AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Gout and pseudogout are the 2 most common crystal-induced arthropathies. They are debilitating illnesses in which pain and joint inflammation are caused by the formation of crystals within the joint space.

Gout is inflammation caused by monosodium urate monohydrate (MSU) crystals.

Pseudogout is inflammation caused by calcium pyrophosphate (CPP) crystals and is sometimes referred to as calcium pyrophosphate disease (CPPD).

Gout is the most common crystal-induced arthritis. Lowenhook first described symptoms in the 1600s. In 1848, Sir Alfred Garrod linked gout with hyperuricemia, but the pathophysiology of acute gouty arthritis was not described fully until 1962. Since then, gout has been associated with a large number of different autoimmune and metabolic disorders. Specific therapies and prophylactic measures have been developed to address the underlying problem.

Pseudogout, which may be clinically indistinguishable from gout, was recognized as a distinct disease entity in 1962. As with gout, pseudogout has been associated with a variety of metabolic disorders as well as with aging and trauma. Treatment of the acute phase of pseudogout is identical to that of gout. Unlike gout, however, no specific therapeutic regimen exists to treat the underlying cause of pseudogout, and no known prophylactic therapy exists.

Pathophysiology

Pain and joint edema of acute arthritis in patients with gout and pseudogout are caused by an inflammatory response triggered by the lysis of polymorphonuclear white blood cells that have ingested MSU crystals or CPP crystals. MSU crystals are formed in synovial fluid when the fluid becomes supersaturated with MSU. This supersaturation can result from overproduction or reduced excretion of MSU. Many conditions and drugs have been associated with an increase in plasma (and subsequent synovial) urate levels. A genetic predisposition for the disease exists. CPP crystals are produced by nucleoside triphosphate pyrophosphohydrolase (NTPPPH), a catalytic enzyme found in vesicles that develop within osteoarthritic cartilage. A genetic predisposition exists for the condition, but any process that leads to osteoarthritis also can be associated with subsequent pseudogout.

Frequency

United States

Gout affects 2.7 of every 1000 adults. Prevalence is approximately 20% in patients with a family history of gout.

Frequency of pseudogout varies with age. The annual incidence of acute attacks of arthritic pain and swelling is about 1.3 per 1000 adults, but nearly half of adults develop radiographic changes typical of CPPD by age 80 years.

Gout has been noted to occur more frequently in the spring and less frequently in the winter, although the reason for this is unknown.

International

Prevalence of gout varies widely from country to country. In England, gout affects 16.4 of every 1000 men and 2.9 of every 1000 women.

Mortality/Morbidity

• Pain and edema of inflammatory crystalline arthritis is extremely debilitating.
• Chronic injury to intra-articular cartilage leaves the joints more susceptible to subsequent joint infections.

Race

• Limited data suggest an increased prevalence of gout in American blacks compared with whites; however, clinically recognized gout is extremely rare in blacks living in Africa.
• Diet may be linked to racial prevalence since diet has a large influence on the clinical expression of gout.

Sex

• For gout, the male-to-female ratio is 9:1.
• For pseudogout, the male-to-female ratio is 1.5:1.

Age

• The predominant age range is 30-60 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The history and physical examination alone cannot reliably determine the cause of new-onset acute monoarticular arthritis.
• Septic arthritis, gout, and pseudogout can present in very similar ways.
• The spontaneous onset of pain, edema, and inflammation in the metatarsal-phalangeal joint of the great toe (podagra) is highly suggestive of acute crystal-induced arthritis. This is the most common presentation of gout.
• Other than the great toe, the most common sites of gouty arthritis are the ankle, wrist, and knee. Consider the diagnosis in any patient with acute monarticular arthritis of any peripheral joint except the glenohumeral joint of the shoulder, in which a crystal-induced arthritis is more likely to be due to pseudogout.
• The most common sites of pseudogout arthritis are the knee, wrist, and shoulder. Case reports have documented carpal tunnel syndrome as an initial presentation of pseudogout. Case reports of pseudogout forming masses in the spinal ligamentum flavum have been documented. These have lead to both single and multi-level myelopathy.
• Crystal-induced arthritis is most commonly monarticular; however, polyarticular acute flares are not rare, and many different joints may be involved simultaneously or in rapid succession. Multiple joints in the same limb often are involved, as when inflammation begins in the great toe and then progresses to involve the midfoot and ankle.
• Although gout and pseudogout cannot reliably be distinguished on clinical grounds, a tendency exists for gout symptoms to develop rapidly over a few hours, whereas the onset of symptoms in pseudogout is usually more insidious and may occur over several days.
• When a patient presents with an identical recurrent attack of crystal-induced arthritis, the diagnosis is rarely in question, but the possibility of septic arthritis must always be considered.
• Fever, chills, and malaise do not distinguish cellulitis or septic arthritis from crystal-induced arthritis because all 3 illnesses can produce these signs and symptoms.
• A careful history may uncover risk factors for cellulitis or septic arthritis, such as possible exposure to gonorrhea, a recent puncture wound over the joint, or systemic signs of disseminated infection.
• Gout is also associated with hyperlipidemia, hypertension, hypertriglyceridemia, kidney failure, obesity, and insulin resistance. Social factors such as alcohol intake also increase the risk of gout.
• It has been suggested that a link exists between several autosomal dominant disorders and the development of gout. However, there has not been a specific genetic marker for those predisposed to developing gout.
• Pseudogout attacks have been reportedly induced by etidronate disodium therapy and post vascular angiography.

