clinical presentation of gout

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Gout is a common and complex form of arthritis that can affect anyone. It's characterized by sudden, severe attacks of pain, swelling, redness and tenderness in one or more joints, most often in the big toe.

An attack of gout can occur suddenly, often waking you up in the middle of the night with the sensation that your big toe is on fire. The affected joint is hot, swollen and so tender that even the weight of the bedsheet on it may seem intolerable.

Gout symptoms may come and go, but there are ways to manage symptoms and prevent flares.

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Gout causes intense pain and swelling around one or more joints. Gout most commonly affects the joint at the base of the big toe.

The signs and symptoms of gout almost always occur suddenly, and often at night. They include:

• Intense joint pain. Gout usually affects the big toe, but it can occur in any joint. Other commonly affected joints include the ankles, knees, elbows, wrists and fingers. The pain is likely to be most severe within the first four to 12 hours after it begins.
• Lingering discomfort. After the most severe pain subsides, some joint discomfort may last from a few days to a few weeks. Later attacks are likely to last longer and affect more joints.
• Inflammation and redness. The affected joint or joints become swollen, tender, warm and red.
• Limited range of motion. As gout progresses, you may not be able to move your joints normally.

When to see a doctor

If you experience sudden, intense pain in a joint, call your doctor. Gout that goes untreated can lead to worsening pain and joint damage. Seek medical care immediately if you have a fever and a joint is hot and inflamed, which can be a sign of infection.

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Gout occurs when urate crystals accumulate in your joint, causing the inflammation and intense pain of a gout attack. Urate crystals can form when you have high levels of uric acid in your blood. Your body produces uric acid when it breaks down purines — substances that are found naturally in your body.

Purines are also found in certain foods, including red meat and organ meats, such as liver. Purine-rich seafood includes anchovies, sardines, mussels, scallops, trout and tuna. Alcoholic beverages, especially beer, and drinks sweetened with fruit sugar (fructose) promote higher levels of uric acid.

Normally, uric acid dissolves in your blood and passes through your kidneys into your urine. But sometimes either your body produces too much uric acid or your kidneys excrete too little uric acid. When this happens, uric acid can build up, forming sharp, needlelike urate crystals in a joint or surrounding tissue that cause pain, inflammation and swelling.

Risk factors

You're more likely to develop gout if you have high levels of uric acid in your body. Factors that increase the uric acid level in your body include:

• Diet. Eating a diet rich in red meat and shellfish and drinking beverages sweetened with fruit sugar (fructose) increase levels of uric acid, which increase your risk of gout. Alcohol consumption, especially of beer, also increases the risk of gout.
• Weight. If you're overweight, your body produces more uric acid and your kidneys have a more difficult time eliminating uric acid.
• Medical conditions. Certain diseases and conditions increase your risk of gout. These include untreated high blood pressure and chronic conditions such as diabetes, obesity, metabolic syndrome, and heart and kidney diseases.
• Certain medications. Low-dose aspirin and some medications used to control hypertension — including thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors and beta blockers — also can increase uric acid levels. So can the use of anti-rejection drugs prescribed for people who have undergone an organ transplant.
• Family history of gout. If other members of your family have had gout, you're more likely to develop the disease.
• Age and sex. Gout occurs more often in men, primarily because women tend to have lower uric acid levels. After menopause, however, women's uric acid levels approach those of men. Men are also more likely to develop gout earlier — usually between the ages of 30 and 50 — whereas women generally develop signs and symptoms after menopause.
• Recent surgery or trauma. Experiencing recent surgery or trauma can sometimes trigger a gout attack. In some people, receiving a vaccination can trigger a gout flare.

Complications

People with gout can develop more-severe conditions, such as:

• Recurrent gout. Some people may never experience gout signs and symptoms again. Others may experience gout several times each year. Medications may help prevent gout attacks in people with recurrent gout. If left untreated, gout can cause erosion and destruction of a joint.
• Advanced gout. Untreated gout may cause deposits of urate crystals to form under the skin in nodules called tophi (TOE-fie). Tophi can develop in several areas, such as your fingers, hands, feet, elbows or Achilles tendons along the backs of your ankles. Tophi usually aren't painful, but they can become swollen and tender during gout attacks.
• Kidney stones. Urate crystals may collect in the urinary tracts of people with gout, causing kidney stones. Medications can help reduce the risk of kidney stones.
• Gout. Centers for Disease Control and Prevention. https://www.cdc.gov/arthritis/basics/gout.html. Accessed Dec. 23, 2020.
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Gout and Pseudogout Clinical Presentation

• Author: Bruce M Rothschild, MD; Chief Editor: Herbert S Diamond, MD  more...
• Sections Gout and Pseudogout
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Complications
• Approach Considerations
• Synovial Fluid Analysis
• Serum Uric Acid
• Urinary Uric Acid
• Blood Studies
• Radiography
• Ultrasonography
• Computed Tomography
• Magnetic Resonance Imaging
• Treatment of Acute Attacks
• Treatment of Chronic Gout
• Diet and Activity
• Consultations
• Long-Term Monitoring
• Guidelines Summary
• American College of Rheumatology Guidelines
• American College of Physicians Guidelines
• Medication Summary
• Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
• Uricosuric Agents
• Corticosteroids
• Xanthine Oxidase Inhibitors
• Selective Uric acid Reabsorption Inhibitor (SURI)
• Rheumatologics, Other
• Interleukin Inhibitors
• Corticotropic Hormones
• Questions & Answers
• Media Gallery

The spontaneous onset of excruciating pain, edema, and inflammation in the metatarsal-phalangeal joint of the great toe (podagra; see the image below) is highly suggestive of acute crystal-induced arthritis. Podagra is the initial joint manifestation in 50% of gout cases; eventually, it is involved in 90% of cases. Podagra is not synonymous with gout, however: it may also be observed in patients with pseudogout, sarcoidosis, gonococcal arthritis, psoriatic arthritis, and reactive arthritis.

Other than the great toe, the most common sites of gouty arthritis are the instep, ankle, wrist, finger joints, and knee. In early gout, only 1 or 2 joints are usually involved. Consider the diagnosis in any patient with acute monoarticular arthritis of any peripheral joint except the glenohumeral joint of the shoulder.

The most common sites of pseudogout arthritis are large joints, such as the knee, wrist, elbow, or ankle. Case reports have documented carpal tunnel syndrome as an initial presentation of pseudogout. Case reports of calcium pyrophosphate (CPP) crystals forming masses in the spinal ligamentum flavum have been documented. [ 88 ] These have led to both single-level and multilevel myelopathy.

Although crystal-induced arthritis is most commonly monoarticular, 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.

Gout attacks begin abruptly and typically reach maximum intensity within 8-12 hours. Affected joints are red, hot, and exquisitely tender; even a bed sheet on the swollen joint is uncomfortable. The onset of symptoms in pseudogout can resemble acute gout or be more insidious and may occur over several days.

Untreated, the first attacks resolve spontaneously in less than 2 weeks. A history of intermittent inflammatory arthritis, in which the joints return to normal between attacks, is typical of crystalline disorders and is characteristic of gouty arthritis early in its course.

Gout initially presents as polyarticular arthritis in 10% of patients. Elderly women, particularly women with kidney insufficiency who are taking a thiazide diuretic, can develop polyarticular arthritis as the first manifestation of gout. These attacks may occur in coexisting Heberden and Bouchard nodes. Such patients may also develop tophi more quickly, occasionally without prior episodes of acute gouty arthritis. [ 89 , 90 , 91 ]

The pattern of symptoms in untreated gout changes over time. The attacks can become more polyarticular. More proximal and upper-extremity joints become involved. Attacks tend to occur more frequently and last longer.

