (VLDL) and triglycerides (previously referred

to as type IV hyperlipoproteinemia) may also have a mild inflammatory

arthritis affecting large and small peripheral joints, usually in an asymmetric pattern, with only a few joints involved at a time. The onset of

arthritis is typically between the age of 40 and 65 years. Arthritis may

be persistent or recurrent, with episodes lasting a few days or weeks.

Severe joint pain and tenderness, morning stiffness, and periarticular

hyperesthesia may also be present, as may synovial thickening. Joint

fluid is usually noninflammatory and without crystals but may have

increased white blood cell counts with predominantly mononuclear

cells. Radiographs may show juxtaarticular osteopenia and cystic

lesions. Large bone cysts have been noted in a few patients. Xanthoma

and bone cysts are also observed in other lipoprotein disorders. The

pathogenesis of arthritis in patients with familial hypercholesterolemia

or with elevated levels of VLDL and triglycerides is not well understood. NSAIDs or analgesics usually provide adequate relief of symptoms when used on an as-needed basis.

Patients may improve clinically as they are treated with lipidlowering agents; however, patients treated with an HMG-CoA reductase

inhibitor may experience myalgias, and a few patients develop myopathy, myositis, or even rhabdomyolysis. Patients who develop myositis

during statin therapy may be susceptible to this adverse effect because of

an underlying muscle disorder and should be reevaluated after discontinuation of the drug. Testing for anti–3-hydroxy-3-methylglutaryl-CoA

reductase (HMGCR) autoantibodies in patients with elevated muscle

enzymes on treatment may identify patients with statin-induced

necrotizing autoimmune myopathy. Myositis has also been reported

with the use of niacin (Chap. 365) but is less common than myalgias.

Musculoskeletal syndromes have not clearly been associated with

the more common mixed hyperlipidemias seen in general practice.

OTHER ARTHRITIDES

■ NEUROPATHIC JOINT DISEASE

Neuropathic joint disease (Charcot joint) is a progressive destructive

arthritis associated with loss of pain sensation, proprioception, or both.

Normal muscular reflexes that modulate joint movement are impaired.

Without these protective mechanisms, joints are subjected to repeated

trauma, resulting in progressive cartilage and bone damage. Today,

diabetes mellitus is the most frequent cause of neuropathic joint disease

(Fig. 374-1). A variety of other disorders are associated with neuropathic arthritis, including tabes dorsalis, leprosy, yaws, syringomyelia,

meningomyelocele, congenital indifference to pain, peroneal muscular

atrophy (Charcot-Marie-Tooth disease), and amyloidosis. An arthritis

resembling neuropathic joint disease has been reported in patients

who have received intraarticular glucocorticoid injections, but this is a

rare complication and was not observed in one series of patients with

knee osteoarthritis who received intraarticular glucocorticoid injections every 3 months for 2 years. The distribution of joint involvement

depends on the underlying neurologic disorder (Table 374-2). In tabes

dorsalis, the knees, hips, and ankles are most commonly affected; in

syringomyelia, the glenohumeral joint, elbow, and wrist; and in diabetes mellitus, the tarsal and tarsometatarsal joints.

■ PATHOLOGY AND PATHOPHYSIOLOGY

The pathologic changes in the neuropathic joint are similar to those

found in the severe osteoarthritic joint. There is fragmentation and

eventual loss of articular cartilage with eburnation of the underlying

bone. Osteophytes are found at the joint margins. With more advanced

2874 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

disease, erosions are present on the joint surface. Fractures, devitalized

bone, intraarticular loose bodies, and microscopic fragments of cartilage and bone may be present.

At least two underlying mechanisms are believed to be involved in

the pathogenesis of neuropathic arthritis. An abnormal autonomic

nervous system is thought to be responsible for the dysregulated blood

flow to the joint with subsequent resorption of bone. Loss of bone, particularly in the diabetic foot, may be the initial finding. With the loss

of deep pain, proprioception, and protective neuromuscular reflexes,

the joint is subjected to repeated microtrauma, resulting in ligamental

tears and bone fractures. The injury that follows frequent intraarticular

glucocorticoid injections is thought to be due to the analgesic effect of

glucocorticoids, leading to overuse of an already damaged joint; the

result is accelerated cartilage damage, although steroid-induced cartilage damage is more common in some other animal species than in

humans. It is not understood why only a few patients with neuropathy

develop clinically evident neuropathic arthritis.

■ CLINICAL MANIFESTATIONS

Neuropathic joint disease usually begins in a single joint and then

becomes apparent in other joints, depending on the underlying neurologic disorder. The involved joint becomes progressively enlarged as

a result of bony overgrowth and synovial effusion. Loose bodies may

be palpated in the joint cavity. Joint instability, subluxation, and crepitus occur as the disease progresses. Neuropathic joints may develop

rapidly, and a totally disorganized joint with multiple bony fragments

may evolve within weeks or months. The amount of pain experienced

by the patient is less than would be anticipated from the degree of joint

damage. Patients may experience sudden joint pain from intraarticular

fractures of osteophytes or condyles.