Physical

• Patients with gout or pseudogout most often present with a single joint that is hot, erythematous, tender, and affected with asymmetric edema. If inflammation is severe, desquamation of overlying skin may be present.
• Extra-articular deposits of MSU, known as tophi, may be seen along the Achilles tendon or on the ear helix, olecranon bursa, or prepatellar bursa.
• Migratory polyarthritis is a rare presentation.
• An inflammatory synovial effusion may be present.
• Although uncommon, acute gout may present with signs of carpal tunnel syndrome.

Causes

• Although the pathophysiology, clinical presentation, and acute-phase treatment of gout and pseudogout are very similar, the underlying causes of the 2 diseases are very different.
• Acute gouty arthritis results from overproduction or reduced secretion of uric acid. Thiazide diuretics and foods that are rich in purines will increase the frequency of attacks.
• Many cases of pseudogout are idiopathic, but pseudogout has also been associated with aging, trauma, and many different metabolic abnormalities, the most common of which are hyperparathyroidism and hemochromatosis.
• Lead poisoning
• Hemo-proliferative disorders
• Renal disease

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Acute sarcoidosis (rare)
Amyloidosis
Calcific periarthritis
Infectious or septic arthritis
Multicentric reticulohistiocytosis
Psoriatic arthropathy
Spondyloarthropathy
Trauma
Type IIa hyperproteinemia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Diagnostic arthrocentesis is indicated for every patient in whom a diagnosis has never been proven by joint aspiration and for those in whom a possibility of septic arthritis exists. A prior history of gout or pseudogout does not rule out the possibility of acute septic arthritis. In fact, the latter is more common in patients with a history of crystal-induced arthritis. Septic arthritis must be diagnosed and treated promptly. Irreversible damage can occur within 4-6 hours, and the joint can be completely destroyed within 24-48 hours.
• Joint fluid analysis
• • Send joint fluid for fluid analysis, including cell count and differential, Gram stain, culture and sensitivity, and microscopic analysis for crystals. If crystals are seen, their shape and appearance under polarized light can aid in diagnosis.
  • In gout, crystals of MSU appear as needle-shaped intracellular and extracellular crystals. When examined with a polarizing filter, they are yellow when aligned parallel to the axis of the red compensator, but they turn blue when aligned across the direction of polarization (ie, they exhibit negative birefringence).
  • In pseudogout, CPP crystals appear shorter and often rhomboidal. Under a polarizing filter, CPP crystals do not change color depending upon their alignment relative to the direction of the red compensator.
  • In crystal arthritis, the WBC count in the joint fluid is usually 50,000-100,000.
• Even in the presence of crystals in the joint fluid, blood cultures are indicated if any sign of systemic toxicity is present. Septic arthritis can occur in patients with active crystalline arthropathy.
• Gouty attacks are triggered by crystal formation in synovial fluid. They are not related to serum levels of uric acid. Thus, a normal serum uric acid level does not exclude the diagnosis of acute gout, and an elevated level does not prove the diagnosis.
• Pseudogout attacks can be triggered by many metabolic abnormalities. Thus, patients who have an initial attack of arthritis with CPP crystals should have a workup including a chemistry screen; magnesium, calcium, and iron levels; and thyroid function tests.
• WBC count usually is elevated.
• Erythrocyte sedimentation rate (ESR) usually is elevated during acute attacks.
• Hyperuricemia may be present but is not diagnostic. Renal uric acid excretion should be obtained in high-risk patients, including those with renal calculi, strong family history of gout, and first attack before age 25 years.