Eventually, patients may develop chronic polyarticular arthritis, sometimes nearly symmetrical, that can resemble rheumatoid arthritis. Indeed, chronic polyarticular arthritis that began as an intermittent arthritis should prompt consideration of a crystalline disorder in the differential diagnosis.

Acute flares of gout can result from situations that lead to increased levels of serum uric acid, such as the consumption of beer or liquor, overconsumption of foods with high purine content, trauma, dehydration, or the use of medications that elevate levels of uric acid. Acute flares of gout also can result from situations that lead to decreased levels of serum uric acid, such as the use of radiocontrast dye or medications that lower the levels of uric acid, including allopurinol and uricosurics. (See Overview/Etiology .)

Patients with gout have as much as 1000 times more uric acid in the body as unaffected individuals do and are almost twice (1.97 times) as likely to develop renal stones as healthy individuals are [ 92 ] ; therefore, they may have a history of renal colic and hematuria. Indeed, renal stones may precede the onset of gout in 14% of affected patients. Whereas 52% of these patients may have stones composed entirely of uric acid, 20% may develop calcium oxalate or sometimes calcium phosphate stones. [ 93 ]

Because gout is frequently present in patients with the metabolic syndrome (eg, insulin resistance or diabetes, hypertension, hypertriglyceridemia, and low levels of high-density lipoproteins) and because the presence of these associated disorders can lead to coronary artery disease, these problems should be sought and treated in patients diagnosed with gout.

It is important to ask about a history of peptic ulcer disease , kidney disease, or other conditions that may complicate the use of the medications used to treat gout.

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.

Patients experiencing an acute attack of gout or pseudogout most often present with involvement of a single joint. However, all joints must be examined to determine whether the patient’s arthritis is monoarticular or polyarticular. Involved joints have all the signs of inflammation: swelling, warmth, erythema, and tenderness.

The erythema over the joint may resemble cellulitis; the skin may desquamate as the attack subsides. The joint capsule becomes quickly swollen, resulting in a loss of range of motion of the involved joint.

Patients may be febrile during an acute gout attack, particularly if it is polyarticular. However, it is important to look for sites of infection that may have seeded the joint and caused an infectious arthritis resembling or coexisting with acute gouty arthritis.

Migratory polyarthritis is a rare presentation. Polyarticular gout commonly involves the small joints of the fingers and toes, as well as the knees. An inflammatory synovial effusion may be present. Uncommonly, acute gout may present as carpal tunnel syndrome.

Posterior interosseous nerve syndrome is a rare compression neuropathy that manifests as inability to extend the fingers actively. The syndrome has been reported in a patient with elbow swelling from an attack of pseudogout; in this case, treatment with intra-articular steroids led to resolution of the nerve palsy. [ 94 ]

Patients with established gout may have chronic arthritis. Affected joints evidence tenderness and swelling, with or without redness, warmth, or joint damage.

Although gout typically causes joint inflammation, it can also cause inflammation in other synovial-based structures, such as bursae and tendons. Tophi are collections of urate crystals in the soft tissues. They tend to develop after about a decade in untreated patients who develop chronic gouty arthritis. Tophi may develop earlier in older women, particularly those receiving diuretics. [ 89 , 90 , 91 ]

Tophi are classically located along the helix of the ear, but they can be found in multiple locations, including the fingers, the toes, the prepatellar bursa, and along the olecranon, where they can resemble rheumatoid nodules (see the images below). Rarely, a creamy discharge may be present. [ 95 , 96 ] The finding of an apparent rheumatoid nodule in a patient with a negative rheumatoid factor assay or a history of drainage from a nodule should prompt consideration of gout in the differential diagnosis. [ 97 ]

Eye involvement

The folklore surrounding gout has also involved the eye, and before the 20th century, a myriad of common and unusual ocular symptoms were falsely ascribed to gout. Medical science has since documented eye involvement as a rare but definite aspect of gout. All manifestations of gout in the eye are secondary to deposition of urate crystals within the ocular tissue. [ 98 , 99 ]

Tophi have been described in the eyelids. [ 100 , 101 , 102 ] Conjunctival nodules containing needlelike crystals have been described within the interpalpebral areas, sometimes associated with a mild marginal keratitis. Band keratopathy with refractile, yellow crystals in the deep corneal epithelial cells and at the level of the Bowman membrane are not uncommon. [ 103 ]

Blurring of vision from the corneal haze or a foreign body sensation due to epithelial breakdown may occur. Gout rarely can be associated with anterior uveitis; Duke-Elder mentions this as a cause of hemorrhagic iritis in his classic Text Book of Ophthalmology . Scleritis and tendinitis have also been described. Besides the cornea, the iris, anterior chamber, lens, and sclera have been found to harbor urate crystals; on postmortem examination, urate crystals have also been found in tarsal cartilage and in the tendons of extraocular muscles. [ 98 , 99 ]

Complications of gout include the following:

• Severe degenerative arthritis
• Secondary infections
• Urate or uric acid nephropathy
• Increased susceptibility to infection
• Urate nephropathy
• Renal stones
• Nerve or spinal cord impingement [ 104 , 105 ]
• Fractures in joints with tophaceous gout [ 106 ]

 Calcification of the atlas transverse ligament has been reported in 44-70% of individuals with calcium pyrophosphate disease (CPPD), with frequency increasing with age. [ 107 ]  A significantly elevated rate of non-union of type II and III  odontoid fractures  has been reported in patients with CPPD (90.3%, versus 32% in controls). [ 108 ]

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Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum . 2008 Nov 15. 59(11):1540-8. [QxMD MEDLINE Link] .

Schumacher HR Jr, Becker MA, Lloyd E, MacDonald PA, Lademacher C. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford) . 2009 Feb. 48(2):188-94. [QxMD MEDLINE Link] .

Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med . 2005 Dec 8. 353(23):2450-61. [QxMD MEDLINE Link] .

Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther . 2010. 12(2):R63. [QxMD MEDLINE Link] . [Full Text] .

Jackson RL, Hunt B, MacDonald PA. The efficacy and safety of febuxostat for urate lowering in gout patients 65+ years of age. BMC Geriatr . 2012 Mar 21. 12:11. [QxMD MEDLINE Link] . [Full Text] .

Wells AF, MacDonald PA, Chefo S, Jackson RL. African American patients with gout: efficacy and safety of febuxostat vs allopurinol. BMC Musculoskelet Disord . 2012 Feb 9. 13:15. [QxMD MEDLINE Link] . [Full Text] .

Chohan S, Becker MA, MacDonald PA, Chefo S, Jackson RL. Women with gout: efficacy and safety of urate-lowering with febuxostat and allopurinol. Arthritis Care Res (Hoboken) . 2012 Feb. 64(2):256-61. [QxMD MEDLINE Link] .

Yamanaka H, Tamaki S, Ide Y, Kim H, Inoue K, Sugimoto M, et al. Stepwise dose increase of febuxostat is comparable with colchicine prophylaxis for the prevention of gout flares during the initial phase of urate-lowering therapy: results from FORTUNE-1, a prospective, multicentre randomised study. Ann Rheum Dis . 2018 Feb. 77 (2):270-276. [QxMD MEDLINE Link] . [Full Text] .

White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med . 2018 Mar 29. 378 (13):1200-1210. [QxMD MEDLINE Link] .

FDA adds Boxed Warning for increased risk of death with gout medicine Uloric (febuxostat). U.S. Food & Drug Administration. Available at https://www.fda.gov/Drugs/DrugSafety/ucm631182.htm . February 21, 2019; Accessed: February 24, 2019.

Committee for Medicinal Products for Human Use (CHMP). Krystexxa (pegloticase). European Medicines Agency. Available at https://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002208/human_med_001591.jsp&mid=WC0b01ac058001d124 . July 22, 2016; Accessed: March 27, 2023.

