Gout

ACRONYMS AND DEFINITIONS

ACR - American College of Rheumatology

CPD - Calcium pyrophosphate deposition

CVD - Cardiovascular disease

MTP - Metatarsophalangeal joint (first joint of the big toe)

NSAIDs - Nonsteroidal anti-inflammatory drugs

PPV - Positive predictive value

NPV - Negative predictive value

EPIDEMIOLOGY

In the U.S., the self-reported prevalence of gout is around 3.9%. Men are affected more than women (6% vs 2%), and blacks have a higher incidence 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 increased over the last 20 - 30 years. The rise in cases 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]

PATHOLOGY

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). [4]

Open scalable image

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]

Reference [2,3,4,17]
RISK FACTORS FOR GOUT
Risk factor	Comment
Hyperuricemia	Main risk factor for developing gout 15-year risk of gout with uric acid level < 6 mg/dl is around 1.1% 15-year risk of gout with uric acid level ≥ 10 mg/dl is around 50%
Males	Gout is much more prevalent in men Male:female ratio is 3-4:1
Age	The incidence of gout increases with age This is likely secondary to decreasing renal function and possibly medications (e.g. diuretics)
Menopause	Estrogen promotes uric acid excretion in the kidneys After menopause, excretion decreases
Obesity	The prevalence of gout is much higher in obese people Weight loss decreases the risk
Kidney disease	In kidney disease, the excretion of uric acid decreases
Organ transplant recipients	Anti-rejection medications raise uric acid levels
Myeloproliferative disorders	Increase in purine turnover
High purine intake	Purines are metabolized to uric acid High purine intake increases uric acid levels High concentrations of purines are found in meats and organ meats (see diet recommendations below)
Alcohol	Alcoholic beverages, particularly beer and liquor, have been associated with an increased risk of gout
High-fructose corn syrup	High fructose corn syrup in beverages and foods has been associated with an increased risk of gout
HGPRT deficiency	Hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) is an enzyme involved in purine metabolism HGPRT deficiency leads to increased uric acid production HGPRT deficiency is a recessive X-linked trait so it is almost exclusively seen in males Lesch-Nyhan syndrome is marked by complete HGPRT deficiency
Genetic defects in renal urate transporters	Uric acid excretion is decreased Rare cause of gout

Reference [1,4,6]
MEDICATIONS THAT RAISE URIC ACID LEVELS
Medication	Comment
Thiazide diuretics	Thiazide diuretics promote uric acid retention in the kidneys
Loop diuretics	Loop diuretics promote uric acid retention in the kidneys
Aspirin	Aspirin has a dose-dependent effect on uric acid excretion Low-dose aspirin (≤ 325 mg/day) has a negligible effect on uric acid levels The American College of Rheumatology does not recommend stopping daily low-dose aspirin in patients with gout Aspirin doses of 600 - 2400 mg/day can cause significant uric acid retention High-dose aspirin (> 4 grams/day) promotes uric acid excretion and can lower plasma uric acid levels
Bempedoic acid (Nexletol®)	Bempedoic acid inhibits renal OAT2 and can raise uric acid levels
Cyclosporine	The immunosuppressant cyclosporine can raise uric acid levels
Niacin	Niacin, which can be used to treat high cholesterol, can raise uric acid levels
Tacrolimus	The immunosuppressant tacrolimus can raise uric acid levels
Ethambutol	The anti-tuberculosis drug ethambutol can raise uric acid levels
Pyrazinamide	The anti-tuberculosis drug pyrazinamide can raise uric acid levels Pyrazinamide inhibits renal excretion of uric acid
Chemotherapy	Cytotoxic agents can increase purine load/turnover
Ribavirin	Ribavirin can cause hemolytic anemia which can lead to elevated uric acid levels
Teriparatide (Forteo®)	The osteoporosis drug teriparatide can raise uric acid levels

DIAGNOSIS

Symptoms

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]