Imaging Studies

• Radiographs
• • Plain radiographs of the affected joint or joints are indicated.
  • Radiographic lesions of chronic gout may appear as rat-bitten, sclerotic regions on the joint surfaces, with overhanging margins.
  • Patients with new onset of acute gout usually have no radiographic findings.
  • Patients with pseudogout usually have degenerative joint changes and may have calcifications in the soft tissues, tendons, or bursae.
• Bone scan reveals increased nuclide concentration at affected sites.
• MRI
• • MRI is capable of detecting crystal deposits but is not part of any routine evaluation for acute arthritis.
  • MRI can be very useful in determining the extent of the disease and may help in the differential diagnosis.
  • MRI with gadolinium is recommended to evaluate any tendon sheath involvement and when osteomyelitis in the differential diagnosis.
  • Large deposits of crystals may be seen in bursae or ligaments. Tophi usually are low or intermediate signal intensity on T1-weighted images.

Procedures

• Aspiration and biopsy
• • Joint aspiration is the principal procedure used to make the diagnosis of crystal-induced arthritis and to rule out septic joint effusion.
  • Biopsy of synovial membrane or subcutaneous nodule includes an examination with polarizing optics.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Emergency Department Care

• The temptation to treat patients without a proven diagnosis must be resisted. Unrecognized septic arthritis can lead to loss of life or of limb. Distinguishing septic arthritis from crystal-induced arthritis is not possible without an examination of joint fluid.
• Arthrocentesis is mandatory for all patients with new onset of acute monoarthritis and is very strongly recommended for those with recurrent attacks whose diagnosis has never been proven by microscopic visualization of crystals.
• Treatment of proven crystal-induced arthritis is directed at relief of the pain and inflammation. Narcotic pain relievers, nonsteroidal anti-inflammatory drugs (NSAIDs), and steroids are the mainstays of treatment.
• When comorbidities limit the use of NSAIDs or oral steroids (eg, a brittle diabetic with peptic ulcer disease), colchicine should be considered. However, a preferred option may be an intra-articular steroid injection, particularly when a large, easily accessible joint is involved.
• Patients should also be counseled to reduce comorbidities. They should be instructed to go on a diet if obese, to stop drinking beer, and to avoid purine-rich foods.

Consultations

• Orthopedic consultation is indicated for any patient with septic arthritis or for any patient in whom a septic arthritis cannot be ruled out.
• If the diagnosis has not been proven by microscopic examination of crystals under polarized light, refer the patient to a rheumatologist as soon as possible.
• Rheumatologic referral should be made for patients with new-onset crystal-induced arthritis. This is not an emergency and should be completed on an outpatient basis.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goal of pharmacotherapy is to terminate the acute attack, to prevent complications, and to prevent recurrent attacks.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Most commonly used for the relief of mild to moderate pain. Although the effects of NSAIDs in the treatment of pain tend to be patient specific, indomethacin usually is the DOC for the initial therapy. Other options include ibuprofen and naproxen.

Drug Category: Uricosuric agents

These agents increase renal clearance of uric acid by inhibiting the renal tubular reabsorption of uric acid.

Drug Category: Corticosteroids

These agents have anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli. Oral corticosteroids may be used for patients with gout or pseudogout who cannot tolerate NSAIDs. Although case reports of adrenal crisis related to multiple interarticular injections of steroids for gout have been documented, this has not been clearly proven.

Drug Category: Corticotropic hormones

These agents are used in diagnostic tests to differentiate primary adrenal insufficiency from secondary adrenal insufficiency. They have limited therapeutic value in conditions responsive to corticosteroid therapy where a corticosteroid should be the DOC.

Drug Category: Narcotics analgesics

Anti-inflammatory agents and other drugs that work against the intra-articular inflammatory process may take hours or days to relieve the pain of acute crystal-induced arthritis.

As in any severely painful condition, the pain of acute crystal-induced arthritis should be treated promptly in the ED. Narcotic analgesics should be used as necessary until the inflammatory process has begun to resolve.

Combinations of acetaminophen with oxycodone, hydrocodone, or codeine may be given orally every 4-6 hours as needed. In severe cases, morphine may be given IV or SC, or meperidine may be used IV or IM as indicated.

Drug Category: COX-2 inhibitors

These are a relatively new type of anti-inflammatory drug that are currently under scrutiny. By inhibition of cyclooxygenase-2, the vicious cycle of inflammation and pain caused by gout is impeded. COX-2 expression in monocytes has been suggested to be induced in response to urate crystals.

