- ACRONYMS AND DEFINITIONS
- In the U.S., the self-reported prevalence of gout is estimated to be 3.9%. Men are affected more than women (6% vs 2%), and in the U.S., blacks are affected more than whites. Uric acid levels are elevated for 10 - 20 years on average before symptoms appear, and the typical age on onset is 30 - 60 years old.
- The prevalence of gout has been increasing over the last 20 - 30 years. The rise in gout is likely secondary to an aging population (with decreased renal function), increased obesity, changes in dietary habits, and prescribing of medications that promote uricemia (e.g. diuretics). [1,4,19]
- High uric acid levels (hyperuricemia)
- Purines are bases that make up part of nucleic acids (DNA and RNA). In the human body, purines are continually being degraded and recycled. Purine metabolism takes place primarily in the liver, and to a lesser extent, in the small intestine. The end product of purine degradation is uric acid. Purines may also be consumed in the diet.
- The kidneys excrete about two-thirds of the uric acid produced daily, and the intestine excretes the rest
- Hyperuricemia occurs when the kidneys do not excrete enough uric acid (90% of cases) or when uric acid is overproduced (10% of cases).
- In most people, gout begins with a period of asymptomatic hyperuricemia. Over time, crystals may develop that deposit in joints and lead to gout attacks (see acute attack below). 
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- Acute gout attack
- In the setting of hyperuricemia, monosodium urate crystals may form in joints. The formation of crystals is dependent on a number of factors including hydration status, temperature, pH, concentration of cations, and the presence of extracellular matrix proteins (e.g. proteoglycans, collagens, chondroitin).
- In an acute gout attack, crystals present in joint synovium are released and phagocytosed by monocytes. Monocytes in turn release a number of inflammatory mediators that propagate an inflammatory reaction.
- Acute gout attacks are marked by the rapid development of severe pain that peaks in 6 - 12 hours. The affected joint is usually swollen and warm with overlying erythema.
- Untreated gout attacks typically resolve spontaneously over 7 - 10 days. Recurrent attacks are common with 66% of patients having another attack within one year of their previous attack.
- If uric acid levels remain high, tophi may form. Tophi are monosodium urate crystals surrounded by chronic inflammatory cells that form masses in soft tissue. Tophi typically form on the outer rim of the ear, over the olecranon bursa, over the Achilles tendon, and around the finger and toe joints. Tophi are usually painless, but in severe cases, they may ulcerate and ooze crystalline material. [3,4]
|RISK FACTORS FOR GOUT|
|Organ transplant recipients||
|High purine intake||
|High-fructose corn syrup||
|Genetic defects in renal urate transporters||
|MEDICATIONS THAT RAISE URIC ACID LEVELS|
|Bempedoic acid (Nexletol®)||
- Gout attacks are marked by a rapid development of severe pain, swelling, and overlying warmth and erythema in the affected joint. Bursa (particularly the prepatellar and olecranon bursa) may also be affected. Symptoms peak within 12 - 24 hours. Untreated attacks will typically resolve spontaneously in 7 - 10 days.
- Most gout attacks involve one joint, although polyarticular attacks can occur. The most common joint affected is the metatarsophalangeal joint of the great toe (referred to as podagra). The next most frequent joints affected are the midfoot, ankles, knees, elbows, and hands. The shoulders and hips are rarely affected.
- After the first attack, recurrence is common with up to 66% of patients having another attack within 2 years. Subsequent attacks are often more severe and may involve more than one joint.
- Gout can be confirmed by viewing fluid samples from affected joints. Crystals can be observed under a regular light microscope, and definitive identification of monosodium urate crystals can be achieved with a polarizing microscope where crystals will appear negatively birefringent. [2,4,6]
|2015 ACR CRITERIA FOR DIAGNOSING GOUT|
Step 1 - patient must have experienced the following:
Step 2 - if monosodium urate crystals have been observed in fluid from an affected joint, then gout is diagnosed, and no other criteria are necessary
Step 3 - if patient meets Step 1 criteria, but not Step 2, then a scoring system is used based on the criteria below. A total score of ≥ 8 classifies
a person as having gout.
NOTE: A person receives one score for each criteria
|Pattern of joint involvement||
Symptoms during episode
Time course of episode
Evidence of tophi
Uric acid level
Negative synovial fluid analysis
Evidence of urate deposition on imaging
- Synovial fluid analysis for crystals
- The gold standard for diagnosing gout is viewing negatively birefringent monosodium urate crystals under polarizing light microscopy in synovial fluid taken from an affected joint
- In many settings, the fluid and/or the ability to view it are not available
- Uric acid levels
- Elevated uric acid levels are the most important risk factor for the development of gout. That being said, not all patients with elevated levels develop gout, and not all patients with gout have elevated levels.
