Author(s): Michael Greenberg, MD, Maria Pereira, MD, Stephen Schaaf, MD, Erin Chew, MD
Originally published: September 20, 2013 Last updated: May 7, 2026
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Disease

Gout

Gout is the most common type of inflammatory arthritis, affecting an estimated 12.1 million adults, or 5.1% of the United States population.1 Gout is a disease of purine metabolism resulting in elevated serum uric acid levels and subsequent deposition of needle-shaped monosodium urate (MSU) crystals in joints and periarticular structures.

The classic description of an acute gout flare is the sudden onset of a swollen, red first metatarsal-phalangeal joint, also known as podagra. Destabilization of uric acid crystals in joints triggers an acute inflammatory response, leading to joint synovitis with severe pain, swelling, and erythema. Symptoms typically peak within the first 24 hours and resolve over 5-14 days without treatment.3

However, gout can present in a variety of ways, ranging from asymptomatic hyperuricemia to acute gouty arthritis (flares) and chronic tophaceous gouty arthritis. Both monoarticular and polyarticular acute and chronic arthritis are possible, affecting the ankles, knees, hands, wrists, and elbows; thus, gout is sometimes overlooked as the etiology of joint pain.

Deposition of MSU crystals can occur in joints when serum uric acid is above the threshold of solubility (uric acid ≥ 6.8 mg/dL).1 Hyperuricemia can result from uric acid overproduction, decreased excretion of uric acid, or acid accumulation, especially with a purine-rich diet (i.e., red meats, shellfish, high fructose, liver, and alcohol).2 Uric acid is excreted via the gastrointestinal tract and kidneys, with approximately 65% excreted renally.3 Several key “carrier molecules” mediate uric acid excretion in the kidneys and the gut. URAT1 (SLC22A12) and GLUT9 (SLC2A9) are primarily reabsorptive transporters in the kidney.2 Variants (polymorphisms) in these genes are strongly linked to “underexcretion,” where the kidneys fail to remove enough uric acid.2 BCRP (ABCG2) is a secretory transporter found in both the kidney and the gut.2 Dysfunction in the BCRP (ABCG2) transporter leads to reduced uric acid elimination in the intestines.2 Subsequent compensatory secretion of uric acid by the kidneys can lead to the “overexcretor paradox,” where patients may have “normal” or even “high” urinary uric acid levels but are still hyperuricemic because their overall body elimination is defective.2

Other 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. An acute gout attack is often precipitated by physiological stressors that drive sudden shifts in uric acid levels, including acute illnesses, myocardial infarctions, stroke, surgery, rapid volume changes, and low-dose aspirin.

CPPD

Calcium pyrophosphate deposition (CPPD) disease is an inflammatory arthritis caused by the deposition of calcium pyrophosphate (CPP) crystals.4,5 Overproduction of inorganic pyrophosphate anions causes CPP crystals deposition in joints and musculoskeletal soft tissues, particularly the cartilage.6 These hyaline and/or fibrocartilage deposits are visualized as chondrocalcinosis on radiographs. CPPD tends to affect 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, elbows, ankles, and spine.

CPPD can present in a variety of ways, mimicking both non-inflammatory and inflammatory arthritis. Although, pseudogout may be asymptomatic, with the sole clinical manifestation as chondrocalcinosis incidentally noted on imaging. A community study in the United Kingdom reported a 7% prevalence of chondrocalcinosis on knee x-rays in 1727 subjects, with a strong association with advanced age.7 Thus, the finding of chondrocalcinosis imaging may be incidental and does not prove that joint symptoms are due to CPP deposition.

Essentials of Assessment

The differential diagnosis for acute joint pain includes both inflammatory and non-inflammatory causes of monoarticular and polyarticular arthritis. For monoarticular arthritis, it is crucial to evaluate for a history of trauma and potential septic arthritis. Notably, gout increases risk for 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 Polyarticular arthritis warrants evaluation for atypical infections such as Lyme disease, parvovirus, or disseminated gonococcal infection. Other rheumatologic causes of arthritis may be considered, though these develop more gradually over weeks to months. Musculoskeletal diagnoses, such as joint osteoarthritis, sprains, and strains, should also be considered; however, these diagnoses tend to be exacerbated by weight-bearing activities and relieved by rest and off-loading, as noted in the history. In contrast, acute crystalline arthritis flares persist at rest, and the joint is more likely to be warm and erythematous.

