Author(s): Daniela Mehech, MD, Kimberly Fazio, MD, MS, Sara Ernst, MD, PhD
Originally published: September 20, 2013 Last updated: April 20, 2023
Jump to:

Disease

Gout is a disease of purine metabolism characterized by acute, subacute, and chronic arthritis, due to deposits of needle shaped monosodium urate (MSU) crystals in joints, tendons, and subcutaneous tissues. Deposition of crystals leads to an acute inflammatory response and this monoarticular synovitis cause severe pain, swelling, redness and tenderness. The classic attack occurs in the first metatarsal phalangeal joint (podagra). However, both monoarticular and polyarticular arthritis is possible with affected joints including ankles, knees, hands, wrist and elbows; and thus, sometimes gout is overlooked as the etiology of joint pain.

Deposition of MSU crystals occur when uric acid levels change rapidly, usually in the setting of hyperuricemia (serum uric acid level greater than 6.9 mg/dL). Hyperuricemia can result from uric acid accumulation, especially with purine rich diet (i.e. red meats, shellfish, high fructose, liver, and alcohol), uric acid overproduction and/or decreased excretion of uric acid. Uric acid is excreted via the gastrointestinal tract and kidneys, with approximately 65% of uric acid excreted renally.1 An acute attack can be precipitated by physiological stressors such as situations causing a relatively rapid rise in uric levels including acute illness, myocardiac infarction, stroke, surgery, rapid volume changes, diuretics, large consumption of alcohol or purine rich foods, and low-dose aspirin can lead to a relatively rapid rise in uric acid levels precipitating an acute gout attack. Non-modifiable risk factors for gout include older age, male gender, post-menopausal women, congenital errors in purine metabolism (i.e., Lesch-Nyhan Syndrome), and African American ethnicity. Comorbidities associated with hyperuricemia include obesity, metabolic syndrome, type 2-diatetes mellitus, hypertension and chronic kidney disease.2

Pseudogout is a similar type of arthritis resulting from crystal deposition of calcium pyrophosphate (CPP) and is also known as calcium pyrophosphate deposition (CPPD) disease.3,4 It is thought that overproduction of inorganic pyrophosphate anions causes CPP crystals deposition in articular cartilage, fibrocartilage and sometimes in ligaments.5 These hyaline and/or fibrocartilage 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, but unlike gout, it involves men and women equally.4 Knees and wrists are most often involved, but other joints may be affected, including the symphysis pubis, hips, shoulders, ankles, and spine.

The prevalence of gout and pseudogout are difficult to estimate for several reasons. Definitive diagnosis of gout and pseudogout relies on crystal examination from fluid which is not commonly performed. Additionally, pseudogout can masquerade as osteoarthritis, gout, rheumatoid arthritis and neuropathic type joint disease. Lastly, pseudogout may be asymptomatic with the sole clinical manifestation as chondrocalcinosis incidentally noted on imaging. A community study from the United Kingdom described a 7% prevalence of chondrocalcinosis in knee x-rays of 1727 subjects, with a strong association with age.6 In the 2015–2016 National Health and Nutrition Examination Survey (NHANES), a stratified, multistage sample representative of the US adult population, the prevalence of self-reported, health professional-diagnosed gout was 3.9%.7,8

Essentials of Assessment

The classic gout attack appears as a sudden onset of pain, swelling, erythema, and warmth of the affected joint or joints. Symptoms typically peak within the first 24 hours and resolve within 5-14 days without treatment.1 Diagnosis is often delayed in cases with less typical presentations of gout attacks involving the wrist, elbow or when multiple joints are involved. On inspection, look for tophi whose presence usually indicates prolonged hyperuricemia and an increased likelihood of gout.

Although the classic gout attack is easily recognized, one should be aware of the broad differential diagnosis for both that of monoarticular and polyarticular arthritis as well as that of acute onset of severe foot pain. When assessing patients with any of these presentations it is important to consider the possibility of trauma, septic arthritis, Lyme disease, disseminated gonococcal infection, and autoimmune arthritis. It is important to be aware that gout can predispose a patient to septic arthritis. In a large cohort study from the UK, gout patients were 2.6 times more likely to be diagnosed with septic arthritis than the general population.8 Additionally, a differential diagnosis for an acute episode of severe foot pain should include 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.