Botson J, Saag K, Peterson J, Parikh N, Ong S, La D, et al. A Randomized, Double Blind, Placebo Controlled, Multicenter, Study Of Methotrexate Combined with Pegloticase in Patients with Uncontrolled Gout (abstract OP0171). Ann Rheum Dis . 2022. 81(Suppl 1):112-113. [Full Text] .

Sundy JS, Baraf HS, Yood RA, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA . 2011 Aug 17. 306(7):711-20. [QxMD MEDLINE Link] .

Perez-Ruiz F, Sundy JS, Miner JN, Cravets M, Storgard C, RDEA594-203 Study Group. Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol. Ann Rheum Dis . 2016 Jan 7. 7 (6):433-42. [QxMD MEDLINE Link] . [Full Text] .

Two Gout Drugs Removed From Market. Arthritis Foundation. Available at https://blog.arthritis.org/news/two-gout-drugs-removed-market/ . April 11, 2019; Accessed: January 10, 2023.

Huang HY, Appel LJ, Choi MJ, et al. The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial. Arthritis Rheum . 2005 Jun. 52(6):1843-7. [QxMD MEDLINE Link] .

Kobylecki CJ, Afzal S, Nordestgaard BG. Genetically high plasma vitamin C and urate: a Mendelian randomization study in 106 147 individuals from the general population. Rheumatology (Oxford) . 2018 Oct 1. 57 (10):1769-1776. [QxMD MEDLINE Link] .

Benzbromarone. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury . National Library of Medicine; September 5, 2017. [Full Text] .

Azevedo VF, Kos IA, Vargas-Santos AB, da Rocha Castelar Pinheiro G, Dos Santos Paiva E. Benzbromarone in the treatment of gout. Adv Rheumatol . 2019 Aug 7. 59 (1):37. [QxMD MEDLINE Link] . [Full Text] .

Wu F, Chen L, Du Y. Comparison of the efficacy and safety of benzbromarone and febuxostat in gout and hyperuricemia: a systematic review and meta-analysis. Clin Rheumatol . 2024 May. 43 (5):1745-1754. [QxMD MEDLINE Link] .

Zhang J, Ji X, Dong Z, Lu J, Zhao Y, Li R, et al. Impact of fenofibrate therapy on serum uric acid concentrations: a review and meta-analysis. Endocr J . 2021 Jul 28. 68 (7):829-837. [QxMD MEDLINE Link] . [Full Text] .

Terkeltaub R, Lee J, Min J, Shin S, Saag KG. Serum Urate-Lowering Efficacy and Safety of Tigulixostat in Gout Patients With Hyperuricemia: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Trial. Arthritis Rheumatol . 2023 Jul. 75 (7):1275-1284. [QxMD MEDLINE Link] .

Qin T, Chu Y, Yao Y, Zhang C, Xu B, Song Q. Coffee intake reduced gout risk by decreasing urate and urea while increasing SHBG levels in plasma: a mediation Mendelian randomization study. Clin Rheumatol . 2024 May. 43 (5):1735-1743. [QxMD MEDLINE Link] .

Yokose C, McCormick N, Choi HK. The role of diet in hyperuricemia and gout. Curr Opin Rheumatol . 2021 Jan 4. Publish Ahead of Print: [QxMD MEDLINE Link] .

Rai SK, Fung TT, Lu N, Keller SF, Curhan GC, Choi HK. The Dietary Approaches to Stop Hypertension (DASH) diet, Western diet, and risk of gout in men: prospective cohort study. BMJ . 2017 May 9. 357:j1794. [QxMD MEDLINE Link] . [Full Text] .

[Guideline] Qaseem A, McLean RM, Starkey M, Forciea MA, Clinical Guidelines Committee of the American College of Physicians. Diagnosis of Acute Gout: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med . 2016 Nov 1. [QxMD MEDLINE Link] . [Full Text] .

• Gout. Acute podagra due to gout in elderly man.
• Gout. Tophaceous deposits in ear.
• Gout. Tophaceous deposits on elbow.
• Gout. Chronic tophaceous gout in untreated patient with end-stage renal disease.
• Gout. Fluid obtained from tophaceous deposit in patient with gout.
• Gout. Strongly negative birefringent, needle-shaped crystals diagnostic of gout obtained from acutely inflamed joint.
• Gout. Plain radiograph showing typical changes of gout in first metatarsophalangeal joint and fourth interphalangeal joint.
• Gout. Plain radiograph showing chronic tophaceous gouty arthritis in hands.
• Gout. Radiograph of erosions with overhanging edges.
• Gout. Needles of urate crystals seen on polarizing microscopy.
• Gout. Hematoxylin and eosin (H&E) stain, low power, showing abundant pale pink areas surrounded by histiocytes and multinucleated giant cells.
• Gout. H&E stain, high power, showing that most urate crystals have been dissolved but that some pale brown-gray crystals did survive processing.
• Pseudogout. H&E stain, high power, under polarized light to highlight rhomboidal crystals.
• H&E stain, medium power, of pseudogout with pale pink fibrocartilage in upper portion and purple crystals of calcium pyrophosphate in lower portion.
• Pseudogout. H&E stain, high power, of calcium pyrophosphate crystals, demonstrating their rhomboidal structure.
• What is gout? Gout is an inflammatory disease where uric acid precipitates into crystals that deposit in various joints around the body, causing pain and inflammation. This video describes the pathophysiology, causes, symptoms, and treatment of gout.
• This wrist radiograph shows chondrocalcinosis of the radiocarpal joint (arrow).
• The most common site of calcium pyrophosphate disease (CPPD) involvement, as seen on radiography, is the patellofemoral joint, followed by the radiocarpal joint (shown). Classic radiographic findings are chondrocalcinosis (yellow arrow), hooked osteophytes, and subchondral cysts (red arrow).

Contributor Information and Disclosures

Bruce M Rothschild, MD Professor of Medicine, IU Health; Research Associate, Carnegie Museum Bruce M Rothschild, MD is a member of the following medical societies: American Association for the Advancement of Science , American College of Rheumatology , International Skeletal Society , New York Academy of Sciences , Sigma Xi, The Scientific Research Honor Society , Society of Skeletal Radiology Disclosure: Nothing to disclose.

Mark L Francis, MD Professor of Medical Education, Department of Medical Education, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center Mark L Francis, MD is a member of the following medical societies: American College of Physicians , Phi Beta Kappa Disclosure: Nothing to disclose.

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American College of Rheumatology , American Medical Association , Phi Beta Kappa Disclosure: Nothing to disclose.

Anne V Miller, MD Chief, Rheumatology Division; Assistant Professor of Internal Medicine, Department of Medicine, Division of Rheumatology, Southern Illinois University School of Medicine Anne V Miller, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Physicians , American College of Rheumatology , International Society for Clinical Densitometry Disclosure: Nothing to disclose.

Richard W Allinson, MD Associate Professor, Department of Ophthalmology, Texas A&M University Health Science Center; Senior Staff Ophthalmologist, Scott and White Clinic

Richard W Allinson, MD, is a member of the following medical societies: American Academy of Ophthalmology , American Medical Association , and Texas Medical Association

Disclosure: Nothing to disclose.