Gout

Diagnosis may be delayed in gout attacks involving atypical joints such as the wrist or elbow, or in cases where multiple joints are involved. In patients with longstanding gout, physical exam may reveal tophi, white, chalky nodules, especially in cooler areas of the body, such as the cartilage of the ears and the extensor surfaces of the elbows. The gold standard for diagnosing an acute gout attack is joint aspiration and synovial fluid analysis, with visualization of negatively birefringent, needle-shaped MSU crystals. Typically, synovial fluid analysis will appear inflammatory, with a white blood cell count (WBC) ranging from 2,000 to 100,000/µL. Other supportive diagnostic modalities include radiographs, ultrasound, and uric acid levels. While elevated uric acid levels may help support a gout diagnosis, serum uric acid levels are often low or normal during an acute gout attack because some inflammatory cytokines are uricosuric, lowering serum uric acid during the acute flare. This scenario is not uncommon, and in one study, it was normal in nearly 50% of acute cases.7 If joint aspiration and assessment of synovial fluid are unable to be obtained, one can consider obtaining subsequent uric acid levels over the next several months to check for hyperuricemia after the acute flare has resolved. Dual-energy CT (DECT) can be a helpful imaging modality for identifying the location and volumetric density of uric acid deposits, even in asymptomatic patients during the intercritical period. A recent meta-analysis found DECT to have a high diagnostic accuracy with 84.7% sensitivity and 93.7% specificity.1,21 Radiologic changes are not usually detectable in the early stages of the disease. However, in long-standing gouty arthritis, subcortical cysts and “rat tooth”- shaped periarticular erosions with an overhanging edge may be seen. Ultrasound is also a valuable imaging modality that can visualize the uric acid crystals within the joint. On ultrasound, the “double contour sign” can be seen at the affected joint, which is a hyperechoic linear density of the uric acid crystals overlying the joint hyaline cartilage that has a high sensitivity (83%) and specificity (76%) for gout.1,3,8

CPPD

The gold standard for the diagnosis of CPPD is also joint aspiration and synovial fluid analysis, which demonstrates weakly positive birefringent, rhomboid-shaped calcium pyrophosphate crystals under polarizing microscopy. Joint aspiration and visualization of CPPD crystals is not always possible, and the diagnosis of CPPD is usually supported by the radiographic appearance of linear or stippled calcification of the articular hyaline or fibrocartilage of the knee or wrist, and at times in the ankle, foot, hip, pubic symphysis, shoulder, or spine. Ultrasound can also detect chondrocalcinosis, which may not be visualized on radiographs.9 On ultrasound, crystal deposition of the affected joint occurs in the middle layer of the hyaline cartilage in CPPD, giving a speckled appearance, compared to gout, in which the crystal deposition is seen on the surface of the cartilage. This can be a distinguishing sonographic feature between gout and CPPD.10

Diagnosing CPPD is particularly challenging due to its wide range of clinical presentations, and confirmation requires integration and combination of findings from the physical exam, imaging studies, and laboratory testing.

Acute monoarticular CPP crystal arthritis is often clinically indistinguishable from gout in the acute setting unless aspiration and CPP crystal visualization are possible. The synovial fluid WBC count is usually elevated in an acute attack and, at times, may be as high as in septic arthritis, complicating the diagnosis.11 Although, uric acid levels are often normal outside of the acute flare, unlike in gout.

When multiple small joints are chronically inflamed, CPPD can mimic rheumatoid arthritis, often termed “pseudo-RA.” Elderly patients with inflammatory arthritis of hands and wrists due to CPP deposition are often misdiagnosed with seronegative RA. Serologies for rheumatoid arthritis (RF and CCP) are usually negative, and x-rays may demonstrate chondrocalcinosis in the triangular fibrocartilage. In addition, radiographs and ultrasound may demonstrate pericapsular hyperechoic calcifications to support the diagnosis.

Another phenotype of CPPD is osteoarthritis (OA) of the metacarpophalangeal (MCP) joints, characterized by hook-shaped osteophytes in the MCPs, an unusual site for classic hand OA. The finding of osteophytes of the MCP joints in a young patient under 40 years old can also suggest an underlying etiology, such as hemochromatosis or hyperparathyroidism, leading to secondary CPP deposition.12

Lastly, an uncommon but important presentation of CPPD is the crowned dens syndrome.13 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), which shows calcific deposits around the odontoid process (dens) of the axis, appearing as a crown-like arrangement.

