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  • GOUT

Gout review

Medications for acute attacks

Medications to lower uric acid






  • PREVALENCE
    • In the U.S., the self-reported prevalence of gout in adults is estimated to be 3.9%. Worldwide, gout is the most common cause of inflammatory arthritis in developed countries.
    • 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 (diuretics, etc.). [1,4]



  • 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]


    • 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 surround 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
    • General risk factors for gout are presented in the table below

  • Reference [2,3,4]
Risk factors for gout
Risk factor Comment
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 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
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 phosphoribosyltransferase (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


  • Medications that raise uric acid levels
    • Medications that increase the risk for gout are presented in the table below

  • Reference [1,4,6]
Medications that increase the risk for gout
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) can raise uric acid levels. The effect is negligible, and the American College of Rheumatology does not recommend stopping daily prophylactic 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
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]

    • Differential
      • Other conditions that can mimic gout 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

    • ACR criteria
      • The American College of Rheumatology published criteria for diagnosing gout in 2015
      • The criteria are presented in the table below

  • Reference [1,4]
ACR 2015 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 Characteristics Score
Pattern of joint involvement
  • Any involvement of the first metatarsophalangeal joint
2
  • Any involvement of ankle or midfoot (without involvement of 1st metatarsophalangeal 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, often with overlying vascularity, located in typical locations: joints, ears, olecranon bursae, finger pads, 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 elevate uric acid levels 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 include the "double contour sign" which is caused by urate crystal deposition along the surface of hyaline cartilage in the affected joint [4]

      • 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]



  • 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."

      • Pathology
        • 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 for CPD
        • 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/diagnosis
        • 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]

      • 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 FOR ACUTE ATTACKS
    • The treatment of gout can be divided into two main parts - treatment of acute attacks and treatment of hyperuricemia
    • In 2012, the American College of Rheumatology published guidelines for the treatment of gout. The guidelines for the treatment of acute attacks are presented in the table below.

  • Reference [2]
ACR 2012 guidelines for treating 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
    • Applying ice to affected joint(s) may be beneficial [2]

  • 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 steroids
    • Colchicine

  • 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

  • For any patient, if monotherapy is ineffective, patient may be switched to another therapy or combination therapy may be tried

Medication dosing guidelines
  • Nonsteroidal anti-inflammatory drugs (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)

Medication
(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) [PubMed abstract]

      • 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 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 OF HYPERURICEMIA
    • The treatment of gout can be divided into two main parts - treatment of acute attacks and treatment of hyperuricemia
    • In 2012, the American College of Rheumatology published guidelines for the treatment of gout
    • The guidelines for medications to treat hyperuricemia are presented in the table below
    • Diet and lifestyle recommendations can be found here - diet and lifestyle recommendations for hyperuricemia

  • Reference [1,10,11,12,13]
ACR 2012 guidelines for the treatment of hyperuricemia
  • Urate-lowering therapy is indicated if there is an established diagnosis of gout and any of the following:
    • Presence of tophi
    • Frequent attacks defined as ≥ 2 attacks/year
    • Chronic kidney disease - stage II (CrCl ≤ 89 ml/min) or worse
    • History of kidney stones - patients should have urine uric acid evaluation (see kidney stones for more)
  • General recommendations for all patients
    • Dietary and lifestyle recommendations
    • Consider stopping non-essential medications that raise uric acid levels (see medications above)
    • Urate-lowering therapy may be started during an acute attack provided effective acute treatment has been established
    • When initiating urate-lowering therapy, gout flare prophylaxis should also be started

      • Regimens for gout flare prophylaxis when initiating urate-lowering therapy
        • 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)
        • DURATION: prophylaxis should continue for at least six months and for 3 months after achieving target serum urate levels, whichever is greater. If tophi are present, prophylaxis should continue for 6 months after achieving target urate level and when there has been resolution of the tophi.