Lawrence H Brent, MD Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science , American Association of Immunologists , American College of Physicians , and American College of Rheumatology

Disclosure: Abbott Honoraria Speaking and teaching; Centocor Consulting fee Consulting; Genentech Grant/research funds Other; HGS/GSK Honoraria Speaking and teaching; Omnicare Consulting fee Consulting; Pfizer Honoraria Speaking and teaching; Roche Speaking and teaching; Savient Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching

Andrew A Dahl, MD Director of Ophthalmology Teaching, Mid-Hudson Family Practice Institute, The Institute for Family Health; Assistant Professor of Surgery (Ophthalmology), New York College of Medicine

Andrew A Dahl, MD is a member of the following medical societies: Alpha Omega Alpha , American Academy of Ophthalmology , American College of Surgeons , American Medical Association , American Society of Cataract and Refractive Surgery , and Wilderness Medical Society

Paul E Di Cesare, MD, FACS Professor and Chair, Department of Orthopedic Sugery, University of California, Davis, School of Medicine

Paul E Di Cesare, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons , American College of Surgeons , and Sigma Xi

Disclosure: Stryker Consulting fee Consulting

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Steven C Dronen, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine and Society for Academic Emergency Medicine

Gino A Farina, MD, FACEP, FAAEM Associate Professor of Clinical Emergency Medicine, Albert Einstein College of Medicine; Program Director, Department of Emergency Medicine, Long Island Jewish Medical Center

Gino A Farina, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine , American College of Emergency Physicians , and Society for Academic Emergency Medicine

Harris Gellman, MD Consulting Surgeon, Broward Hand Center; Voluntary Clinical Professor of Orthopedic Surgery and Plastic Surgery, Departments of Orthopedic Surgery and Surgery, University of Miami, Leonard M Miller School of Medicine

Harris Gellman, MD is a member of the following medical societies: American Academy of Medical Acupuncture , American Academy of Orthopaedic Surgeons , American Orthopaedic Association , American Society for Surgery of the Hand , and Arkansas Medical Society

Joseph Kaplan, MD, MS, FACEP Attending Physician, Department of Emergency Medicine, Martin Army Community Hospital, Fort Benning

Joseph Kaplan, MD, MS, FACEP is a member of the following medical societies: American College of Emergency Physicians

Jegan Krishnan, MBBS, FRACS, PhD Professor, Chair, Department of Orthopedic Surgery, Flinders University of South Australia; Senior Clinical Director of Orthopedic Surgery, Repatriation General Hospital; Private Practice, Orthopaedics SA, Flinders Private Hospital

Jegan Krishnan, MBBS, FRACS, PhD, is a member of the following medical societies: Australian Medical Association , Australian Orthopaedic Association , and Royal Australasian College of Surgeons

Edward A Michelson, MD Associate Professor, Program Director, Department of Emergency Medicine, University Hospital Health Systems of Cleveland

Edward A Michelson, MD is a member of the following medical societies: American College of Emergency Physicians , National Association of EMS Physicians , and Society for Academic Emergency Medicine

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Hampton Roy Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology , American College of Surgeons , and Pan-American Association of Ophthalmology

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Shekelle PG, FitzGerald J, Newberry SJ, et al. Management of Gout [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Mar. (Comparative Effectiveness Reviews, No. 176.)

Management of Gout [Internet].

Introduction.

Gout is the most common form of inflammatory arthritis and is characterized by acute intermittent episodes of synovitis presenting with joint swelling and pain (referred to as acute gouty arthritis, or acute gout attacks, or acute gout flares). It has been described as a disease of the foot since antiquity. 1 Approximately 8 million patients in the United States have gout. Gout is caused when excess urate in the body crystalizes (as monosodium urate [MSU]) in joint fluid, cartilage, bones, tendons, bursas, or other sites. These crystals can directly stimulate an acute inflammatory attack. In some patients, acute gout attacks become progressively more frequent, protracted, and severe, and may eventually progress to a chronic inflammatory condition. Additionally, in some patients, the deposits of urate crystals grow into larger collections, called tophi (singular tophus) when clinically apparent.

Based on data from the 2007-2008 National Health and Nutrition Examination Survey (NHANES), the prevalence of gout among adults in the United States was estimated to be 3.9 percent (8.3 million individuals), ranging from 2.0 percent in women to 5.9 percent in men. 2 Comparing the most recent figures for the prevalence of gout to those of previous cycles of NHANES shows that the prevalence of gout appears to be increasing. The rise in the prevalence of gout has paralleled the increase in prevalence of conditions associated with hyperuricemia, including obesity, hypertension, hypertriglyceridemia, hypercholesterolemia, type 2 diabetes and metabolic syndrome, and chronic kidney disease. 3 Certain dietary factors and medications also may increase the risk for developing gout (e.g., thiazide diuretics).

A 2013 study of ambulatory care costs associated with gout estimated the costs to be nearly $1 billion (in 2008 figures). Of this figure, 32 percent of the costs were attributed to office visits for acute attacks (flares), and 61 percent were attributed to expenditures for prescription medications to treat the condition. 4

The aim of this report is to review the evidence for the efficacy and safety of treatments for patients with gout, focusing on the primary care setting.

Etiology of Gout

Gout initially presents as an episode of acute inflammatory arthritis, most commonly involving the first meta-tarsal-phalanx joint, a condition commonly referred to as podagra. Typical attacks during the first few years last 7 to 14 days before resolving. Over time, these attacks become prolonged and can become chronic. The acute gout attack is a result of urate (the salt form of uric acid [UA]) crystals directly interacting with the immune system. Several factors affect deposition of urate crystals, including temperature, local pH, and most critically, the concentration of serum urate. The solubility factor of urate is 6.8mg/dl; urate concentrations above this threshold lead to crystal deposition; levels below this threshold lead to crystal dissolution. UA is a breakdown product of dietary or endogenous purines, (which are among the building blocks of nucleic acids) and is associated with the formation and deposition of the UA crystals. Hyperuricemia can result from UA overproduction or inadequate renal excretion. The latter is far more common than the former, affecting 90 percent of patients: Renal disease and medications can affect the excretion of serum urate. As serum urate concentration rises above 6.0mg/dl, the risk for developing an acute gout attack increases. The Framingham Heart Study found that, among men, the 5-year incidence of acute gout attack increases from 10 percent when serum urate is between 6.0 and 6.9mg/dl to 48 percent for serum urate greater than 8mg/dl. 5 Once a patient has had an initial attack, hyperuricemia increases the risk of repeat attacks. The 1-year incidence of recurrent attack is 30 percent for patients with serum urate between 6.0 and 6.9mg/dl and over 70 percent for patients with serum urate greater than 8mg/dl. 6 Although the primary risk factor for gout is hyperuricemia, not all patients with hyperuricemia go on to develop clinical gout; hyperuricemia in the absence of gout is known as asymptomatic hyperuricemia. Patients with asymptomatic hyperuricemia may or may not have evidence of urate deposits in their joints (as documented by advanced imaging methods). 7 The prevalence of hyperuricemia is about 21 percent, four-to ten-fold higher than the prevalence of gout. 2

The causes of gout are unclear but appear to be multifactorial, including a combination of genetic, hormonal, metabolic, and dietary factors. Family history, advancing age, male sex, or, in women, early menopause have been associated with a higher risk of gout and/or gout attacks (flares). 8 Dietary risk factors are discussed further below. Some prescription medications such as thiazides are also believed to be risk factors for gout.

Diagnosis of Gout

A number of methods have been proposed to establish the diagnosis of gout. The evidence supporting the various methods for the diagnosis of gout is the subject of a separate systematic review. 9

Clinical Presentation and Management

Gout is commonly divided into acute and chronic phases.

Acute Gouty Arthritis

The acute phase of gout is self-limited and characterized by recurrent attacks of synovitis (articular inflammation) that present with pain, erythema, and swelling, most frequently in the large toe, but other joints, tendons, bursae, or other areas may be involved.

A number of pharmacologic agents have been advocated for use in the management of acute gout. Commonly advocated agents to treat acute gout include non-steroidal anti-inflammatories (NSAIDS), colchicine (the microtubule disrupting agent), and/or corticosteroids (intra-articular or systemic) to manage pain and inflammation. The evidence for the efficacy of these agents in treating acute gout is a topic of this review.