Treatment

Gout

Treatment modalities for gout aim to reduce inflammation and serum uric acid levels. Anti-inflammatory medications are the mainstay for managing acute flares and providing prophylaxis, while urate-lowering therapy (ULT) is used to prevent disease progression, promote tophi resolution, and reduce the recurrence of gout flares.1

Management of acute gout flares is guided by the severity of symptoms and the number of joints involved. For mild to moderate pain affecting one or a few joints, first-line therapy includes nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or glucocorticoids, with selection based on patient-specific comorbidities and contraindications. In cases of monoarticular involvement, a guided intra-articular glucocorticoid injection may provide effective, targeted relief. For polyarticular flares or more severe presentations, combination therapy may be required, such as colchicine with NSAIDs, oral, or multiple guided intra-articular glucocorticoid injections.1

In addition to selecting appropriate therapy, understanding the dosing and safety considerations of anti-inflammatory agents is essential for effective and safe treatment. Colchicine should ideally be started within 12 hours of flare onset and is typically dosed with a loading dose of 1.2 mg, followed by 0.6 mg 1 hour later, then 2-3 tablets daily until symptoms resolve, for up to 14 days.1,14–16 Colchicine should be avoided in patients with moderate to severe renal or hepatic dysfunction and concurrent use of a CYP3A4 inhibitor, as this can increase the likelihood of toxicity, which can present as gastrointestinal symptoms, myelosuppression, and multiorgan failure. Naproxen is a commonly used NSAID, with typical dosing of 500 mg twice daily until the flare resolves. Although NSAIDs are a mainstay of treatment, they have various contraindications, including significant renal impairment, hyperkalemia, gastritis, gastric ulcers, moderate to severe heart failure, concurrent use of anticoagulants, and poorly controlled hypertension. Oral prednisone is a glucocorticoid that may be used if contraindications to NSAID or colchicine use exist. It is typically dosed at 0.5 mg/kg daily for the first three days, followed by a taper to complete a 10-14 day course. Important considerations when prescribing any form of glucocorticoid include uncontrolled diabetes, recent surgery, and confirmed or suspected active infection.

For those with refractory symptoms or contraindication to colchicine, NSAIDs, or steroids, IL-1 inhibitors can be considered. IL-1 is a critical driver of inflammation in gout, as it is a primary cytokine in the acute inflammatory response to monosodium urate crystals. Canakinumab, an IL-1 inhibitor, is more effective than traditional agents and is FDA-approved for treating gout flares; however, its high cost limits its clinical use. Therefore, Anakinra, another IL-1 inhibitor, is commonly used off-label for refractory gout flares.1 Anakinra is typically dosed at 100 mg subcutaneously daily for 3 days.1 Anakinra should be avoided in patients taking tacrolimus and other immunosuppressive therapies, given the high risk of infection.

While these therapies are effective for controlling acute inflammation, they do not address the underlying hyperuricemia that drives gout. Long-term management, therefore, focuses on urate-lowering therapy (ULT), which reduces serum urate levels, prevents recurrent flares, and promotes resolution of tophaceous deposits. Although ULT was historically avoided during acute flares due to concerns about exacerbating symptoms, current evidence indicates that the risk of flare is related to the initiation of ULT itself, not to its timing relative to a flare. Therefore, ULT should be started during an acute episode, when indicated, per the latest American College of Rheumatology (ACR) guidelines as outlined below.

Initiation of ULT is recommended for patients with two or more gout flares per year, a tophus on physical exam, or erosions on imaging. Additional indications include moderate to severe chronic kidney disease (CKD stage ≥ 3), marked hyperuricemia (serum urate > 9 mg/dL), or nephrolithiasis. Treatment should be initiated alongside anti-inflammatory prophylaxis, typically with colchicine or NSAIDs, for 3-6 months. Dosing is gradually increased every 3-6 weeks to reach the target serum urate <6 mg/dL, and both ULT and anti-inflammatory prophylaxis should be continued even if flares occur during the initiation phase.1

First-line options for ULT include xanthine oxidase inhibitors, which inhibit urate synthesis, such as allopurinol and febuxostat. In patients who do not achieve a therapeutic lowering of urate levels with xanthine oxidase inhibitors or cannot tolerate them, probenecid, which increases urate renal excretion, may be considered.