The gold standard for diagnosis of acute gout attack is joint aspiration and visualization of the negatively birefringent needle shaped MSU crystals. Typically, the synovial fluid analysis will appear inflammatory with white blood cell count (WBC) ranging from 10,000-100,000. Other less specific and sensitive modalities of diagnosis include radiographs, ultrasound, or uric acid levels. While an elevated uric acid level is helpful to confirm gout, serum uric acid levels can be normal during an acute gout attack, leading to difficulty in making the diagnosis. This scenario is not uncommon, and in one study, it was normal in nearly 50% of acute cases.6 In such cases, gout is confirmed by identification of strongly negative birefringent urate crystals from the synovial fluid with a polarizing microscope. If joint aspiration and assessment of synovial fluid is unable to be obtained, one can consider obtaining subsequent uric acid levels over the next several months to check for hyperuricemia. Radiologic changes are not usually detectable in early stages of disease. Chronic gout arthritis can reveal subcortical cysts. Ultrasound may be useful in first gout attacks with the “double contour sign”, a hyperechoic linear density overlying the hyaline cartilage, being a highly specific diagnostic feature.1

Presentation of pseudogout varies from asymptomatic deposition of calcium pyrophosphate in the cartilage of the knees and wrist to arthralgia or acute synovitis of knees or wrists and less commonly symphysis pubis, hips, shoulders, ankles, and spine. When multiple joints are inflamed the presentation can mimic rheumatoid arthritis but, serology will be negative and x-rays confirm the calcification. Osteoarthritis (OA) of the metacarpophalangeal (MCP), exclusive of the thumb, does not usually occur, but can be seen in pseudogout, and is a clue to this diagnosis. The finding of OA of the MCP joins can also suggest an underlying etiology such as hemochromatosis or hyperparathyroidism leading to secondary CPP deposition.

The diagnosis of pseudogout 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, foot, hip, pubic symphysis, shoulder hip or spine. An unrelated hydroxyapatite calcification can occur in the rotator cuff as part of calcific tendinitis. Ultrasonography can detect chondrocalcinosis than can be visualized on radiograph.9 The crystal deposition occurs in the middle layer of the cartilage in pseudogout compared to the gout in which the crystal deposition is seen on the surface of the cartilage. This can be a distinguishing feature of ultrasonographic findings between the gout and pseudogout.

In addition 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 as high as is seen with septic arthritis, complicating the diagnosis.10

Because pseudogout can mimic many other rheumatic diseases, it is likely underdiagnosed. For example, elderly patients with polyarthritis due to CPP deposition are often misdiagnosed with RA. Conversely, the finding of chondrocalcinosis on x-ray does not prove that the joint symptoms are definitely due to CPP deposition. Lastly an uncommon but important presentation of pseudogout is the crowned dens syndrome.11 The diagnosis may be suggested by a rather acute onset of neck pain with limitation of motion on rotation, a slightly elevated CRP, and identification of CPPD in other joints. Confirmation of this diagnosis is by computed tomography (CT scan) showing the presence of calcific deposits around the odontoid process (dens) of the axis, appearing as a crowned arrangement around the dens.

Treatment

The foundation of management of gout, and particularly tophaceous gout, is well explained by Le Chatelier principle12, 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 strategies are different for acute gout, chronic tophaceous gout, and 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. Most commonly NSAIDs, glucocorticoids (oral or intraarticular), or colchicine are used in gout flare management, all with similar efficacy. Therefore, the best option must be chosen based on patient presentation (length of symptoms, number of gout flare recurrences) and patient comorbidities which may make one medication’s side effect profile more favorable than another.

Colchicine is a common choice for treatment of acute gout. Historically, colchicine was dosed as one 0.6 mg tablet every 1-2 hours until joint relief occurs or until nausea, vomiting or diarrhea make treatment intolerable. Studies now indicate that gout flares can be adequately treated with an initial starting dose of 1.2 mg followed by 0.6 mg one hour later then 2-3 tablets daily until symptoms resolve.13,14 In this manner gout flares are adequately treated while minimizing GI side effects.15 Possible drug interactions as well as renal or hepatic impairment can lead to higher levels of colchicine in the body increasing the risk of adverse effects. While renal or hepatic impairment is not an absolute contraindication to treatment with colchicine, each should be considered when choosing and dosing colchicine.