Chronic Gout

Although initial episodes may be brief and rare, acute episodes may increase in frequency and duration over time and lead to the development of chronic gout. In addition to more frequent attacks, chronic gout may be associated with deposits of uric acid crystals known as tophi. Tophi may develop in joints, cartilage, bone, and auricular or other cutaneous tissues. 10 The average interval between the onset of gout and appearance of tophi, in the absence of treatment, is approximately 10 years. 10 Increased frequency of attacks and tophi are highly correlated with the presence of hyperuricemia. In addition to the aforementioned manifestations of chronic gout, patients with long standing gout can develop uric acid nephrolithiasis and chronic interstitial nephropathy. Gout has also been associated with a higher risk for progression of kidney disease 11 and increased risk of atherosclerotic disease, including myocardial infarction, heart failure, and stroke. 12

Management of chronic gout may include both pharmacologic and non-pharmacologic strategies. Historically, the treatment of chronic gout began with identification of patients as “overproducers” or “underexcretors” of uric acid, based on 24-hour urine collection. “Overproducers” were treated preferentially with allopurinol, whereas “underexcretors” were treated preferentially with the uricosuric probenecid. However, uricosuric agents may increase the risk of renal stones, requiring increased fluid intake and alkalinization for prevention. Probenecid use has also fallen out of favor, because allopurinol was found to be effective in “underexcretors.” 13 , 14 Urate lowering strategies are the primary pharmacologic intervention for management of long-term complications of gout.

Lifestyle Changes

Non-pharmacologic methods advocated for management of chronic gout include a combination of lifestyle changes, including weight loss, exercise, hydration, and dietary changes, based on observational evidence that particular dietary and other lifestyle factors are associated with a greater or lesser risk for developing gout. Dietary risk factors for gout have been postulated to include alcohol consumption, as well as consumption of meat, seafood, sugar-sweetened soft drinks, and foods high in fructose, whereas dairy foods and coffee have been associated with a lower risk of incident gout and in some cases a lower rate of gout attacks (flares). Based on evidence that purines increase serum urate levels, avoidance of high–purine foods has been the mainstay of dietary management of gout for decades. Further evidence from recent trials and observational studies suggests that a number of additional dietary factors may affect the risk for gout or hyperuricemia.

A 2011 systematic review examined 53 observational studies that assessed the association of a variety of foods, other dietary factors, and other factors with the risk for incident gout. 8 Meat intake, seafood intake, consumption of alcohol, consumption of sugar-sweetened beverages and other high-fructose foods, and overweight were associated with an increased risk for gout. A 2013 5-year prospective cohort study of hyperuricemic Chinese men that used a food frequency questionnaire found a significant association between consumption of shellfish, but not other foods, and risk for gout. 15

A 2012 systematic review that included 18 RCTs examined the effects of fructose intake on serum urate levels in normo-glycemic and diabetic patients. The review included both studies in which fructose isocalorically replaced other dietary components and those that added fructose to increase the caloric load. The review found no increase in serum urate with isocaloric fructose consumption but high levels of fructose that increased overall calorie intake increased serum urate. 16 Analysis of data from the large, observational Nurses' Health Study also found an association between consumption of fructose-sweetened beverages and increased risk for gout among women. 17

The association between alcohol consumption and risk for incident gout was examined in a 2013 SR and meta-analysis that included 17 observational studies, reported in 12 articles. 18 Light (≤1 drink/day), moderate (>1 to <3 drinks/day), and heavy (≥3 drinks/day) drinking were associated with significant increases in the risk for gout, compared with non- or occasional drinking (RR1.16 (95 % CI, 1.07–1.25), 1.58 (95 % CI, 1.50–1.66), and 2.64 (95 % CI, 2.26–3.09), respectively. We also identified an additional study not included in the 2013 SR that assessed the association between alcohol consumption and risk for gout. ARIC, a 12-year prospective cohort study, identified an association between high levels of alcohol consumption and increased risk for incident gout. 19

Studies have also identified dietary factors that reduce the risk for gout or lower serum urate levels. The 2011 systematic review by Singh found that consumption of dairy products and caffeine-containing beverages was associated with a decreased risk for gout. 8 Analyzing data from the Nurses' Health Study, Choi and colleagues also found that increasing coffee consumption was associated with a dose-dependent decrease in the risk for gout among women. 20 A 2011 SR by Juraschek and colleagues reviewed 13 trials on the effects of administration of vitamin C supplements on serum urate. 21 These trials enrolled a total of 556 participants, the median dosage of vitamin C was 500mg/day, trial size ranged from 8–184 participants, and the median study duration was 30 days. Pretreatment serum urate ranged from 2.9 to 7mg/dL. The pooled decrease in serum urate compared with placebo was a significant -0.35mg/dl (95% confidence interval -0.66, -0.03 [ P =0.032]). Trials showed significant heterogeneity.

Risk for gout and gout-related outcomes have also been associated with obesity, body mass index, and weight loss. The systematic review by Singh found an association between low BMI and decreased risk for gout 8 , and a 2014 systematic review that included 10 prospective studies found an association between increasing BMI and risk for gout. 22 The MRFIT trial, a prospective cohort study of U.S. men at increased risk for CVD found that weight loss was associated with decreased serum urate although less effective than ULT. 23 A recent RCT, the Dietary Intervention Randomized Controlled Trial (DIRECT), found that among 74 overweight and obese participants, a 6-month high-protein, low carbohydrate and low calorie diet resulted in significant weight loss and significant decrease in serum urate levels (0.8mg/dL, p<0.0001); among 18 whose baseline sUA was over 7mg/dL, 61 percent reached the target sUA level. 24

The evidence for the efficacy of specific dietary changes in managing gout (preventing attacks) is a topic of this review.

Pharmacologic Agents

Pharmacologic management of chronic gout consists primarily of agents that lower serum urate. These agents include xanthine oxidase inhibitors (XOIs: allopurinol and febuxostat) to reduce serum urate production; uricosurics (probenecid), which prevent renal reabsorption of UA (and increase urinary uric acid excretion); and uricases, which stimulate the breakdown of uric acid (pegloticase). These agents can be used alone or in specific combinations (e.g., XOI plus probenecid). Pegloticase will not be included in this review because it would not be prescribed in a primary care setting (see below).

Table 1 lists the drugs used to treat gout and notes the ones covered in this systematic review.

Pharmacologic agents used in the treatment of gout.

Several interleukin-1ß-inhibitory anti-inflammatory agents currently approved for treatment of rheumatoid arthritis are in Phase II and III trials for treatment of gout, including anakinra, canakinumab, and rilonacept; 25 - 27 these agents will not be included in this systematic review, because they are not prescribed in the primary care setting (see below). These treatments do not act by lowering serum urate levels.

Additional off-label agents that have been proposed as useful in the management of gout include the lipid lowering agent, fenofibrate; the angiotensin 2 receptor blocker, losartan; estrogen; and calcium channel blockers (in patients being treated with these agents for other indications). These agents are not included in this review.

Issues of Concern for Management of Gout in Primary Care Settings

The treatment of gout has spawned a proliferation of evidence-based guidelines, 28 - 34 including a recently completed set of guidelines by the American College of Rheumatology (ACR) that consider the treatment of both acute gout and hyperuricemia associated with chronic gout. 31 , 32

However, the majority of individuals with gout are initially seen, diagnosed, and treated in primary care or emergent care settings and may continue to receive their care in these settings. Therefore primary care physicians (PCPs) and emergency physicians need to be well-positioned to diagnose early-stage gout and implement management strategies. It is established that specialists and generalists systematically rate the benefits and harms of treatment differently, 35 and in some instances, guidelines on the same clinical topic developed by specialists have had somewhat different recommendations than those developed by generalists. 36 Therefore, a new guideline, developed mainly by primary care practitioners and focused on primary care practice, is warranted. This review is intended to provide the evidence for such a guideline.