As mentioned above, various pharmacologic classes are available for ULT, all with distinct mechanisms and clinical considerations. Allopurinol is initiated at 100 mg daily and gradually increased by 100 mg every 4-6 weeks in individuals with normal renal function, up to a maximum of 800 mg daily.1 In patients with renal impairment, lower starting doses and slower titration (e.g., 50 mg increments every 4-6 weeks) are recommended. Additional considerations when prescribing allopurinol include the rare possibility of a hypersensitivity reaction leading to Stevens-Johnson Syndrome, hepatitis, and renal failure.1 The goal of ULT treatment is to lower the uric level to approximately 1.5 mg below the upper limit of normal value (goal varies in ACP and ACR guidelines, but the target should be 6.0 mg/dL or lower). Febuxostat is an alternative xanthine oxidase inhibitor that may be used when intolerance to allopurinol occurs, such as rash or hypersensitivity reaction, and is suitable for patients with moderate renal insufficiency.1 It is started at 40 mg daily and may be increased to 80 mg as needed, with monitoring of liver function tests. As with all ULT, gout flares can occur when first starting the drug without concomitant colchicine or NSAID use. Probenecid, a uricosuric agent, may be combined with a xanthine oxidase inhibitor for ULT. However, probenecid is seldom used given its low efficacy and increased rate of side effects.1 The typical starting dose is 250 mg twice daily, but patients may require up to 2-3 grams per day in two divided doses. Uricosurics are contraindicated in renal impairment, increase the risk of nephrolithiasis, and have many drug interactions to consider, including NSAIDs and penicillin.1

In patients with tophaceous gout, ULT is considered first-line therapy, with the target urate levels of 4–5 mg/dL to promote gradual tophi resolution over 1–3 years. After serum urate levels are controlled and tophi have resolved, allopurinol dosage may be reduced, but usually not discontinued.

In terms of lifestyle modification, 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, large amounts of shellfish, liver, kidney, red meats, and alcohol.1

CPPD

Treatment of acute CPPD is similar to treatment of acute gout flares with NSAIDs, oral steroids, and guided intra-articular glucocorticoid injections. However, results from the COLCHICORT trial recommend first-line use of 30 mg oral prednisone daily in acute CPP-crystal arthritis. Unlike the treatment for gout flares, a 2-day regimen of prednisone and colchicine was sufficient to achieve a good response by day 3. If colchicine is chosen, early administration (<12 h after arthritis onset) is key to achieving a favorable response for CPPD.19 Adjunctive treatment with magnesium supplementation (30 mmol/day) also showed promising results on reducing inflammatory symptoms of CPPD, including joint swelling and stiffness.20 However, these results have not been confirmed in a large clinical trial.

Of note, chronic inflammatory CPPD treatment may need to be treated concomitantly with a referral to a rheumatologist to use chronic colchicine, methotrexate, hydroxychloroquine, or IL-6 inhibitors. Unfortunately, there is currently no medication proven to remove CPPD crystal deposits from the joint once this has occurred.

Cutting Edge Concepts in Practice

Gout

If tophaceous gout is refractory to maximum doses of ULTs such as allopurinol, a rheumatology referral should be made for consideration of pegloticase. Pegloticase is a recombinant porcine-like uricase that converts uric acid to the more soluble compound allantoin.1 A history of G6PD deficiency is a contraindication, and caution is advised in patients with congestive heart failure. Pegloticase is dosed as an 8mg IV infusion every two weeks for 3 to 6 months. However, there is a significant risk of antibody development, leading to subsequent infusion reactions and anaphylaxis. However, in 2022, the FDA approved co-administration of methotrexate along with pegloticase to prevent the development of anti-drug antibodies and support a more complete response to therapy.17

CPPD

Though a mainstay diagnostic tool for gout, DECT imaging may also have value in detecting calcium pyrophosphate crystals, especially in sites less accessible to ultrasound, such as the spine. This can be helpful when there is a high clinical suspicion for gout or CPPD, but no crystals are identified on joint aspiration.18