Nonsteroidal anti-inflammatory drugs (NSAID’s) are widely used to reduce acute inflammation, as in a gout attack.16-18 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. Other NSAID’s for acute gout include, but is not limited to, diclofenac, ibuprofen, naproxen, and nabumetone. 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. Adverse effects of NSAIDs include gastric irritation, peripheral edema, renal impairment, and in the elderly some dizziness and confusion. While NSAID’s are a mainstay of treatment, they have many contraindications including renal impairment, hyperkalemia, gastritis, gastric ulcers, moderate to severe heart failure, concurrent use of anticoagulants, and poorly controlled hypertension.

Oral prednisone is appropriate to treat an acute gout attack, particularly if gastrointestinal or renal impairments exist. Typical doses can range from 20 to 40mg daily for several days. An intramuscular (IM) injection of 40 mg of methylprednisolone is an effective option in some cases, followed by NSAIDs, or low dose of 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. Considerations when prescribing any form of glucocorticoid include diabetes, recent surgery, and confirmed or suspected active infection.

As an acute attack subsides, treatment will transition occurs from addressing the acute attack to prophylactic treatment. This period from gout flare to recurrent gout flare is called the inter-critical period. Often, urate lowering therapy (allopurinol, febuxostat) is started following resolution of acute gout flares. Given the high propensity for recurrent flares as the urate level is lowered toward normal, low dose colchicine or NSAIDS are usually co-prescribed for the first 3 months of urate lowering therapy.19

Severe purine-free dietary restrictions in gout are typically not helpful as they are impractical 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.6

Allopurinol (a xanthine oxidase inhibitor) is given to lower the serum urate level, starting at 100mg. daily.2,18 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 as needed, to a maximum dose of 800 mg daily, to lower the uric level to about 1.5 mg below the upper limit of normal value (goal 6.8 mg/dL or lower). Considerations when prescribing allopurinol include renal impairment and the rare possibility of a hypersensitivity reaction leading to Steven-Johnsons Syndrome, hepatitis, and renal failure.1

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 al19 were successful in treatment with allopurinol at a dose higher than the usual dose when based on creatinine clearance.

Febuxostat is another xanthine oxidase inhibitor which is useful when intolerance to allopurinol has occurred, such as rash or hypersensitivity reaction, and it can be used in patients with moderate renal insufficiency.21 The starting dose is 40 mg. daily and may be increased to 80 mg. Liver function must be monitored when prescribing febuxostat. As with allopurinol, gout flares can occur when first starting the drug without protection by colchicine or NSAIDs.

In patients who do not achieve therapeutic lowering of urate levels with or cannot tolerate xanthine oxidase inhibitors, probenecid may be trialed. Probenecid is considered a uricosuric which increases uric acid excretion in kidneys. Starting dose is 250mg twice daily. Uricosurics are contraindicated in renal impairment and have many drug interactions to consider.1

When tophaceous deposits are present, the goal is to treat to a target uric acid level of 4-5 mg/dl. At this level 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 have resolved, dosage may be reduced, but usually not discontinued.

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.

Cutting Edge Concepts in Practice

A recently developed imaging modality called Dual-Energy Computed Tomography (DECT) has been used to diagnose both gout and pseudogout. DECT is able to identify and differentiate between uric acid and calcium in musculoskeletal tissue. This can be helpful when there is a high clinical suspicion for gout or pseudogout but no crystals were identified through joint aspiration. DECT may also be able to identify deposits in asymptomatic patients during the inter-critical period. A recent metanalysis found DECT to have a high diagnostic accuracy with 84.7% sensitivity and 93.7% specificity. 1,22

Additional treatments for severe and refractory gout have been approved for use in appropriate patients who have failed first-line therapy. Thus far, studies have not shown these newer medications to be more effective than the traditional first-line agents mentioned above.

Pegloticase is a recombinant porcine-like uricase that converts uric acid to the more soluble compound allantoin. 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. There is a risk of allergic reactions during and after infusions.

One of the newer drugs for the treatment of hyperuricemia is lesinurad. Lesinurad works by a renal mechanism in reducing uric acid resorption in the proximal tubule of the kidney, thus increasing excretion of uric acid and lowering serum uric acid.22 It is given at a 200 mg daily in conjunction with allopurinol or febuxostat. A study completed in 2016 found superior urate lowering abilities with the combination of lesinurad and allopurinol versus allopurinol alone.24 The FDA approved use of lesinurad in 2016 only as a combination therapy with allopurinol in patients who have failed monotherapy. There is a warning of possible renal injury with this new drug.