• Scope and Key Questions

Scope of the Review

The purpose of this review is to assess the evidence on the management of patients with gout, in both the acute and chronic phases, including patients with tophaceous gout, and to assess management therapies that are FDA-approved and within the scope of practice of typical primary care providers. AHRQ assigned this report to the Southern CA Evidence-based Practice Center (HHSA290201200006I). A protocol for the review was accepted and publicly posted on the AHRQ Web site on November 3, 2014 at http://effectivehealthcare.ahrq.gov/ehc/products/564/1992/Gout-managment-protocol-141103.pdf . The protocol was approved by the AHRQ Center for Evidence and Practice Improvement.

Key Questions

The key questions.

The Key Questions (KQs) that guided this review are based on questions posed by the American College of Physicians (ACP). These questions underwent revision based on input from a group of key informants, public comments, and input from a Technical Expert Panel (TEP).

Key Question 1. Acute Gout Treatment

• In patients with acute gout, what are the benefits and harms of different pharmacological therapies?
• Does effectiveness (benefits and harms) differ according to patient baseline demographic characteristics and co-morbid conditions (including renal function)?
• Does effectiveness (benefits and harms) differ according to disease severity, including initial clinical presentation (e.g., extent of joint involvement and time since start of flare) and laboratory values (serum and/or urine UA levels)?

Key Question 2. Dietary and Lifestyle Management of Gout

• In adults with gout, what are the benefits and harms of different dietary therapies and life style measures on intermediate (serum and/or urine UA levels) and final health outcomes (including recurrence of gout episodes and progression [e.g., development of tophi])?
• Does effectiveness and comparative effectiveness of dietary modification differ according to disease severity (including presence of tophi and baseline serum UA), underlying mechanisms of hyperuricemia, or baseline demographic and co-morbid characteristics?

Key Question 3. Pharmacologic Management of Hyperuricemia in Gout Patients

• In adults with gout, what are the benefits and harms of different pharmacological therapies on intermediate (serum and/or urine UA levels) and long-term clinical health outcomes (including recurrence of gout episodes and progression)?
• Does effectiveness and comparative effectiveness of urate lowering therapy differ according to disease severity (including presence of tophi and baseline serum UA), underlying mechanisms of hyperuricemia, or baseline demographic and co-morbid characteristics?
• What is the effect of dietary modification in combination with pharmacologic therapy?

Key Question 4. Treatment Monitoring of Patients with Gout

• In adults with gout, does monitoring serum urate levels with pharmacologic treatment and/or dietary and/or lifestyle change measures (e.g., compliance) improve treatment outcomes?
• Is achieving lower subsequent serum urate levels (less than 5 vs. 5–7mg/dL) associated with decreased risk for recurrent acute gout attack, progression to chronic arthritis or disability, resolution of tophi, or other clinical outcomes (including risk for comorbidities or progression of comorbidities) or patient-reported outcomes?

Key Question 5. Discontinuation of Pharmaceutical Management for Patients on Acute or Chronic Gout Medications

In adults with gout, are there criteria that can identify patients who are good candidates for discontinuing

• urate lowering therapy?
• anti-inflammatory prophylaxis against acute gout attack for patients on urate lowering therapy after an acute gout attack?
• Organization of This Report

The remainder of this report presents the methods used to conduct the literature searches, data abstraction, and analysis for this review; the results of the literature searches, organized by KQ; the conclusions; and a discussion of the findings within the context of what is already known, the limitations of the review and the literature, and suggestions for future research.

• Cite this Page Shekelle PG, FitzGerald J, Newberry SJ, et al. Management of Gout [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Mar. (Comparative Effectiveness Reviews, No. 176.) Introduction.
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• Pathophysiology |
• Symptoms and Signs |
• Diagnosis |
• Prognosis |
• Treatment |
• Key Points |
• Asymptomatic Hyperuricemia |

(See also Overview of Crystal-Induced Arthritides .)

Gout is more common among men than women. Usually, gout develops during middle age in men and after menopause in women. Gout is rare in younger people but is often more severe in people who develop the disorder before age 30. Gout often runs in families. Patients with metabolic syndrome are at increased risk of gout.

Pathophysiology of Gout

The greater the degree and duration of hyperuricemia, the greater is the likelihood that gout will develop. Urate levels can be elevated because of

Decreased renal (most common) or gastrointestinal excretion

Increased production (rare)

Increased purine intake (usually in combination with decreased excretion)

Why only some people with elevated serum uric acid (urate) levels develop gout flares is not known.

Decreased renal excretion

Increased production of urate may be caused by increased nucleoprotein turnover in hematologic conditions (eg, lymphoma, leukemia, hemolytic anemia) and in conditions with increased rates of cellular proliferation and cell death (eg, psoriasis, cytotoxic cancer therapy, radiation therapy). Increased urate production may also occur as a primary hereditary abnormality and in obesity, because urate production correlates with body surface area. In most cases, the cause of urate overproduction is unknown, but rarely can be attributable to enzyme abnormalities; deficiency of hypoxanthine-guanine phosphoribosyltransferase (complete deficiency is Lesch-Nyhan syndrome ) is a possible cause, as is overactivity of phosphoribosylpyrophosphate synthetase.

Increased intake of purine-rich foods (eg, liver, kidney, anchovies, asparagus, consommé, herring, meat gravies and broths, mushrooms, mussels, sardines, sweetbreads) can contribute to hyperuricemia. Beer, including nonalcoholic beer, is particularly rich in guanosine, a purine nucleoside. However, a strict low-purine diet lowers serum urate by only about 1 mg/dL (0.1 mmol/L) and thus is rarely sufficient therapy for patients with gout.

Urate precipitates as needle-shaped monosodium urate (MSU) crystals, which are deposited extracellularly in avascular tissues (eg, cartilage) or in relatively avascular tissues (eg, tendons, tendon sheaths, ligaments, walls of bursae) and skin around cooler distal joints and tissues (eg, ears, finger pads). In severe, long-standing hyperuricemia, MSU crystals may be deposited in larger central joints and in the parenchyma of organs such as the kidney. At the acid pH of urine, urate precipitates readily as small platelike or diamond-shaped uric acid crystals that may aggregate to form gravel or stones, which may obstruct urine outflow. Tophi are MSU crystal aggregates that most often develop in joint and cutaneous tissue. They are usually encased in a fibrous granulomatous matrix, which prevents them from causing acute inflammation.

secondary osteoarthritis .

Symptoms and Signs of Gout

© Springer Science+Business Media

Acute gouty arthritis usually begins with sudden onset of pain (often nocturnal). The metatarsophalangeal joint of a great toe is most often involved (called podagra), but the instep, ankle, knee, wrist, and elbow are also common sites. Rarely, the hip, shoulder, sacroiliac, sternoclavicular, or cervical spine joints are involved. The pain becomes progressively more severe, usually over a few hours, and is often excruciating. Swelling, warmth, redness, and exquisite tenderness may suggest infection. The overlying skin may become tense, warm, shiny, and red or purplish. Fever, tachycardia, chills, and malaise sometimes occur.

The first few flares usually affect only a single joint and last only a few days. Later flares may affect several joints simultaneously or sequentially and persist up to 3 weeks if untreated. Subsequent flares develop after progressively shorter symptom-free intervals. Eventually, multiple flares may occur each year. If ongoing urate-lowering therapy is not initiated, patients can develop chronic deforming arthritis from tophaceous gout due to ongoing urate deposition.

Palpable tophi develop in patients with gout and can rarely occur in patients who have never had acute gouty arthritis. They are usually firm yellow or white papules or nodules, single or multiple. They can develop in various locations, commonly the fingers, hands, feet, and around the olecranon or Achilles tendon. Tophi can also develop in the kidneys and other organs and under the skin on the ears. Patients with osteoarthritic Heberden nodes may develop tophi in the nodes. This development occurs most often in older women taking diuretics, and these can become dramatically inflamed and misdiagnosed as inflammatory osteoarthritis. Normally painless, tophi, especially in the olecranon bursae, can become acutely inflamed and painful, often after mild or inapparent injury. Tophi may erupt through the skin, discharging chalky masses of urate crystals. These sinus tracts can become infected. Tophi in and around joints may eventually cause deformities and secondary osteoarthritis.