- The ACR defines an elevated uric acid level as > 6.8 mg/dl. Up to 33% of patients have normal uric acid levels during an acute gout attack.
- In one study, the following incidence rates for gout were observed:
- Uric acid level < 7 mg/dl - 0.1% annual incidence rate
- Uric acid level 7 - 8.9 mg/dl - 0.5% annual incidence rate
- Uric acid level ≥ 9 mg/dl - 4.9% annual incidence rate
- In patients with uric acid levels ≥ 9 mg/dl, the cumulative 5-year incidence rate was 22% 
- In chronic hyperuricemia, plain films of the hands and feet may show changes consistent with urate deposition
- X-ray findings consistent with chronic hyperuricemia include extra-articular bone erosions that are typically punched-out and occur along the long axis of the bone
- Soft tissue prominences may be present if there is soft tissue urate deposition
- Because it takes years for these changes to develop, X-rays are not typically helpful in making the initial diagnosis 
- Ultrasound imaging of an affected joint can be helpful in diagnosing gout
- Findings consistent with gout on an ultrasound include the "double contour sign" (urate crystal deposition along the surface of hyaline cartilage), tophus, and "snowstorm appearance" (mobile crystals within the fluid) 
- In one study, the accuracy of ultrasound for detecting gout in a symptomatic joint was evaluated using urate crystals on arthrocentesis as the reference standard. Ultrasound had a sensitivity of 76.9%, a specificity of 84.3%, a PPV of 83.8%, and a NPV of 78.2%. [PMID 27748084]
- Dual-energy CT scan
- A special type of CT scanning called "dual-energy CT scanning" can detect urate deposition in joints
- The modality requires special equipment and software that may not be widely available 
- Two conditions that can mimic an acute gout attack include a septic joint and pseudogout (calcium pyrophosphate deposition). If synovial fluid is available for evaluation, a gram stain and culture should be performed to exclude an infection.
- Features of other arthritis syndromes and how they compare to gout are presented in the table below
|Features of Different Arthritis Syndromes|
|Finding||Psoriatic arthritis||Rheumatoid arthritis||Lupus||Gout||Ankylosing spondylitis||Reactive arthritis||IBD-associated arthritis|
|Age of onset
|30 - 40s
|35 - 50s
|20 - 30s
|30 - 60s
|17 - 30s
|20 - 30s
||Fingers and toes including DIP
≤ 4 joints
|Fingers and toes, spares DIP
> 4 joints
|Hands, wrists, knees
> 4 joints
|Great toe, foot, ankle, knees, elbow
< 4 joints
|Lower limbs(30 - 50%)
< 4 joints
|Knees, ankles, hips
< 4 joints
|Hands and knees
|Spine disease||Axial joints - 50%
Sacroiliitis - 40%
|Uncommon||Uncommon||Absent||100%||Sacroiliitis - 50%
Back pain - 50%
|Enthesitis||30 - 50%, Plantar fascia and Achilles's tendon||Absent||Absent||Absent||Common||Common, Achilles tendon and plantar fascia||Uncommon|
|Dactylitis||40 - 50%||Absent||Absent||Uncommon||Uncommon||Common||Absent|
|HLA-B27 positive||40 - 50%||Not associated||Not associated||Not associated||90 - 95%||75%||30%|
|Eye disease||Uveitis - 8%||Dry eyes - 20%||Dry eyes - 15%||Absent||Uveitis - up to 30%||Conjunctivitis (common)
Anterior uveitis - 25%
|Uveitis - up to 7%|
|Other features||Psoriasis - 100%
Nail disease - 85%
|Positive RF and Anti-CCP||Positive ANA
Joint disease is non-erosive
|Elevated uric acid||Primarily affects the spine and pelvis||✝Preceding infection
Self-limited - 80%
|Occurs in 10 - 20% of patients with IBD|
- CALCIUM PYROPHOSPHATE DEPOSITION (PSEUDOGOUT)
- Calcium pyrophosphate deposition is another crystal-induced inflammatory joint disease that can present in a similar fashion to gout. Because of this, it is sometimes referred to as "pseudogout."