Reference [1,4]
2015 ACR CRITERIA FOR DIAGNOSING GOUT
Step 1 - patient must have experienced the following: At least one episode of swelling, pain, or tenderness in a peripheral joint or bursa
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 If crystals have not been observed, then proceed to Step 3
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
Criteria	Finding	Score
Pattern of joint involvement	Any involvement of the first MTP joint	2
Pattern of joint involvement	Any involvement of ankle or midfoot (without involvement of 1st MTP joint)	1
Symptoms during episode Erythema overlying affected joint (patient-reported or physician-observed) Can’t bear touch or pressure to affected joint Great difficulty with walking or inability to use affected joint	One symptom	1
	Two symptoms	2
	Three symptoms	3
Time course of episode Typical episode defined by ≥ 2 of the following, regardless of treatment: Time to maximal pain < 24 hours Resolution of symptoms in ≤ 14 days Complete resolution (to baseline level) between symptomatic episodes	One typical episode	1
	Two or more typical episodes	2
Evidence of tophi Draining or chalk-like subcutaneous nodule under transparent skin Overlying vascularity is often present Typical locations include joints, ears, olecranon bursae, finger pads, and tendons (e.g. Achilles)	Present	4
Uric acid level Ideally measured off of urate-lowering therapy and at > 4 weeks from the start of an episode	< 4 mg/dl (< 0.24 mmol/L)	- 4
	6 - <8 mg/dl (0.36 – <0.48 mmol/L)	2
	8 - <10 mg/dl (0.48 - <0.60 mmol/L)	3
	≥ 10 mg/dl (≥ 0.60 mmol/L)	4
Negative synovial fluid analysis If patient had synovial fluid evaluated during a symptomatic episode and no monosodium urate crystals were observed	True	- 2
Evidence of urate deposition on imaging Presence of any of the following: Ultrasound evidence of double-contour sign Dual-energy CT imaging demonstrating urate deposition X-ray evidence of gout-related joint damage of the hands and/or feet	Present	4

Laboratories

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% [7]

Imaging

X-ray

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 [4]

Ultrasound

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) [4]
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 [5]

Differential

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

^✝Reactive arthritis typically occurs 2 - 4 weeks after an infection with Shigella, Salmonella, Campylobacter, Chlamydia, or Strep throat

Reference [20,21,22,23]
Features of Different Arthritis Syndromes
Finding	Psoriatic arthritis	Rheumatoid arthritis	Lupus	Gout	Ankylosing spondylitis	Reactive arthritis	IBD-associated arthritis
Age of onset Male:Female	30 - 40s 1:1	35 - 50s 1:3	20 - 30s 1:9	30 - 60s 3:1	17 - 30s 3:1	20 - 30s 5:1	30s 2:1
Distal joints	Fingers and toes including DIP Asymmetric ≤ 4 joints	Fingers and toes, spares DIP Symmetric > 4 joints	Hands, wrists, knees Symmetric > 4 joints	Great toe, foot, ankle, knees, elbow Asymmetric < 4 joints	Lower limbs (30 - 50%) Asymmetric < 4 joints	Knees, ankles, hips Asymmetric < 4 joints	Hands and knees Asymmetric
Spine disease	Axial joints - 50% Sacroiliitis - 40%	Uncommon	Uncommon	Absent	100%	Sacroiliitis - 50% Back pain - 50%	30%
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 Urethritis (common) Self-limited - 80%	Occurs in 10 - 20% of patients with IBD

CALCIUM PYROPHOSPHATE DEPOSITION (PSEUDOGOUT)

Overview
- 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 [8]

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]

Symptoms

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.

Diagnosis

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]

Treatment

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
NSAIDs
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 [9]

TREATMENT | ACUTE ATTACKS

Reference [2,18]
2020 ACR recommendations for the treatment of acute gout attacks
General guidelines in all patients For optimal care, initiate therapy within 24 hours of symptom onset Urate-lowering therapy should be continued during an acute gout attack. It is okay to start urate-lowering therapy during an acute attack once it is under control. Applying ice to affected joint(s) may be beneficial
For mild-moderate pain affecting one or a few small joints, or 1 - 2 large joints, use one of the following: NSAID or COX-2 inhibitor Systemic (oral or intramuscular) steroids Intra-articular steroids Low-dose colchicine (1.2 mg immediately followed by 0.6 mg an hour later) For any patient, if monotherapy is ineffective, patient may be switched to another therapy or combination therapy (see below) may be tried
For severe pain affecting multiple joints, consider the following combination therapy: NSAID + colchicine Systemic steroids + colchicine Intra-articular steroids + NSAIDs OR Colchicine OR Systemic steroids
Patients who cannot tolerate or have contraindications to anti-inflammatory therapy Consider canakinumab (Ilaris®)

