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Gout is a disease of purine metabolism characterized by acute, subacute, and chronic arthritis, and deposits of urate crystals (known as tophi) in joints, tendons, and subcutaneous tissues. Gout attacks usually occur with an acute onset of monarticular synovitis in joints of the lower extremities causing severe pain, swelling, redness and tenderness. The classic attack occurs in the 1st MTP joint (podagra). However, gout can occur in ankles, knees, hands, wrist and elbows; and thus, sometimes gout is overlooked as the etiology. An acute attack can be precipitated by medically stressful situations causing a relatively rapid rise in uric levels including acute illness (e.g. myocardiac infarction, stroke), surgery, dehydration, diuretics, and low-dose aspirin.

Comorbidities that promote hyperuricemia have long been known. These include obesity, metabolic syndrome, type 2-diatetes mellitus, hypertension and chronic kidney disease.1

A second arthritis resulting from crystal deposition is calcium pyrophosphate deposition (CPPD) disease, also known as pseudogout for the acute attacks.2,3 CPPD crystals deposit in articular cartilage, fibrocartilage and sometimes in ligaments. These deposits have given rise to the use of chondrocalcinosis as an additional name of the condition, especially on x-ray reports. It affects older adults, involving men and women about equally.3 Knees and wrists are mostly involved, but other joints may be affected, including the symphysis pubis, hips, shoulders, ankles, and spine.

The prevalence of gout and CPPD Disease is difficult to measure. This is because the definitive diagnosis of gout and CPPD relies on crystal examination from fluid which is not commonly done. As well, CPPD can masquerade as osteoarthritis, gout, rheumatoid arthritis and neuropathic type joint disease. CPPD may be asymptomatic with the sole clinical manifestation as chondrocalcinosis. A community study from the United Kingdom described a crude prevalence of chondrocalcinosis of 7 % in knee x-rays of 1727 subjects, with a strong association with age.4 The prevalence of self- reported gout in US adults was 3.9% in 2007-2008.5


Although the classic gout attack is easily recognized, one should be aware that a history of acute onset of severe foot pain is not always due to gout. Sometimes the acute episode of severe foot pain could be due to critical illness ischemia, acute compartment syndrome, or herpes zoster infection. Musculoskeletal diagnosis such as a metatarsal stress fracture is considered however these diagnoses tend to be exacerbated by weight bearing activities and relieved by rest and off-loading in history. In contrast, acute gout pain continues at rest, and the site is more likely to be warm. A confusing picture can occur when less typical attacks of gout occur, involving the wrist, elbow or when multiple joints are involved. Always look for i tophi whose presence usually indicates prolonged hyperuricemia and the likelihood of gout. While an elevated uric acid level is helpful to confirm gout, a difficulty in diagnosis can arise when it is normal during an acute attack. This scenario is not uncommon, and in one study, it was normal in nearly 50% of acute cases.4 In such cases, as well as in more apparent cases, gout is confirmed by identification of strongly negative birefringent urate crystals from the synovial fluid with a polarizing microscope. If synovial fluid is unable to be obtained in such cases, then one must obtain subsequent uric acid determinations in the next several months to check for the appearance of hyperuricemia.

CPPD disease varies from asymptomatic deposition of calcium pyrophosphate in the cartilage of the knees and wrist to arthralgia or acute synovitis. Additional sites of acute symptoms may involve the other above described sites. The acute monarticular or oligoarticular attacks often involve the knee or wrist, and is often termed pseudogout. Less commonly, multiple joints are inflamed and give somewhat of an RA appearance. But, serology is negative and x-rays confirm the calcification. OA of the metacarpophalangeal (MCP), exclusive of the thumb, does not usually occur, but is seen in CPPD, and is a clue to this diagnosis. The finding of OA of the MCP joins is also a clue to an underlying etiology such as secondary CPPD due to hemochromatosis or hyperparathyroidism.