Complications of gout

Gouty arthritis can cause pain, deformity, and limited joint motion. Inflammation can be flaring in some joints while subsiding in others. Patients with gout may develop urolithiasis with uric acid stones or calcium oxalate stones.

Complications of gout include renal obstruction and infection, with secondary tubulointerstitial disease. Untreated progressive renal dysfunction, most often related to coexisting hypertension or, less often, some other cause of nephropathy, further impairs excretion of urate, accelerating crystal deposition in tissues.

Cardiovascular disease , obstructive sleep apnea , nonalcoholic fatty liver disease , and components of metabolic syndrome are common among patients with gout.

Diagnosis of Gout

Clinical criteria

Synovial fluid analysis

The diagnosis of gout should be suspected in patients with acute monoarticular arthritis or oligoarticular arthritis , particularly older adults or those with other risk factors. Podagra and recurrent instep inflammation are particularly suggestive. Previous flares that began explosively and resolved spontaneously within 7 to 10 days are also characteristic. Similar symptoms can result from the following:

Acute calcium pyrophosphate arthritis (calcium pyrophosphate dihydrate (CPPD) crystal deposition disease) (however, calcium pyrophosphate deposition generally occurs in larger joints, is not associated with tophi, and its clinical course is often milder but protracted)

Acute rheumatic fever with joint involvement and juvenile idiopathic arthritis (however, these disorders occur mostly in young people, who rarely get gout)

Rheumatoid arthritis (RA) (however, RA tends to be symmetrical and persistent, with more affected joints during a flare, flares persisting for longer periods of time, and flares in all joints subsiding together; whereas in gout, inflammation is usually flaring in some joints while subsiding in others)

Acute fracture in patients unable to provide a history of injury (particularly metatarsal stress fractures)

Acute infectious arthritis or chronic infectious arthritis (differentiation requires synovial fluid analysis)

Palindromic rheumatism

Acute calcific periarthritis caused by

Palindromic rheumatism is characterized by acute, recurrent flares of inflammation in or near one or occasionally several joints or tendon sheaths with spontaneous resolution; pain and erythema can be as severe as in gout. Flares often subside spontaneously and completely in 1 to 3 days. Such flares may herald the onset of RA, and rheumatoid factor tests can help in differentiation; they are positive in about 50% of patients (these tests are positive in 10% of gouty patients also).

If acute gouty arthritis is suspected, arthrocentesis and synovial fluid analysis should be done at the initial presentation. A typical recurrence in a patient with previously documented gout does not mandate arthrocentesis, but it should be done if there is any question of the diagnosis or if the patient’s risk factors or any clinical characteristics suggest infectious arthritis. In some cases, a diagnosis of gout may be reasonably presumed based on the patient’s history and clinical features or on imaging results in cases when joint fluid cannot be obtained; however, every attempt should be made to document the presence of MSU crystals in synovial fluid from an affected joint.

By permission of the publisher. From Myers S: Atlas of Rheumatology . Edited by G Hunder. Philadelphia, Current Medicine, 2005.

Synovial fluid analysis can confirm the diagnosis by identifying needle-shaped, strongly negatively birefringent urate crystals that are free in the fluid or engulfed by phagocytes. Synovial fluid during flares has inflammatory characteristics (see table Microscopic Examination of Crystals in Joints ), usually 2,000 to 100,000 white blood cells/mcL, with > 80% polymorphonuclear white blood cells. These findings overlap considerably with infectious arthritis, which must be excluded by Gram stain (which is insensitive) and culture.

Microscopic Examination of Crystals in Joints

Serum urate level

X-rays of the affected joint may be taken to look for bony erosions or tophi, but they are unnecessary if the diagnosis of acute gout has been established by synovial fluid analysis and rarely show erosions at the time of first flares. In calcium pyrophosphate arthritis, radiopaque deposits may sometimes be present in fibrocartilage, hyaline articular cartilage (particularly the knee), or both, but calcinosis can be seen in the absence of acute flares.

Ultrasonography is more sensitive (although operator-dependent) than plain x-rays for the diagnosis of gout. Urate deposition over the articular cartilage (double-contour sign) and clinically inapparent tophi are characteristic changes. These findings may be evident even before the first gout flare. Dual-energy CT scans (DECTs) can also reveal uric acid deposits and can be useful if the diagnosis is unclear based on standard clinical evaluation and testing, particularly if synovial fluid aspiration and analysis cannot be done.

Image courtesy of N. Lawrence Edwards, MD.

Images courtesy of Brian F. Mandell, MD.

Diagnosis of chronic gouty arthritis

Chronic gouty arthritis should be considered in patients with persistent unexplained joint disease or subcutaneous or bony tophi. Plain x-rays of the 1st metatarsophalangeal joint or other affected joint may be useful. These x-rays may show punched-out lesions of subchondral bone with overhanging bony margins, most commonly in the 1st metatarsophalangeal joint; lesions must be ≥ 5 mm in diameter to be visible on x-ray. Joint space is typically preserved until very late in the course of disease. Synovial fluid findings from chronic effusions of affected joints are usually diagnostic.

Diagnostic ultrasonography is increasingly used to detect a typical double-contour sign suggesting urate crystal deposition, but sensitivity is operator-dependent and differentiation from calcium pyrophosphate crystal deposits may be more difficult to do conclusively.

Prognosis for Gout

With early gout diagnosis, life-long urate-lowering therapy enables most patients to live a normal life. For many patients with advanced disease, aggressive lowering of the serum urate level can resolve tophi and improve joint function. Gout is generally more severe in patients whose initial symptoms appear before age 30 and whose baseline serum uric acid level is > 9 mg/dL (> 0.5 mmol/L). The high prevalence of metabolic syndrome and cardiovascular disease probably increases mortality in patients with gout.

Some patients do not improve sufficiently with treatment. The usual reasons include inadequate education provided to patients, nonadherence, alcoholism, and mainly undertreatment of the hyperuricemia by physicians.

Treatment of Gout

Treatment of coexisting hypertension, hyperlipidemia, and obesity and avoidance of excess dietary purines

(See also the 2020 American College of Rheumatology Guideline for the Management of Gout .)

Treatment of acute flares

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in treating acute flares and are generally well-tolerated. However, they can have adverse effects, including gastrointestinal upset or bleeding, hyperkalemia, increases in creatinine, and fluid retention. Older and dehydrated patients are at particular risk, especially if there is a history of renal disease. Virtually any NSAID used in anti-inflammatory (high) doses is effective and is likely to exert an analgesic effect beginning within a few hours. Treatment should be continued for several days after the pain and signs of inflammation have resolved to prevent relapse.

is no longer available in the US.

Corticosteroids

In addition to NSAIDs or corticosteroids, supplementary analgesics, rest, ice application, and splinting of the inflamed joint may be helpful. If patients are taking urate-lowering drugs when an acute flare begins, the drugs should be continued at the same dose; dose adjustments are deferred until the flare has subsided. There is no contraindication to initiating urate-lowering therapy during an acute flare if appropriate antiinflammatory therapy is being provided.

Prevention of recurrent flares

Flare frequency can also be decreased with daily low-dose NSAIDs if renal function allows. Chronic corticosteroid use is not an ideal prophylactic therapy because of its adverse effect potential.