  • 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.
    • Preferred first-line agent is a xanthine oxidase inhibitor - allopurinol or 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
    • If allopurinol does not achieve target uric acid level, patient may be switched to febuxostat, and vice versa
    • 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 is not achieved with xanthine oxidase inhibitor, add uricosuric drug
    • Probenecid is the first choice
    • Other uricosuric drugs (fenofibrate, losartan) may be used if appropriate.
    • NOTE: When the guidelines were published, lesinurad was not available. In addition, the diabetic drug class called SGLT2 inhibitors is also uricosuric but was not available when the guidelines were published.

  • Step 3 - if target uric acid level is not achieved with xanthine oxidase inhibitor + probenecid, use pegloticase

Medication 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.
    • Consider HLA-B*5801 testing in high-risk populations (e.g. Koreans with CrCl ≤ 59 ml/min, and Han Chinese and Thai irrespective of renal function)

  • 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, then 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

  • 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 < 50 ml/min then probenecid should not be used as a first-line agent
    • If patient has history of kidney stones, then probenecid should not be used as a first-line agent
    • Urinary uric acid levels should be measured before and during therapy as appropriate. If levels are elevated, uricosurics are contraindicated. If urinary uric acid rises above 700 mg/day during therapy, the risk of kidney stones is increased and the dosage should be reduced.
    • Consider urinary alkalinization (potassium citrate), increased fluids, and urinary pH monitoring to prevent kidney stones

  • 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.


  • DIET AND LIFESTYLE CHANGES TO TREAT HYPERURICEMIA
    • The ACR published dietary and lifestyle recommendations in 2012 for patients with gout
    • The recommendations are presented in the table below

  • Reference [1]
ACR 2012 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
    • 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]









Drug Dosage form Dosage Generic/Price Other Mechanism of Action/
FDA-approved indications
Side Effects
P = % of patients on placebo
who experienced side effect
Drug Interactions Precautions/
Contraindications
Colchicine

(Colcrys®)
(Mitigare®)
Tablet - Colcrys®
  • 0.6 mg

Capsule - Mitigare®
  • 0.6 mg

Col-Probenecid®
  • Colchicine : Probenecid
    • 0.5 mg : 500 mg
Colcrys®   
Treatment of acute gout flare - Adults
  • 1.2 mg at the first sign of a flare followed by 0.6 mg one hour later
  • The maximum dose for an acute flare is 1.8 mg over one hour
  • If taking during a prophylactic regimen, wait 12 hours before resuming the regimen
Gout flare prophylaxis (≥ 16 years old)
  • 0.6 mg once or twice daily
  • Maximum recommended dose is 1.2 mg/day
Familial Mediterranean Fever - Adults
  • 1.2 - 2.4 mg/day given in one or two divided doses
  • Increase dose in increments of 0.3 mg/day as tolerated
Familial Mediterranean Fever - Children ≥ 4 years
  • 4 - 6 years: 0.3 - 1.8 mg/day given in one or two divided doses
  • 6 - 12 years: 0.9 - 1.8 mg/day given in one or two divided doses
  • > 12 years: 1.2 - 2.4 mg/day given in one or two divided doses

Mitigare®   
Gout flare prophylaxis - Adults
  • 0.6 mg once or twice daily
  • Maximum recommended dose is 1.2 mg/day

Dosing with CYP3A4 and/or P-glycoprotein inhibitors
Col-Probenecid®   
Treatment of gout - Adults
  • Starting: one tablet once daily for a week
  • Maintenance: one tablet twice a day
  • Maximum: 4 tablets a day
  • Increase dose by 1 tablet every 4 weeks if symptoms are not controlled
  • If urinary uric acid excretion exceeds 700 mg/day, the risk of kidney stones increases and the dose should be reduced
  • See probenecid for more
Colcrys®
NO/$ (3 tablets)

Mitigare®
NO/$$$ (30 capsules)

Col-probenecid®
YES/$ (60 tablets)

  • May take without regard to food
Mechanism of action
  • Mechanism not completely understood
  • Evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β
  • Additionally, colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules, and consequently prevents the activation, degranulation, and migration of neutrophils thought to mediate some gout symptoms

FDA-approved indications

Colcrys
  • Treatment of acute gout attacks
  • Gout flare prophylaxis
  • Familial Mediterranean fever

Mitigare
  • Gout flare prophylaxis

Col-Probenecid
  • Hyperuricemia in gout complicated by frequent attacks
NOTE: only side effects that occurred at an overall incidence of ≥ 2% and at an incidence greater than placebo are listed. Data is from Colcrys PI.