Neuropathic arthritis is encountered most often in patients with

diabetes mellitus, with an incidence of ~0.5%. The onset of disease

usually comes at an age of ≥50 years in a patient who has had diabetes

for several years, but exceptions occur. The tarsal and tarsometatarsal

joints are most often affected, with the metatarsophalangeal and talotibial joints next most commonly involved. The knees and spine are

occasionally involved. Patients often attribute the onset of foot pain to

antecedent trauma such as twisting of the foot. Neuropathic changes

may develop rapidly after a foot fracture or dislocation. The foot and

ankle are often swollen. Downward collapse of the tarsal bones leads to

convexity of the sole, referred to as a “rocker foot.” Large osteophytes

may protrude from the top of the foot. Calluses frequently form over

the metatarsal heads and may lead to infected ulcers and osteomyelitis.

The value of protective inserts and orthotics, as well as regular foot

examination, cannot be overstated. Radiographs may show resorption

and tapering of the distal metatarsal bones. The term Lisfranc fracturedislocation is sometimes used to describe the destructive changes at the

tarsometatarsal joints.

■ DIAGNOSIS

The diagnosis of neuropathic arthritis is based on the clinical features

and characteristic radiographic findings in a patient with underlying

sensory neuropathy. The differential diagnosis of neuropathic arthritis

depends upon the severity of the process and includes osteomyelitis, avascular necrosis, advanced osteoarthritis, stress fractures, and

calcium pyrophosphate deposition disease. Radiographs in neuropathic arthritis initially show changes of osteoarthritis with joint

space narrowing, subchondral bone sclerosis, osteophytes, and joint

effusions; marked destructive and hypertrophic changes follow later.

The radiographic findings of neuropathic arthritis may be difficult to

differentiate from those of osteomyelitis, especially in the diabetic foot.

The joint margins in a neuropathic joint tend to be distinct, while in

osteomyelitis, they are blurred. Imaging studies may be helpful, but

cultures of tissue from the joint are often required to exclude osteomyelitis. MRI and bone scans using indium-111–labeled white blood cells

or indium-111–labeled immunoglobulin G, which will show increased

uptake in osteomyelitis but not in a neuropathic joint, may be useful. A technetium bone scan will not distinguish osteomyelitis from

neuropathic arthritis, as increased uptake is observed in both. The

joint fluid in neuropathic arthritis is noninflammatory; it may be xanthochromic or even bloody and may contain fragments of synovium,

cartilage, and bone. The finding of calcium pyrophosphate dihydrate

crystals supports the diagnosis of crystal-associated arthropathy. In

the absence of such crystals, an increased number of leukocytes may

indicate osteomyelitis.

TREATMENT

Neuropathic Joint Disease

The primary focus of treatment is to stabilize the joint. Treatment

of the underlying disorder, even if successful, does not usually affect

established joint disease. Braces and splints are helpful. Their use

requires close surveillance, because patients may be unable to appreciate pressure from a poorly adjusted brace. In the diabetic patient,

early recognition of Charcot foot and its treatment—prohibition

of weight bearing by the foot for at least 8 weeks—may possibly

prevent severe disease from developing. Fusion of an unstable joint

may improve function and reduce pain, but nonunion is frequent,

especially when immobilization of the joint is inadequate.

■ HYPERTROPHIC OSTEOARTHROPATHY

AND CLUBBING

Hypertrophic osteoarthropathy (HOA) is characterized by clubbing of

digits and, in more advanced stages, by periosteal new bone formation

and synovial effusions. HOA may be primary or familial and may

begin in childhood. Secondary HOA is associated with intrathoracic

malignancies, suppurative and some hypoxemic lung diseases, congenital heart disease, and a variety of other disorders. Clubbing is almost

always a feature of HOA but can also occur as an isolated finding

(Fig. 374-2). The presence of clubbing in isolation may be congenital

or represent either an early stage or one element in the spectrum of

HOA. Isolated acquired clubbing has the same clinical significance as

clubbing associated with periostitis.

Pathology and Pathophysiology of Acquired HOA In HOA,

bone changes in the distal extremities begin as periostitis followed by

new bone formation. At this stage, a radiolucent area may be observed

between the new periosteal bone and the subjacent cortex. As the process progresses, multiple layers of new bone are deposited and become

contiguous with the cortex, with consequent cortical thickening. The

outer portion of the bone is laminated in appearance, with an irregular

TABLE 374-2 Disorders Associated with Neuropathic Joint Disease

Diabetes mellitus Amyloidosis

Tabes dorsalis Leprosy

Meningomyelocele Congenital indifference to pain

Syringomyelia Peroneal muscular atrophy

FIGURE 374-1 Charcot arthropathy associated with diabetes mellitus. Lateral foot

radiograph demonstrating complete loss of the arch due to bony fragmentation and

dislocation in the midfoot. (Courtesy of Andrew Neckers, MD, and Jean Schils, MD;

with permission.)