The diagnosis of CPPD disease is usually made by radiographic appearance of linear or stippled calcification of the articular cartilage of the knee or wrist, and at times in the ankle, shoulder hip or spine. Similar radiographic findings may be found in the symphysis pubis, hip, foot or shoulder. An unrelated hydroxyapatite calcification can occur in the rotator cuff as part of tendinitis. Ultrasonography can detect chondrocalcinosis in early states prior to visualization on radiograph.5 The crystal deposition occurs in the middle layer of the cartilage in CPPD compared to the gout for which the crystal deposition can be on the surface of the cartilage. This can be distinguishing feature of ultrasonographic findings between the gout and pseudogout. The exact mechanism causing the deposition of the CPPD crystals in joints is unknown.

In additional to imaging studies, examination of joint fluid under a polarizing microscope can show the weakly positive birefringent, rhomboid-shaped calcium pyrophosphate crystal characteristic of this condition. The synovial fluid WBC is usually elevated in an acute attack, and at times may be extremely high, and even in the septic range, complicating the diagnosis.6

Because CPPD disease can mimic many other rheumatic diseases, it is likely underdiagnosed. For example, RA could be misdiagnosed in the elderly with polyarthritis with polyarthritis due to CPPD. Conversely, the finding of chondrocalcinosis on x-ray does not prove that the joint symptoms are definitely due to CPPD.

An uncommon but important presentation of CPPD disease is the crowned dens syndrome.7 The diagnosis may be suggested by a rather acute onset of neck pain with limitation of motion on rotation, a somewhat elevated CRP, and the identification of CPPD in other joins. Confirmation of this diagnosis is by computed tomography showing the presence of calcific deposits around the odontoid process (dens) of the axis, in somewhat of a crowned arrangement around the dens.


Treatment strategies are different for acute gout, and for chronic tophaceous gout, and for asymptomatic hyperuricemia. A variety of options exist for the treatment of acute gout, and the focus is on reducing the inflammation, which is the cause of the pain. Colchicine is historically known for treatment of acute gout. However, the old regimen of one tablet of 0.6 mg of colchicine every 1-2 hours until joint relief or until nausea, vomiting on diarrhea occur has been long abandoned because in all cases nausea, vomiting or diarrhea will occur if 4 or more colchicine per day is given. Yet, colchicine at a dose of 3 tablets per day may be sufficient to treat an acute attack. Additionally, a dose of two tablets per day is sometimes given as a supplement to other treatment. Generally, the GI effects are not common at this low dose.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to reduce acute inflammation, as in a gout attack.8,9,10 Classically, indomethacin has been recommended at 50 mg. three times a day for several days, followed by 25 mg. four times a day, and tapered as the attack subsides. Although potent, this drug also has adverse reactions including gastric irritation, peripheral edema, renal impairment, and in the elderly some dizziness and confusion. Other NSAIDs for acute gout include diclofenac, ibuprofen, naproxen, and nabumetone and others. In general a larger dose may be used in the first 2 days of treatment, and then followed by a more conventional dose until the attack is over.

Oral prednisone is appropriate to treat an acute attack, particularly if GI or renal impairments exist, at a total daily dose of 20-30mg in divided doses for several days. An intramuscular (IM) injection of 40 mg. of methylprednisolone is an effective option in some cases, followed by NSAID’s, or low dose oral prednisone or two colchicine tablets daily. As another option, intra-articular corticosteroids may be used in acute gout in the larger joints like the knee, wrist or ankle, especially if GI problems exist.

As an acute attack subsides, a transition occurs from treatment of the acute attack to prophylactic treatment to prevent further acute attacks. Treatment to decrease the uric acid level to a normal value is started, and colchicine 0.6 mg twice a day is prescribed to prevent attacks during this period. In some cases, low dose NSAIDS could be substituted for the colchicine.

Severe dietary restrictions in gout are not usually very helpful because a total purine-free diet is not practical and would lower the serum uric acid level by only 1 mg/dL. However, certain high purine foods should be restricted, including anchovies, sardines, liver, kidney and large amount of shell fish.4

Allopurinol (a xanthine oxidase inhibitor) is given to lower the serum urate level, starting at 100mg. daily.1,10 This initial lower dose is chosen over a 300 mg dose to lessen the possibility of a flare-up of acute gout by a more rapid drop in uric acid level. Allopurinol is gradually increased to a dose needed to lower the uric level to about 1.5 mg below the normal value with the goal of preventing any future attacks.