  • Diarrhea - 23%, P - 14%
  • Gout - 4%, P - 2%
  • Throat pain - 3%, P - 0%
  • Colchicine is a CYP3A4 and P-glycoprotein sensitive substrate. Colchicine has an extensive list of potential drug interactions. See the Colcrys PI [sec 2.4 and 7] for a list of interactions and recommendations.
  • Colchicine should not be given with P-glycoprotein inhibitors or strong CYP3A4 inhibitors in patients with renal or hepatic disease. Patients with normal renal and hepatic function may require dose adjustments.
  • Drug interactions - colchicine should not be given with P-glycoprotein inhibitors or strong CYP3A4 inhibitors in patients with renal or hepatic disease. Patients with normal renal and hepatic function may require dose adjustments. See the Colcrys PI [sec 2.4 and 7] for recommendations.
  • Blood dyscrasias - blood dyscrasias including leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported in patients taking colchicine
  • Muscle toxicity - neuromuscular toxicity including rhabdomyolysis has been reported in patients receiving colchicine. Elderly patients and patients with kidney disease may be at increased risk. Concomitant statins, fibrates, or cyclosporine may also increase the risk.
  • Liver disease
    • Gout flare prophylaxis
      • Mild to moderate (Child-Pugh A/B): no dose adjustment necessary
      • Severe (Child-Pugh C): consider dose adjustment. Manufacturer makes no specific recommendation.
    • Treatment of acute attack
      • Mild to moderate (Child-Pugh A/B): no dose adjustment necessary
      • Severe (Child-Pugh C): no dose adjustment necessary. Do not repeat treatment course more than once every 2 weeks.
      • Patients receiving colchicine prophylaxis with any degree liver disease: do not use colchicine for acute attack
  • Kidney disease
    • Gout flare prophylaxis
      • CrCl ≥ 30 ml/min: no dose adjustment necessary
      • CrCl < 30 ml/min: starting dose is 0.3 mg once daily. Increase dose with caution.
    • Treatment of acute attack
      • CrCl ≥ 30 ml/min: no dose adjustment necessary
      • CrCl < 30 ml/min: no dose adjustment necessary. Do not repeat treatment course more than once every 2 weeks.
      • Patients receiving colchicine prophylaxis with any degree kidney disease: do not use colchicine for acute attack

Drug Dosage form Dosage Generic/Price Other Mechanism of Action/
FDA-approved indications
Side Effects Drug Interactions Precautions/
Contraindications
Allopurinol

(Zyloprim®)
Tablet
  • 100 mg
  • 300 mg
Hyperuricemia in gout
  • Starting: 100 mg once daily
  • Maintenance:
    • Mild gout: 200 - 300 mg/day
    • Moderate-severe: 400 - 600 mg/day
  • Maximum: 800 mg/day
  • Increase dose by 100 mg/day at weekly intervals
  • Doses > 300 mg/day should be given in divided doses
  • Target uric acid level is < 6 mg/dl
  • When initiating therapy, patients should receive prophylaxis against acute attacks - see ACR recommendations for more
  • Check uric acid level every 2 - 5 weeks during titration

Hyperuricosuria in patients with calcium oxalate stones
  • Dosing: 200 - 300 mg/day
  • Adjust dose up or down until desired effect
  • Dose may be given in one or two divided doses
  • Normal uric acid excretion is < 800 mg/day in men, and < 750 mg/day in women
  • See kidney stones for more
Allopurinol
YES/$ (30 tablets)

  • Take after meals to minimize stomach upset

  • It is not necessary to discontinue allopurinol during an acute gout flare

  • Maintain good fluid intake
Mechanism of action
  • Xanthine oxidase is a key enzyme involved in the metabolism of purines. Allopurinol inhibits xanthine oxidase and prevents the production of uric acid.