NSAIDs

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)

Medications (FDA-approved)	Dosing
Naproxen	750 mg starting dose followed by 250 mg every 8 hours until attack resolves
Indomethacin	50 mg three times a day until pain is tolerable, then taper
Sulindac	200 mg twice a day until satisfactory response, then taper

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

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

Corticosteroids

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

Intramuscular

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

Intra-articular

Dosing should be based on size of the joint
Can be used in combination with NSAIDs, colchicine, or oral corticosteroids

TREATMENT | HYPERURICEMIA

Reference [1,2,18]
2020 ACR recommendations for the treatment of hyperuricemia
Indications for treatment Urate-lowering therapy is indicated if there is an established diagnosis of gout and any of the following: Presence of tophi Radiographic damage (any modality) attributable to gout Frequent attacks defined as ≥ 2 attacks/year Chronic kidney disease (CrCl ≤ 59 ml/min) History of kidney stones - treatment helps prevent calcium oxalate (most common type) and uric acid stones Serum urate ≥ 9 mg/dl Treatment is not recommended in the following: Asymptomatic hyperuricemia Patients with first gout flare and uric acid < 9 mg/dl
General recommendations Dietary and lifestyle recommendations Consider stopping nonessential medications that raise uric acid levels (see medications above) In patients with hypertension, consider using losartan as part of the antihypertensive regimen when feasible Low-dose daily aspirin should not be stopped When initiating urate-lowering therapy, gout flare prophylaxis should also be started (see below)
Gout flare prophylaxis during treatment initiation When initiating urate-lowering therapy, the risk of acute gout attack is increased All patients should take a gout flare prophylaxis regimen when starting urate-lowering therapy. The duration of prophylaxis should be 3 - 6 months in most patients. Patients who continue to have attacks may require longer prophylaxis. If tophi are present, prophylaxis should continue for 6 months after achieving target urate level and when there has been resolution of the tophi. Gout flare prophylaxis regimens include the following: Colchicine - 0.5 - 0.6 mg once or twice daily (first-line) Low-dose NSAID - for example, naproxen 250 mg twice a day with PPI if necessary (first-line) Low-dose corticosteroids - defined as prednisone ≤ 10 mg/day (second-line)
Treatment steps Step 1 - initiate urate-lowering therapy Target serum uric acid level should be < 6 mg/dl. A target of < 5 mg/dl may be appropriate in patients with continued symptoms. Urate-lowering therapy may be started during an acute attack provided effective acute treatment has been established Urate-lowering therapy should be continued indefinitely in most patients Preferred first-line agent is allopurinol in all patients including those with CrCl < 60 ml/min. Second-line choice is febuxostat. If patient has contraindication or cannot tolerate a xanthine oxidase inhibitor, then probenecid may be used Titrate monotherapy to maximum appropriate dose in order to achieve target uric acid level Check serum uric acid level every 2 - 5 weeks during titration All patients should receive gout flare prophylaxis as above Step 2 - if target uric acid level and/or control is not achieved with first xanthine oxidase inhibitor Switch to the other xanthine oxidase inhibitor - febuxostat or allopurinol Step 3 - if target uric acid level and/or control is not achieved with other xanthine oxidase inhibitor Add probenecid Step 4 - if target uric acid level and/or control is not achieved with xanthine oxidase inhibitor + probenecid, consider switching to pegloticase in some patients Pegloticase should be reserved for patients who have failed to achieve target uric acid levels and who have frequent gout flares or nonresolving subcutaneous tophi. Pegloticase is not recommended in patients who are not at target uric acid levels but have infrequent attacks and no tophi.

Medication-specific recommendations

Allopurinol

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.