- Calcium pyrophosphate deposition (CPD) occurs when calcium pyrophosphate crystals deposit in the fibrocartilage and hyaline cartilage of joints
- CPD appears to occur more frequently in joints that have osteoarthritis. It can also cause calcification of cartilage (chondrocalcinosis) which can be seen on an X-ray.
- Similar to gout, CPD may be asymptomatic or it may induce an acute inflammatory reaction that leads to pain, swelling, warmth, and erythema 
- Risk factors
- Advanced age - CPD is rare before the age of 50 years. The risk increases significantly after age 50.
- Osteoarthritis - presence of osteoarthritis in a joint increases the risk
- Chondrocalcinosis - presence of chondrocalcinosis in a joint increases the risk. Chondrocalcinosis is not diagnostic for CPD, because basic calcium phosphate may also cause chondrocalcinosis.
- Previous joint trauma - previous trauma to a joint increases the risk of CPD
- Family history - some forms of CPD may be inherited
- Hypophosphatasia - a congenital syndrome caused by low functional levels of alkaline phosphatase
- Hyperparathyroidism - hyperparathyroidism increases the risk of CPD
- Hypomagnesemia - hypomagnesemia increases the risk of CPD
- Hemochromatosis - patients with hemochromatosis are at increased risk of CPD [8,16]
- CPD inflammatory disease typically presents as a rapid onset of joint pain, swelling, and tenderness that reaches a maximum in 6 - 24 hours. Unlike a gout attack which typically lasts 7 - 10 days, CPD attacks may last weeks to months.
- Certain surgeries including parathyroidectomy and hip fracture repair have been associated with precipitating an acute CPD attack. Medications associated with CPD attacks include intra-articular hyaluronan preparations, loop diuretics, granulocyte–macrophage colony-stimulating factor, and pamidronate.
- The most commonly affected joints are the knee, wrist, and shoulder. CPD typically occurs in older patients (≥ 65 years), and a diagnosis in patients < 55 years should raise suspicion for metabolic causes and/or familial predisposition.
- A definitive diagnosis of CPD is made by observing calcium pyrophosphate crystals in synovial fluid from an affected joint. Calcium pyrophosphate crystals have weak positive birefringence when viewed under a polarizing light microscope (contrast to monosodium urate crystals that are negatively birefringent).
- Chondrocalcinosis on an X-ray increases the likelihood of CPD, but it is not diagnostic since basic calcium phosphate may also cause chondrocalcinosis. The absence of chondrocalcinosis on an X-ray does not exclude CPD.
- Ultrasound may be more sensitive than X-rays in identifying chondrocalcinosis. On ultrasound, chondrocalcinosis appears as a thin hyperechoic band within hyaline cartilage and as hyperechoic sparkling spots in fibrocartilage.
- In some patients, CDP may lead to a chronic inflammatory joint condition that is polyarticular [8,16]
- The treatment of acute CPD flares is similar to the treatment of acute gout flares. Unlike gout, there is no chronic treatment to address the underlying pathology in CPD.
- The European League Against Rheumatism recommends the following treatment options for acute flares of CDP:
- Ice and rest - affected joint(s) should be iced and rested
- Intra-articular steroids - when feasible, joint aspiration and intra-articular steroid injection may be performed
- Colchicine - 0.5 mg three to four times a day with or without an initial dose of 1 mg
- Oral or parenteral corticosteroids - short tapering course
- For patients with frequent attacks, the following may be used for prophylaxis:
- NSAIDs - daily low-dose NSAID (with PPI if indicated)
- Colchicine - 0.5 - 1 mg/day
- For patients with chronic inflammatory CPD arthritis, the following may be used:
- NSAIDs - daily low-dose NSAID (with PPI if indicated)
- Colchicine - 0.5 - 1 mg/day
- Low-dose corticosteroids
- Methotrexate - based on one small study [PMID 17265505]
- Hydroxychloroquine - based on one small study 
- TREATMENT | ACUTE ATTACKS
|2020 ACR recommendations for the treatment of acute gout attacks|
General guidelines in all patients
For mild-moderate pain affecting one or a few small joints, or 1 - 2 large joints, use one of the following:
For severe pain affecting multiple joints, consider the following combination therapy:
Patients who cannot tolerate or have contraindications to anti-inflammatory therapy
- Three NSAIDs (naproxen, indomethacin, sulindac) have been FDA-approved to treat acute gout, but all NSAIDs appear to be effective
- NSAIDs should be prescribed at their maximally recommended doses until the gout attack has resolved (if tolerated by patient)
- COX-2 inhibitors
- The COX-2 inhibitor, celecoxib (Celebrex®), has been compared to indomethacin in one randomized controlled trial
- High-dose celecoxib was found to be equally effective to indomethacin (50 mg three times a day) [PMID 22859357]
- High-dose celecoxib: 800 mg initially followed by 400 mg later on Day 1, then 400 mg twice a day for 7 days
- Colchicine may be initiated for an acute attack
- For patients who are taking prophylactic colchicine, acute dosing may be used if an attack occurs and the patient has not received acute colchicine dosing within the past 14 days
- If the patient has received acute colchicine dosing within the past 14 days, another therapy (NSAIDs or corticosteroids) should be used.