Lowering the serum urate level

Using both types of drugs together in severe tophaceous gout or in patients intolerant of higher doses of a XOI

Increasing urate excretion by converting urate to allantoin, which is more soluble and readily excreted, with uricase replacement therapy in patients such as those who have severe tophaceous gout or did not respond to other urate-lowering therapy

Urate-lowering therapy is indicated for patients with

Tophaceous deposits

Evidence of joint damage due to gout on imaging studies

Frequent or disabling flares (eg, > 2 flares times a year) of gouty arthritis

Urolithiasis

Patients with infrequent flares but whose serum uric acid level is > 9 mg/dL (> 0.5 mmol/L) or for whom having any flares poses particular hardship

Multiple comorbidities (eg, peptic ulcer disease, chronic kidney disease) that are relative contraindications to the drugs used to treat recurrent acute flares (NSAIDs or corticosteroids)

Hyperuricemia is not usually treated in the absence of gout flares or uric acid nephrolithiasis.

The goal of urate-lowering therapy is to lower the serum urate level. If tophi are not present, a reasonable target level is 6.8 mg/dL [0.4 mmol/L] at normal core body temperature and pH). Compelling data demonstrate decreased frequency of flares when the serum urate level decreases to 1 ).

If palpable tophi are present or if there is marked disability from tophaceous deposits, a reasonable goal is to dissolve them more rapidly, and this requires an even lower target level. The lower the serum urate level, the faster tophi resolve. After presumed complete dissolution of deposits, the serum urate can be allowed to increase to a level

Drugs are effective in lowering serum urate; dietary restriction of purines is less effective, but high intake of high-purine food, alcohol (beer in particular), and nonalcoholic beer should be avoided. Carbohydrate restriction (especially high-fructose corn syrup) and weight loss can lower serum urate level, particularly in patients with insulin resistance because high insulin

Resolution of tophi may take many months even with maintenance of serum urate at low levels. Serum urate should be measured periodically, usually monthly while determining required drug dosage and then at least yearly to confirm the effectiveness of therapy or more often if there are drug changes or weight gain. Urate-lowering therapy should not be stopped if a patient has a flare.

a xanthine oxidase inhibitor of urate synthesis, is the most commonly prescribed and preferred initial urate-lowering therapy. Uric acid stones or gravel may dissolve during allopurinol treatment. Treatment usually begins with 50 to100 mg orally once a day and can be slowly dose escalated up to 800 mg orally once a day. The dose can be split if single daily dosing causes gastrointestinal distress. Some clinicians recommend decreasing the starting dose in patients with renal insufficiency (eg, 50 mg orally once a day if creatinine clearance is 2 ) to decrease the incidence of rare but severe systemic hypersensitivity reactions; however, data that confirm the effectiveness of this intervention are limited. The final dose of allopurinol

allopurinol reactions, and HLA-B*5801 prevalence varies by race ( 2 ). Therefore, the 2020 American College of Rheumatology Guideline for the Management of Gout recommends testing patients of Southeast Asian descent (eg, Han Chinese, Korean, Thai) and Black American patients for HLA B*5801 and using an alternative drug if that genetic marker is present. Allopurinol

Febuxostat appears to prevent acute flares as efficaciously as allopurinol ( 3 ). Febuxostat is begun at 40 mg orally once a day and increased to 80 to 120 mg orally once a day if urate does not decrease to Febuxostat (like allopurinol allopurinol , febuxostat increased the risk of mortality in one study of patients with known cardiovascular disease ( 4 ), but several additional studies have not confirmed this observation ( 5 ). Transaminase levels can become elevated and should be measured periodically.

is a pegylated form of recombinant uricase. Uricase is an enzyme, absent in humans, that converts urate to allantoin, which is more soluble. Pegloticase is expensive and is used primarily in patients with gout in whom other treatments have been unsuccessful in lowering the serum urate level. Pegloticase can also be used in patients who have a high burden of tophaceous deposits that would not likely be dissolved in a reasonable time period by other urate-lowering therapies. It is given IV every 2 to 3 weeks for many months (typically at least 6 to 9 months) to totally deplete the excess urate deposits; it often lowers the serum urate level to Pegloticase is contraindicated in patients with G6PD deficiency because it can cause hemolysis and methemoglobinemia. Pegloticase infusion can be associated with symptoms consistent with anaphylaxis. The effectiveness of the currently available preparation is limited by a high rate of development of drug neutralizing antibodies. Failure of urate levels to decrease to pegloticase infusion indicates the likely presence of antipolyethylene glycol (anti-PEG) antibodies and an increased risk of future allergic reactions; regular infusions are then stopped. To prevent other urate-lowering drugs from masking ineffectiveness of pegloticase , other urate-lowering drugs should not be used together with pegloticase pegloticase may prevent development of the neutralizing antibodies.

Uricosuric therapy

Probenecid loses efficacy with declining renal function and is generally not as useful with a glomerular filtration rate 2 . Probenecid treatment begins with 250 mg orally 2 times a day, with doses increased as needed, to a maximum of 1 g orally 3 times a day. It is also effective when added to a xanthine oxidase inhibitor.

not be avoided if otherwise indicated as in secondary prevention of cardiovascular disease.

Other treatments

Fluid intake ≥ 3 L per day is desirable for all patients, especially those who chronically pass urate gravel or stones.

Extracorporeal shock wave lithotripsy may be needed to disintegrate renal stones.

Large tophi in areas with healthy skin may be removed surgically; all others should slowly resolve under adequate hypouricemic therapy.

Treatment references

1. Stamp LK, Frampton C, Morillon MB, et al : Association between serum urate and flares in people with gout and evidence for surrogate status: a secondary analysis of two randomised controlled trials. Lancet Rheumatol 4: e53-e60, 2022. doi.org/10.1016/S2665-9913(21)00319-2

2. Jutkowitz E, Dubreuil M, Lu N, et al : The cost-effectiveness of HLA-B*5801 screening to guide initial urate-lowering therapy for gout in the United States. Semin Arth Rheum 46:594-600, 2017. doi: 10.1016/j.semarthrit.2016.10.009

3. O'Dell JR, Brophy MT, Pillinger MH, et al : Comparative effectiveness of allopurinol and febuxostat in gout management. NEJM Evid 1(3):10.1056/evidoa2100028, 2022. doi: 10.1056/evidoa2100028. Epub 2022 Feb 3. PMID: 35434725; PMCID: PMC9012032.

4. White WR, Saag KG, Becker MA, et al N Engl J Med 378:1200-1210, 2018. doi: 10.1056/NEJMoa1710895

5. Mackenzie IS, Ford I, Nuki G, et al : Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet 396(10264):1745-1757, 2020. doi: 10.1016/S0140-6736(20)32234-0

Although increased purine intake and increased production can contribute to hyperuricemia, the most common cause of gout is decreased urate excretion secondary to kidney disorders or genetic variability in uric acid transporter efficiency.

Suspect gout in patients with sudden, unexplained acute monoarticular or oligoarticular arthritis, particularly if the great toe or midfoot is affected or there is a prior history of sudden, unexplained episodes of acute arthritis with spontaneous remission in 7 to 10 days.

Confirm the diagnosis by finding needle-shaped, strongly negatively birefringent urate crystals in joint fluid; or by dual-energy CT scans or ultrasound imaging. Documentation of hyperuricemia is insufficient to confirm the diagnosis of gouty arthritis.

Give drugs that decrease serum urate levels if patients have tophi, > 2 flares of gout per year, urolithiasis, or multiple comorbidities that contraindicate the drugs used to relieve acute flares; individualize the use of urate-lowering ongoing therapy in other patients.

Asymptomatic Hyperuricemia

Asymptomatic hyperuricemia is elevation of serum urate > 7 mg/dL (> 0.4 mmol/L) in the absence of clinical gout.

Observational data suggested that hyperuricemia may contribute to the progression of chronic kidney disease, cardiovascular disease, and, in adolescents, primary hypertension. Interventional studies, however, have not demonstrated that lowering the serum urate level reduces progression of renal disease.

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