Reference [1]
2012 ACR diet and lifestyle recommendations for patients with gout
General recommendations for all patients Weight loss for obese patients Smoking cessation Exercise Stay well hydrated (≥ 1.5 liters of fluid/day)
MEAT RECOMMENDATIONS
AVOID	LIMIT	ENCOURAGE
Organ meats high in purines Kidney, liver, sweetbreads	Serving sizes of: Beef, lamb, pork Anchovies, sardines, herring, mackerel, scallops, mussels	Low-fat or nonfat dairy products
High concentrations of purines are found in anchovies, sardines, herring, mackerel, scallops, mussels, waterfowl, organ meats, glandular tissue, gravies, and meat extracts Moderate-high concentrations of purines are found in shellfish, fish, game meats, mutton, beef, pork, poultry, and meat-based soups and broths See the U.K. Gout Society dietary recommendations pdf for more information on diet and gout
SUGAR RECOMMENDATIONS
AVOID	LIMIT	ENCOURAGE
High-fructose corn syrup-sweetened sodas, other beverages, and foods	Servings of naturally sweet fruit juices Table sugar, sweetened beverages and desserts Table salt including what is in sauces and gravies	Vegetables
ALCOHOL RECOMMENDATIONS
AVOID	LIMIT	ENCOURAGE
Alcohol overuse (> 2 drinks/day in men, > 1 drink/day in women) Avoid all alcohol during acute attacks or periods of uncontrolled gout	All alcohol intake, particularly beer but also wine and liquor

SEQUELAE

Overview

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]

STUDIES

Allopurinol vs Febuxostat for Prevention of Gout Flare, NEJM Evidence (2022) [PubMed abstract]

The study enrolled 940 adults with gout and hyperuricemia, with at least 33% having stage 3 kidney disease (GFR 30 - 60 ml/min)

Main inclusion criteria

Age ≥ 18 years
Meet ACR gout criteria
Serum urate ≥ 6.8 mg/dl

Main exclusion criteria

GFR < 30 ml/min
Uric acid > 15 mg/dl
High-risk for HLA-B*5801 haplotype
Previous allopurinol failure at doses > 300 mg/day

Baseline characteristics

Average age 62 years
Male sex - 98%
Average BMI - 33.7
CrCl 30 - 59 ml/min - 37%
Average uric acid - 8.5 mg/dl
Average length of gout - 10 years
Taking allopurinol - 36.7%

Randomized treatment groups

Group 1 (468 patients): Allopurinol titrated up to 800 mg/day to achieve a uric acid level < 6 mg/dl (< 5 mg/dl if tophi were present)
Group 2 (472 patients): Febuxostat titrated up to 120 mg/day to achieve a uric acid level < 6 mg/dl (< 5 mg/dl if tophi were present)
The trial had 3 treatment phases: titration (weeks 0 to 24), maintenance (weeks 25 to 48), and observation (weeks 49 to 72)
Allopurinol and febuxostat were initiated at daily doses of 100 and 40 mg, respectively. Allopurinol was increased by 100 mg every 3 weeks as needed. Febuxostat was increased by 40 mg every 9 weeks as needed.
All participants received guideline-directed antiinflammatory prophylaxis with colchicine, NSAIDs, or glucocorticoids per investigator choice during phases 1 and 2

Primary outcome: Proportion of participants experiencing one or more gout flares during phase 3. Gout flare was based on patient reporting.

Results

Outcome	Allopurinol	Febuxostat	Comparisons
Duration: 72 weeks
Primary outcome	36.5%	43.5%	diff -7%, 95%CI (-∞ to -1.2)
Uric acid < 6 mg/dl in phase 2	81.1%	78.4%	RR 1.04, 95%CI (0.96 to 1.11)
Cardiovascular events	8.1%	6.8%	RR 1.20, 95%CI (0.76 to 1.88)
Median drug dose	400 mg	40 mg	N/A
90% of participants were given colchicine for prophylaxis during phases 1 and 2 For patients with chronic kidney disease, the primary outcome occurred in 31.9% of allopurinol-treated patients and 45.3% of febuxostat-treated patients. Adverse events were similar between groups Both groups had a 21% dropout rate

Findings: Allopurinol and febuxostat achieved serum urate goals in patients with gout; allopurinol was noninferior to febuxostat in controlling flares. Similar outcomes were noted in participants with stage 3 chronic kidney disease.

Pegloticase vs Placebo in Allopurinol-Refractory Gout, JAMA (2011) [PubMed abstract]

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)

Baseline characteristics

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.

Results

Outcome	Peg biweekly	Peg monthly	Placebo	Comparisons
Duration: 6 months
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
Infusion reactions	26%	42%	5%	N/A
Anti-pegloticase antibodies developed in 89% of patients in the pegloticase groups

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.

STUDY
Colchicine vs Naproxen for Acute Gout Flare, BMJ (2020) [PubMed abstract]

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
Results:

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.

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GOUT

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