- Acute dosing: 1.2 mg followed by 0.6 mg one hour later. Start prophylactic dosing 12 hours later and continue until symptoms resolve.
- Prophylactic dosing: 0.6 mg once or twice daily
- 0.5 mg dose can be substituted for 0.6 mg dose in countries where it is available
- Systemic (one of the following)
- Prednisone or prednisolone
- Regimen 1 - at least 0.5 mg/kg/day for 5 - 10 days then discontinue
- Regimen 2 - at least 0.5 mg/kg/day for 2 - 5 days, then taper for 7 - 10 days
- Methylprednisolone (Medrol®) dose pack
- Triamcinolone acetonide 60 mg IM, followed by prednisone as above
- IM triamcinolone may be given as monotherapy, but no consensus was reached on this recommendation
- Dosing should be based on size of the joint
- Can be used in combination with NSAIDs, colchicine, or oral corticosteroids
- TREATMENT | HYPERURICEMIA
|2020 ACR recommendations for the treatment of hyperuricemia|
Indications for treatment
Gout flare prophylaxis during treatment initiation
- Medication-specific recommendations
- Starting dose should be 100 mg/day. If CrCl is ≤ 29 ml/min, then starting dose is 50 mg/day.
- Titrate dose every 2 - 5 weeks to achieve target uric acid level
- Dose may be raised above 300 mg/day with appropriate monitoring even in patients with kidney disease. Monitor for pruritus, rash, elevated hepatic transaminases, and eosinophilia.
- Perform HLA-B*5801 testing in patients of Southeast Asian descent (e.g., Han Chinese, Korean, Thai) and African Americans
- Febuxostat (Uloric®)
- Starting dose is 40 mg once daily for patients with CrCl ≥ 30 ml/min. It has not been studied in patients with CrCl < 30 ml/min.
- If target uric acid level is not achieved after 2 weeks, increase dose to 80 mg once daily
- Febuxostat may be increased to a dose of 120 mg once daily (a dose approved in many countries outside the U.S.)
- Patients who do not tolerate allopurinol can be switched to febuxostat
- Febuxostat should not be given concomitantly with allopurinol
- Some studies have shown a higher risk of cardiovascular death in febuxostat-treated patients. The ACR recommends that patients with CVD avoid febuxostat if possible.
- Probenecid (Probalan®)
- Starting dose is 250 mg twice a day for one week, followed by 500 mg twice a day thereafter
- Daily dose may be increased by 500 mg every 4 weeks to a maximum of 2000 mg/day
- If CrCl < 60 ml/min then probenecid should not be used as a first-line agent
- If patient has history of kidney stones, then probenecid should be avoided if possible
- The ACR recommends against checking urinary uric acid levels before and during treatment. They also recommend against the use of urinary alkalinizing agents.
- Pegloticase (Krystexxa®)
- Pegloticase dosage is 8 mg by IV infusion every 2 weeks
- Pegloticase should only be used in patients with severe gout who cannot tolerate or did not respond to other therapies
- There is no consensus on the appropriate duration of therapy
- Pegloticase should not be given concurrently with other urate-lowering therapies to avoid masking the loss of a pegloticase serum urate–lowering effect. Loss of pegloticase serum urate–lowering effect is associated with an increased risk of anaphylaxis and infusion reactions.
|2012 ACR diet and lifestyle recommendations for patients with gout|
General recommendations for all patients
|Organ meats high in purines
||Serving sizes of:
- Chronic untreated gout can lead to a number of sequelae
- In developed countries where urate-lowering therapy is widely available, these chronic sequelae have become infrequent
- Main sequelae of chronic untreated gout:
- Recurrent, debilitating acute attacks
- Chronic, low-grade, polyarticular joint inflammation that can lead to joint destruction and deformity
- Tophi - tophi typically form on the outer rim of the ear, over the olecranon bursa, over the Achilles tendon, and around the finger and toe joints. In rare cases, tophi may form in the spinal cord, on tendons and nerves, and in other organs including the colon, heart, and eye. Tophi may rupture and extrude crystalline material.