  • See pathology above for more

FDA-approved indications

  • Hyperuricemia in gout
  • Hyperuricosuria in patients with calcium oxalate stones
  • Hyperuricemia associated with cancer treatment
NOTE: incidence of side effects is not well-defined

  • Acute gout attack - up to 6%
  • Rash - up to 3%
  • Diarrhea
  • Nausea
  • Elevated liver enzymes
  • Drowsiness
  • Azathioprine - allopurinol inhibits one pathway of azathioprine metabolism and may lead to toxicity if given concomitantly. Reduce azathioprine dose to a fourth or a third of the usual dose when given with allopurinol. If patients have low TPMT activity, allopurinol should not be given with azathioprine.
  • Mercaptopurine - allopurinol inhibits one pathway of mercaptopurine metabolism and may lead to toxicity if given concomitantly. Reduce mercaptopurine dose to a fourth or a third of the usual dose when given with allopurinol. If patients have low TPMT activity, allopurinol should not be given with azathioprine.
  • Uricosuric agents - uricosuric agents may increase the excretion of oxipurinol, the major active metabolite of allopurinol. This may decrease the effectiveness of allopurinol.
  • Thiazide diuretics - there have been case reports of renal toxicity in patients receiving allopurinol with thiazide diuretics. It's unclear if the toxicity was related to a drug interaction.
  • Cytotoxic agents (e.g. cyclophosphamide) - cases of enhanced bone marrow suppression have been reported in patients receiving allopurinol with cytotoxic agents
  • Chlorpropamide - allopurinol may increase the half-life of chlorpropamide and increase the risk of hypoglycemia
  • Cyclosporine - allopurinol may increase levels of cyclosporine. Monitor levels closely when co-administered
  • Ampicillin and amoxicillin - there have been reports of an increase in the frequency of skin rashes in patients receiving ampicillin/amoxicillin with allopurinol
  • Dicumarol - allopurinol may prolong the half-life of the anticoagulant, dicumarol
  • Acute gout attack - when initiating allopurinol, the risk of an acute gout attack is increased. This may be due to the mobilization of uric acid from tissue deposits which causes fluctuations in uric acid levels. The ACR recommends prophylactic therapy when initiating allopurinol - see gout flare prophylaxis for more.
  • Skin rash - allopurinol may cause a skin rash in some patients. The most common rash is a pruritic, maculopapular rash that may become scaly or exfoliative. Severe skin reactions including Stevens-Johnson syndrome and/or vasculitis may occur. Patients should stop allopurinol immediately at the first signs of a skin rash.
  • Allopurinol hypersensitivity syndrome - allopurinol may cause a hypersensitivity syndrome marked by Stevens-Johnson syndrome, toxic epidermal necrolysis, eosinophilia, vasculitis, rash, and major end-organ disease. The incidence of the syndrome is estimated to be ∼ 1:1000 in the U.S.. The syndrome has a morbidity and mortality rate of up to 25%. The HLA-B*5801 haplotype has been associated with an increased risk. The ACR recommends testing high-risk individuals for the HLA-B*5801 haplotype before initiating allopurinol therapy. High-risk individuals include Han Chinese and Thai regardless of kidney function, and Koreans with CrCl ≤ 59 ml/min.
  • Liver toxicity - cases of reversible liver toxicity including asymptomatic liver enzyme elevations have been reported in some patients. If signs of liver toxicity develop (e.g. weight loss, jaundice, anorexia), liver functions should be evaluated. In patients with pre-existing liver disease, liver function tests should be monitored periodically when beginning therapy.
  • Renal toxicity - cases of renal toxicity have been observed in patients receiving allopurinol. Patients with kidney disease should be monitored closely when receiving allopurinol.
  • Bone marrow suppression - cases of bone marrow suppression have been reported in patients receiving allopurinol. In most cases, patients were receiving other medications that are potentially myelosuppressive.
  • Liver disease - in patients with liver disease, periodic liver function tests are recommended during the early stages of therapy. Manufacturer makes no dosage recommendations.
  • Kidney disease
    • CrCl 10 - 20 ml/min: recommended dose is 200 mg/day
    • CrCl < 10 ml/min: do not exceed 100 mg/day. Consider increasing dosing interval.