Several drugs in this class are currently under investigation and are suspected to be linked to an increased risk of cardiac disease. One of these drugs, rofecoxib (Vioxx), has already been removed from the market.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• No prophylactic or deterrent regimen for patients with idiopathic pseudogout is known. If an underlying metabolic problem is responsible for pseudogout, the arthritis may be cured when the underlying problem is addressed.
• Consumption of purine-rich foods increases the frequency of attacks in patients with gout. Alcohol, yeasty foods, oily fish, and liver have been implicated in gout attacks. A consultation with a dietitian may be helpful for such patients.
• Gout prophylaxis may be carried out with allopurinol (100-300 mg/d) or with a combination of colchicine (0.6 mg qd/bid) with probenecid (250-500 mg bid). Increasing dosage of or starting patients on probenecid and allopurinol is contraindicated during an acute attack of gouty arthritis. Long-term continuation is controversial.

Complications

• Gout patients who have a 24-hour urinary excretion of uric acid above 1100 mg have a 50% risk of developing urate and oxalate kidney stones. Those with a measured urate excretion greater than 800 mg per 24 hours may benefit from allopurinol prophylaxis to prevent urate nephropathy.
• Severe degenerative arthritis
• Secondary infections
• Recurrent painful episodes
• Carpal tunnel syndrome (rare)
• Urate or uric acid nephropathy
• Nerve or spinal cord impingement

Prognosis

• Gout
• • With early treatment, total control usually is attained.
  • If attacks recur, successful uric acid adjustment (requiring lifelong use of uricosuric or allopurinol medication) usually is effective.
  • During the first 6-24 months of uricosuric or allopurinol therapy, acute gout may occur.
• Pseudogout
• • Acute attacks usually resolve within 10 days. Prognosis for resolutions of acute attacks is excellent.
  • Some patients experience progressive joint damage with functional limitation.

Patient Education

• Advise patients to begin a low-purine diet.
• For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education article Gout.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose a septic joint in a patient with what is assumed to be an acute crystal-induced arthritis
• Failure to inform patient of the risks associated with medication used to treat crystal-induced arthritis

Special Concerns

• Posterior interosseous nerve syndrome has been reported because of elbow inflammation causing compression of the nerve. In patients presenting with a swollen elbow and inability to extend the fingers actively, this should be considered. Treatment with intra-articular steroids has led to resolution of the nerve palsy in a case report.
• Allopurinol is a drug that is a hypoxanthine analog. It is not used in acute gouty arthritis but is a competitive inhibitor of xanthine oxidase at low doses and is a noncompetitive inhibitor at high doses. This decreases the amount of uric acid produced. However, it is not innocuous and is associated with allopurinol hypersensitivity syndrome. It is also associated with the drug rash with eosinophilia and systemic symptoms (DRESS) syndrome.
• • Allopurinol hypersensitivity syndrome occurs in 2% of those on the drug. It entails a slight rash, which will usually resolve with discontinuation of the drug.
  • DRESS syndrome affects the liver, kidney, and skin. It is a delayed-hypersensitivity response occurring 6-8 weeks after beginning allopurinol. The underlying mechanism is thought to be a cell-mediated immunity to allopurinol and its metabolites. Although occurrence is 0.4 %, the rate of organ failure and death is high. Treatment is with intravenous N-acetyl cystine and steroids.
  • Accumulation of allopurinol and its metabolite oxypurinol is felt to increase the risk of hypersensitivity reaction. Dosing guidelines are being developed to decrease their accumulation based on creatinine clearance while decreasing the amount of serum uric acid.
• Because of the hypersensitivity syndromes associated with allopurinol, other uricosuric drugs have been investigated. These include probenecid, sulfinpyrazone, and benzbromarone. Although probenecid (1-2 g/d) and sulfinpyrazone were shown not to be as effective in lowering uric levels as allopurinol, they are not associated with DRESS syndrome. However, they cannot be used in patients with renal impairment. Benzbromarone can significantly reduce uric acid levels but is associated with hepatic problems and, in some cases, hepatic failure. For this reason, its use is restricted in the United States.
• Recent research has indicated that the lipid-lowering drug fenofibrate, a fibric acid derivative, will lower serum uric acid levels while reducing very-low-density lipoprotein (VLDL), total cholesterol, and triglyceride levels. However, the creatinine level increases, and all effects are negated once the drug has been discontinued.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Mar 14, 2007