- Kidney stones - hyperuricemia increases the risk of several types of kidney stones. Uric acid stones may form from supersaturation, and the risk of calcium stones is increased because hyperuricosuria decreases the solubility of calcium oxalate. [4,6]
- A study in the JAMA enrolled 225 patients with gout and an uric acid level ≥ 8 mg/dl who were refractory to allopurinol
Main inclusion criteria
- Serum uric acid ≥ 8 mg/dl and at least one of the following: ≥ 3 attacks in previous 18 months, ≥ 1 tophi, gouty arthropathy
- Contraindication to allopurinol or treatment failure
Main exclusion criteria
- G6PD deficiency
- Uncontrolled hypertension (> 150/95)
- Average age 55 years
- Average duration of gout ∼ 15 years
- Tophi present ∼ 72%
- Arthropathy ∼ 59%
- Average uric acid level ∼ 9.75 mg/dl
Randomized treatment groups
- Group 1 (85 patients) - Pegloticase 8 mg biweekly
- Group 2 (84 patients) - Pegloticase 8 mg monthly
- Group 3 (43 patients) - Placebo
- All patients received acute gout flare prophylaxis with colchicine or NSAIDs starting 1 week before first infusion and lasting throughout the trial
- Patients received the following before each infusion: fexofenadine 60 mg the evening before and again before
- Acetaminophen 1000 mg + hydrocortisone 200 mg IV immediately before infusion
- Data is pooled from 2 replicate trials
Primary outcome: Proportion of patients with plasma uric acid < 6.0 mg/dl for 80% of the time or longer during both months 3 and 6. Uric acid levels were checked 7 times during month 3 and month 6.
|Duration: 6 months|
|Outcome||Peg biweekly||Peg monthly||Placebo||Comparisons|
|Primary outcome||42%||35%||0%||p<0.001 for 1 or 2 vs 3|
|Gout flare (months 1 - 3)||75%||81%||53%||1 vs 3 p=0.02 | 2 vs 3 p=0.002|
|Discontinue due to adverse event||18%||19%||2%||N/A|
Findings: Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo.
- Design: Randomized open-label trial (N=399 | length = 7 days) in adults with acute gout flare
- Treatment: Colchicine 500 mcg every 8 hours for 4 days vs Naproxen 750 mg one time followed by 250 mg every 8 hours for up to 7 days
- Primary outcome: Change in pain intensity (measured on a scale of 0 - 10 with 10 being worst) from baseline measured over the first 7 days
- Primary outcome (change in pain): Colchicine -3.5, Naproxen -3.8 (p=0.22)
- Complete resolution of pain: Colchicine 67.3%, Naproxen 67.1% (p=0.87)
- Findings: We found no difference in pain intensity over 7 days between people with a gout flare randomised to either naproxen or low-dose colchicine. Naproxen caused fewer side effects supporting naproxen as first-line treatment for gout flares in primary care in the absence of contraindications.
- 1 - PMID 23024028 - ACR GL Part 1
- 2 - PMID 23024029 - ACR GL Part 2
- 3 - PMID 21288096 - NEJM review
- 4 - PMID 19692116 - Lancet review
- 5 - PMID 26359487 - ACR classification
- 6 - PMID 17522099 - British Rheum GL
- 7 - PMID 3826098 - Gout incidence study
- 8 - PMID 21216817 - EULAR CPD GL part I
- 9 - PMID 21257614 - EULAR CPD GL part II
- 10 - Allopurinol PI
- 11 - Febuxostat PI
- 12 - Probenecid PI
- 13 - Pegloticase PI
- 14 - PMID 11128679 - low dose ASA and probenecid
- 15 - PMID 21846852 - Pegloticase studies
- 16 - PMID 27355536 - NEJM pseudogout review
- 17 - PMID 29463518 - Relationship between serum urate concentration and clinically evident incident gout: an individual participant data analysis, Ann Rheum Dis (2018)
- 18 - PMID 32391934 - 2020 American College of Rheumatology Guideline for the Management of Gout, Arthritis Care & Research (2020)
- 19 - Medscape, Gout and Pseudogout
- 20 - PMID 28273019 - Psoriatic Arthritis, NEJM (2017)
- 21 - PMID 15222650 - Spondyloarthropathies, Am Fam Physician, (2004)
- 22 - Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy, Medscape
- 23 - Reactive arthritis, Medscape