Drug Dosage form Dosage Generic/Price Other Mechanism of Action/
FDA-approved indications
Side Effects
P = % of patients on placebo
who experienced side effect
Drug Interactions Precautions/
Contraindications
Febuxostat

(Uloric®)
Tablet
  • 40 mg
  • 80 mg
Hyperuricemia in gout
  • Starting: 40 mg once daily
  • If patients do not achieve uric acid < 6 mg/dl after 2 weeks then increase dose to 80 mg once daily
  • The ACR states that the dose may be raised to 120 mg once daily (a dose approved in many countries outside the U.S.)
  • When initiating therapy, patients should receive prophylaxis against acute attacks - see ACR recommendations for more
Febuxostat
NO/$$$$ (30 tablets)

  • May take without regard to food or antacids

  • It is not necessary to discontinue febuxostat during an acute gout flare

  • Maintain good fluid intake
Mechanism of action
  • Xanthine oxidase is a key enzyme involved in the metabolism of purines. Febuxostat inhibits xanthine oxidase and prevents the production of uric acid.

  • See pathology above for more

FDA-approved indications
  • Hyperuricemia in gout
NOTE: Only side effects that were seen in ≥ 1% of febuxostat patients and at an incidence ≥ 0.5% more than placebo are listed. Data is for febuxostat 80 mg.

  • Elevated liver enzymes - 4.6%, P - 0.7%
  • Nausea - 1.3%, P - 0.7%
  • Arthralgia - 0.7%, P - 0%
  • Rash - 1.6%, P - 0.7%
  • Azathioprine - DO NOT COMBINE. Febuxostat may inhibit azathioprine metabolism and lead to toxicity.
  • Mercaptopurine - DO NOT COMBINE. Febuxostat may inhibit mercaptopurine metabolism and lead to toxicity.
  • Theophylline - febuxostat inhibits theophylline metabolism. In studies, febuxostat caused a 400-fold increase in the major theophylline metabolite, 1-methylxanthine. Use caution if given concomitantly.
  • Febuxostat is metabolized by UGT1A1, UGT1A3, UGT1A9, and UGT2B7. It also undergoes oxidation via CYP1A2, CYP2C8, and CYP2C9. Febuxostat is a CYP2D6 weak inhibitor.
  • Acute gout attack - when initiating febuxostat, the risk of an acute gout attack is increased. This may be due to the mobilization of uric acid from tissue deposits which causes fluctuations in uric acid levels. The ACR recommends prophylactic therapy when initiating febuxostat - see gout flare prophylaxis for more.
  • Cardiovascular events - in long-term studies, there was a slightly higher risk of cardiovascular events in febuxostat-treated patients (0.74 events/100 patients-years) when compared to allopurinol-treated patients (0.60 events/ 100 patient-years). A causal link between febuxostat and events has not been established.
  • Liver toxicity - there have been case reports of liver toxicity in patients receiving febuxostat. In trials, 3% of febuxostat-treated patients had ALT elevations ≥ 3 X ULN. The manufacturer recommends checking liver enzymes at baseline and in patients who develop signs of liver disease (e.g. fatigue, anorexia, right upper abdominal discomfort, dark urine, jaundice). Febuxostat should be discontinued in patients who have ALT levels > 3 X the reference range with serum total bilirubin > 2 X the reference range.
  • Liver disease
    • Mild to moderate (Child-Pugh A/B): no dose adjustment necessary
    • Severe (Child-Pugh C): has not been studied. Use caution.
  • Kidney disease
    • CrCl ≥ 30 ml/min: no dose adjustment necessary
    • CrCl < 30 ml/min: has not been studied. Use caution.