References

  1. Sidari, Anthony, and Erica Hill. “Diagnosis and Treatment of Gout and Pseudogout for Everyday Practice.” Primary Care: Clinics in Office Practice, vol. 45, no. 2, 2018, pp. 213–236
  2. Khanna D, Fitzgerald JD, Khanna P, et al: American college of rheumatology guidelines for management of Gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care & Res. 2012;64:1431-1446.
  3. Rosenthal AK, Ryan LM:Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016 Ju30;374;26 2575-84
  4. Richette P, Bardin P, and Doherty, M: An update on the epidemiology of calcium pyrophosphate dehydrate crystal deposition disease. Rheumatology. 2009;48:711-715
  5. Chen-Xu, M., Yokose, C., Rai, S. K., Pillinger, M. H. & Choi, H. K. Contemporary prevalence of gout and hyperuricemia in the United States and decadal trends: the National Health and Nutrition Examination Survey, 2007–2016. Arthritis Rheumatol. 71, 991–999 (2019).
  6. Dore, RK: Gout: What Primary Care Physicians Want to Know. J Clin Rheumat. 2008;14:S47- S54.
  7. Dehlin, M., Jacobsson, L. & Roddy, E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol 16, 380–390 (2020).
  8. Lim, Sian Yik, et al. “Septic Arthritis in Gout Patients: A Population-Based Cohort Study.” Rheumatology, vol. 54, no. 11, 2015, pp. 2095–2099.
  9. Dufauret-Lombard C, Vergne-Salle P, Simon A, et al: Ultrasonography in Chondrocalcinosis. Joint, Bone, Spine. 2010;77:218-221.
  10. Hughes GM, Biundo JJ, Scheib JS, Et al: Pseudogout and pseudosepsis of the shoulder. Orthopedics 1990;13:1169-1172.
  11. Goto, S, Umehara J, Alzawa T, et al. Crowned Dens Syndrome. JBJS. 2007;89:2732-36
  12. Reference for Le Chatelier’s Principle. https://en.wikipedia.org/wiki/Le_Chatelier%27s_principle
  13. Qaseem A, Harris RP, Forciea MA, et al. Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2017;166(1):58-68. doi:10.7326/M16-0570
  14. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180
  15. Terkeltaub, Robert A., et al. “High versus Low Dosing of Oral Colchicine for Early Acute Gout Flare: Twenty-Four-Hour Outcome of the First Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Dose-Comparison Colchicine Study.” Arthritis & Rheumatism, vol. 62, no. 4, 2010, pp. 1060–1068., https://doi.org/10.1002/art.27327.
  16. Neogi T: Gout. NEJM. 2011;364:443-452.
  17. Khanna D, Fitzgerald JD, Khanna P, et al: American college of rheumatology guidelines for management of Gout. Part 2: Therapy and anti-inflammatory prophylaxis of acute gouty arthritis. Arthritis Care & Res. 2012;64:1447-1461.
  18. Rider TG, Jordan KM: The Modern management of gout. Rheumatology. 2010;49:5-14.
  19. Becker, Michael A., et al. “Determinants of the Clinical Outcomes of Gout during the First Year of Urate-Lowering Therapy.” Nucleosides, Nucleotides and Nucleic Acids, vol. 27, no. 6-7, 2008, pp. 585–591., https://doi.org/10.1080/15257770802136032.
  20. 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.
  21. 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.
  22. Lee, Young Ho, and Gwan Gyu Song. “Diagnostic Accuracy of Dual-Energy Computed Tomography in Patients with Gout: A Meta-Analysis.” Seminars in Arthritis and Rheumatism, vol. 47, no. 1, 2017, pp. 95–101.
  23. Zurampic (package insert) Wilmington, DE: AstraZenca; 2015
  24. Bardin, Thomas, et al. “Lesinurad in Combination with Allopurinol: A Randomised, Double-Blind, Placebo-Controlled Study in Patients with Gout with Inadequate Response to Standard of Care (the Multinational Clear 2 Study).” Annals of the Rheumatic Diseases, vol. 76, no. 5, 2016, pp. 811–820., https://doi.org/10.1136/annrheumdis-2016-209213.

Original Version of the Topic

Joseph J. Biundo, MD, Perry J. Rush, MD. Gout and pseudogout. 9/20/2013.

Previous Revision(s) of the Topic

Joseph J. Biundo, MD, Perry J. Rush, MD. Gout and pseudogout. 8/16/2017.

Author Disclosure

Daniela Mehech, MD
Nothing to Disclose

Kimberly Fazio, MD, MS
Nothing to Disclose

Sara Ernst, MD, PhD
Nothing to Disclose