References

  1. FitzGerald JD. Gout. Ann Intern Med. 2025;178(3):ITC33-ITC48. doi:10.7326/ANNALS-24-03951
  2. BECKER MA, SIMKIN PA, SORENSEN LB. Urate Transporters: Transforming the Face of Hyperuricemia and Gout. J Rheumatol. 2014;41(10):1910-1912. doi:10.3899/jrheum.141019
  3. Sidari A, Hill E. Diagnosis and Treatment of Gout and Pseudogout for Everyday Practice. Prim Care. 2018;45(2):213-236. doi:10.1016/j.pop.2018.02.004
  4. Rosenthal AK, Ryan LM. Calcium Pyrophosphate Deposition Disease. N Engl J Med. 2016;374(26):2575-2584. doi:10.1056/NEJMra1511117
  5. Richette P, Bardin T, Doherty M. An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease. Rheumatology. 2009;48(7):711-715. doi:10.1093/rheumatology/kep081
  6. Chen-Xu M, Yokose C, Rai SK, Pillinger MH, Choi HK. Contemporary Prevalence of Gout and Hyperuricemia in the United States and Decadal Trends: The National Health and Nutrition Examination Survey, 2007-2016. Arthritis Rheumatol. 2019;71(6):991-999. doi:10.1002/art.40807
  7. Dore RK. Gout: what primary care physicians want to know. J Clin Rheumatol Pract Rep Rheum Musculoskelet Dis. 2008;14(5 Suppl):S47-54. doi:10.1097/RHU.0b013e3181896c35
  8. Ogdie A, Taylor W, Weatherall M, et al. AB0826 Imaging Modalities for the Classification of Gout: Systematic Literature Review and Meta-Analysis. Ann Rheum Dis. 2014;73(Suppl 2):1076-. doi:10.1136/annrheumdis-2014-eular.1774
  9. Dufauret-Lombard C, Vergne-Salle P, Simon A, Bonnet C, Treves R, Bertin P. Ultrasonography in chondrocalcinosis. Joint Bone Spine. 2010;77(3):218-221. doi:10.1016/j.jbspin.2009.12.001
  10. Jacobsson J. Fundamentals of Musculoskeletal Ultrasound: 4th Edition. 4th ed. 2025.
  11. Hughes GM, Biundo JJ, Scheib JS, Kumar P. PSEUDOGOUT AND PSEUDOSEPSIS OF THE SHOULDER. Orthop Thorofare NJ. 1990;13(10):1169-1172. doi:10.3928/0147-7447-19901001-15
  12. Pascart T, Filippou G, Lioté F, Sirotti S, Jauffret C, Abhishek A. Calcium pyrophosphate deposition disease. Lancet Rheumatol. 2024;6(11):e791-e804. doi:10.1016/S2665-9913(24)00122-X
  13. Goto S, Umehara J, Aizawa T, Kokubun S. Crowned Dens syndrome. J Bone Joint Surg Am. 2007;89(12):2732-2736. doi:10.2106/JBJS.F.01322
  14. 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
  15. Chen-Xu M, Yokose C, Rai SK, Pillinger MH, Choi HK. Contemporary Prevalence of Gout and Hyperuricemia in the United States and Decadal Trends: The National Health and Nutrition Examination Survey, 2007-2016. Arthritis Rheumatol. 2019;71(6):991-999. doi:10.1002/art.40807
  16. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res. 2020;72(6):744-760. doi:10.1002/acr.24180
  17. Botson JK, Tesser JRP, Bennett R, et al. Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR). J Rheumatol. 2021;48(5):767-774. doi:10.3899/jrheum.200460
  18. Imaging of crystalline arthropathy in 2020 – ClinicalKey. Accessed April 23, 2026. https://www-clinicalkey-com.proxy.library.vanderbilt.edu/#!/content/journal/1-s2.0-S1521694220301121

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.

Daniela Mehech, MD, Kimberly Fazio, MD, MS, Sara Ernst, MD, PhD. Gout and Pseudogout. 4/20/2023

Author Disclosure

Michael Greenberg, MD
Nothing to Disclose

Maria Pereira, MD
Nothing to Disclose

Stephen Schaaf, MD
Nothing to Disclose

Erin Chew, MD
Nothing to Disclose