Drug Dosage form Dosage Generic/Price Other Mechanism of Action/
FDA-approved indications
Side Effects Drug/Lab Interactions Precautions/
Contraindications
Probenecid

(Probalan®)
Tablet - Probenecid
  • 500 mg

Col-Probenecid®
  • Colchicine : Probenecid
    • 0.5 mg : 500 mg
Probenecid   
Hyperuricemia in gout
  • Starting: 250 mg twice a day for 1 week
  • Maintenance: 500 mg twice a day
  • Maximum: 2000 mg/day
  • Increase daily dose by 500 mg every 4 weeks if necessary
  • If urinary uric acid excretion exceeds 700 mg/day, the risk of kidney stones increases and the dose should be reduced
  • Patients should maintain good fluid intake to help prevent kidney stones
  • Urinary alkalinization with potassium citrate is recommended until serum urate levels return to normal and tophi disappear
  • When initiating therapy, patients should receive prophylaxis against acute gout attacks - see ACR recommendations for more
  • After uric acid levels normalize, dose should be reduced by 500 mg every 6 months to lowest effective dose

Facilitate increase in beta-lactam antibiotic levels
  • 2000 mg/day given in divided doses
  • Beta-lactams include penicillins, cephalosporins, and carbapenems

Col-Probenecid®   
Treatment of gout
  • Starting: one tablet once daily for a week
  • Maintenance: one tablet twice a day
  • Maximum: 4 tablets a day
  • Increase dose by 1 tablet every 4 weeks if symptoms are not controlled
  • If urinary uric acid excretion exceeds 700 mg/day, the risk of kidney stones increases and the dose should be reduced
  • See colchicine for more
Probenecid
YES/$ (60 tablets)

Col-Probenecid®
YES/$ (60 tablets)
  • It is not necessary to discontinue probenecid during a gout flare

  • Maintain good fluid intake
Mechanism of action
  • Probenecid inhibits renal tubular reabsorption of urate. This causes urate to be lost in the urine.

  • Probenecid inhibits renal secretion of beta-lactam antibiotics. This causes a 2 - 4 fold increase in beta-lactam plasma levels. Beta-lactams include penicillins, cephalosporins, and carbapenems.

FDA-approved indications

Probenecid
  • Hyperuricemia in gout
  • Facilitate increase in beta-lactam antibiotic levels

Col-Probenecid
  • Hyperuricemia in gout complicated by frequent attacks
NOTE: Incidence of side effects and strength of association are not well-defined

  • Acute gout attack
  • Kidney stones
  • Urinary frequency
  • Headache
  • Dizziness
  • Vomiting/Nausea/Anorexia
  • Hepatic necrosis
  • Nephrotic syndrome
  • Hypersensitivity reactions
  • Aplastic anemia/leukopenia/hemolytic anemia
  • Dermatitis
  • Alopecia
  • Flushing
  • Sore gums
Drug interactions
  • Salicylates (aspirin, etc.) - salicylates reduce the uricosuric effects of probenecid. Low-dose aspirin does not appear to have this effect. [12,14]
  • Beta-lactam antibiotics - probenecid blocks the secretion of beta-lactam antibiotics and raises their plasma levels. This effect can be used therapeutically in some cases, but may lead to adverse drug reactions in other cases. Beta-lactams include penicillins, cephalosporins, and carbapenems.
  • Pyrazinamide - pyrazinamide reduces the uricosuric effects of probenecid
  • Sulfonamides (e.g. antibiotics, diuretics, sulfonylureas) - probenecid increases sulfonamide levels. The effect is generally mild, but may become significant with prolonged coadministration. Patients taking sulfonylureas should monitor blood glucose levels closely while taking probenecid.
  • Indomethacin - probenecid may increase the half-life of indomethacin. Lower doses of indomethacin may be necessary.
  • Acetaminophen - probenecid may increase the half-life of acetaminophen. Lower doses of acetaminophen may be necessary.
  • Naproxen - probenecid may increase the half-life of naproxen. Lower doses of naproxen may be necessary.
  • Ketoprofen - probenecid may increase the half-life of ketoprofen. Lower doses of ketoprofen may be necessary.
  • Meclofenamate - probenecid may increase the half-life of meclofenamate. Lower doses of meclofenamate may be necessary.
  • Sulindac - probenecid may increase levels of sulindac. Sulindac may cause a modest reduction in the uricosuric effect of probenecid.
  • Lorazepam - probenecid may increase the half-life of lorazepam. Lorazepam dose should be decreased by 50% when taken with probenecid.
  • Methotrexate - probenecid may increase plasma concentrations of methotrexate. If given concomitantly, reduce methotrexate dose and monitor blood levels.
  • Rifampin - probenecid may increase the half-life of rifampin. Lower doses of rifampin may be necessary.
  • Thiopental - probenecid may increase the effects of thiopental
  • Ketamine - probenecid may increase the effects of ketamine