A newer xanthine oxidase inhibitor is febuxostat.11 It is useful when some intolerance to allopurinol has occurred, such as a skin rash, or when moderate renal insufficiency is present. The starting dose is 40 mg. daily and may be increased to 80 mg. Liver function needs to be monitored. As with allopurinol, gout flares can occur when first starting the drug without protection by colchicine or NSAIDs.

In gout with mild hyperuricemia the usual maintenance allopurinol dose ranges from 100 to 300 mg daily. For moderately severe to severe tophaceous gout the dose may be increased to 400 to 600 mg daily. Contrary to some reports, 300 mg is not the maximum daily dose of allopurinol. In fact, the manufacturer’s recommended maximum dose is 800 mg daily. Stamp et al12 were successful in treatment with allopurinol at a dose higher than the usual dose when based on creatinine clearance.

When tophaceous deposits are present, the goal is to treat to a target uric acid level of 4-5 mg/dl. Thus the tophi can slowly decrease in size and resolve over 1-3 years with allopurinol therapy and prophylactic colchicine. After serum urate levels are controlled and tophi are resolved, dosage may be reduced, but usually not discontinued.

The foundation of management of gout, and particularly tophaceous gout, is well explained by Le Chatelier principle13, reflecting an equilibrium in changes of serum urate levels and urate deposits in joints. Hyperuricemia leads to joint deposition. Conversely, as serum urate level is lowered, the urate crystal deposits in the joints are solubilized, and phagocytosis of the crystals can initiate an acute attack. This is the explanation of why acute attacks can occur when uric acid is being decreased to normal by allopurinol. Colchicine is needed to prevent this potential acute attack.

Treatment of acute attacks of CPPD disease includes the usual treatments of acute arthritis including NSAIDs, oral steroids, and intra-articular steroids. Colchicine has also been used for acute attacks, and also for prophylaxis, with varying success. There is no proven medication that can remove CPPD crystal deposits from the joint.


A newer drug approved for gout is a recombinant porcine-like uricase, pegloticase. It is indicated for patients with severe, tophaceous gout unresponsive to other traditional treatment and is given intravenously every 2 weeks for 3 to 6 months. It is expensive, and oral xanthine oxidase inhibitors are capable of reducing large tophi over time when given at the proper dose. One must be aware of possible allergic reactions. The newest drug for hyperuricemia is lesinurad (urate transporter inhibitor), which works by a renal mechanism in reducing uric acid resorption in the proximal tubule, thus lowering serum uric acid.14 It is given at a 200 mg. dose daily in conjunction with allopurinol or febuxostat. There is a warning of possible renal injury with this new drug.


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  7. Goto, S, Umehara J, Alzawa T, et al. Crowned Dens Syndrome. JBJS. 2007;89:2732-36
  8. Neogi T: Gout. NEJM. 2011;364:443-452.
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  10. Rider TG, Jordan KM: The Modern management of gout. Rheumatology. 2010;49:5-14.
  11. Becker MA, Schumacher HR, Espinoza LR, Wells AF, McDonals P, Loyd E, et al. The urate lowering efficacy and safety of febuxostat in the treatment of hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 2010; 12(2):R63.
  12. Stamp LK, O’Donnell JL, Zhang M, et al: Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum. 2011;63:412-421.
  13. Reference for Le Chatelier’s Principle. https://en.wikipedia.org/wiki/Le_Chatelier%27s_principle
  14. Zurampic (package insert) Wilmington, DE: AstraZenca; 2015

Original Version of the Topic

Joseph J. Biundo, MD, Perry J. Rush, MD. Gout and pseudogout. 09/20/2013.

Author Disclosure

Joseph J. Biundo, MD
Nothing to Disclose

Perry J. Rush, MD
Nothing to Disclose