Lab interactions
  • Theophylline - probenecid may cause falsely elevated theophylline levels when measured with the Schack and Waxler technique
  • Urine glucose - probenecid may cause a false-positive urine glucose test
  • Uric acid kidney stones - DO NOT USE. Probenecid should not be given to patients with a history of uric acid kidney stones.
  • Blood dyscrasias - DO NOT USE
  • Calcium kidney stones - probenecid increases the risk of both uric acid and calcium kidney stones. Probenecid should not be used as a first-line agent in patients with a history of calcium stones. Urinary alkalinization with potassium citrate may be necessary to prevent kidney stones in some patients. See kidney stones for more.
  • Uricosuria - urinary uric acid levels should be measured before and during therapy as appropriate. If levels are elevated, probenecid is contraindicated. If urinary uric acid rises above 700 mg/day during therapy, the risk of kidney stones is increased and the dosage should be reduced.
  • Acute gout attack - when initiating probenecid, the risk of an acute gout attack is increased. This may be due to the mobilization of uric acid from tissue deposits which causes fluctuations in uric acid levels. The ACR recommends prophylactic therapy when initiating probenecid - see gout flare prophylaxis for more.
  • Hypersensitivity reactions - hypersensitivity reactions including anaphylaxis have been reported with probenecid
  • Peptic ulcers - use caution
  • Liver disease - manufacturer makes no specific recommendation
  • Kidney disease - probenecid may be less effective in patients with kidney disease, particularly when the CrCl is less than 30 ml/min. Probenecid should not be used as a first-line agent when the CrCl is less than 50 ml/min. Probenecid should not be used to increase beta-lactam levels in patients with kidney disease.

Drug Dosage form Dosage Generic/Price Other Mechanism of Action/
FDA-approved indications
Side Effects
P = % of patients on placebo
who experienced side effect
Drug/Lab Interactions Precautions/
Contraindications
Lesinurad

(Zurampic®)
Tablet - lesinurad
  • 200 mg
Hyperuricemia in gout
  • Dosing: 200 mg once daily
  • Maximum: 200 mg once daily
  • Lesinurad should be taken with a xanthine oxidase inhibitor (allopurinol or febuxostat). It should not be used as monotherapy.
  • Lesinurad is not recommended in patients taking < 300 mg of allopurinol (or < 200 mg in patients with CrCl < 60 ml/min)
  • If xanthine oxidase inhibitor therapy is interrupted, lesinurad should also be interrupted. Failure to do so may increase risk of renal events.
  • When initiating therapy, patients should receive prophylaxis for acute gout attacks - see ACR recommendations for more
Lesinurad (Zurampic®)
NO/$$$$
  • Take in the morning with food or water

  • Take at the same time as xanthine oxidase inhibitor

  • Maintain good fluid intake of at least 2 liters/day

  • It is not necessary to stop lesinurad therapy during an acute gout flare
Mechanism of action
  • Lesinurad inhibits renal tubular reabsorption of uric acid. Lesinurad has been shown to inhibit uric acid transporter 1 (URAT1) and organic anion transporter 4 (OAT4). URAT1 is responsible for the majority of the reabsorption of filtered uric acid from the renal tubular lumen.


FDA-approved indications
  • Hyperuricemia in gout - should only be used in combination with a xanthine oxidase inhibitor in patients who have not achieved target uric acid levels on a xanthine oxidase inhibitor alone
NOTE: Only side effects that occurred at an overall incidence of ≥ 2% and ≥ 1% more than placebo are listed

  • Headache - 5.3%, P - 4.1%
  • Influenza - 5.1%, P - 2.7%
  • Increased serum creatinine - 4.3%, P - 2.3%
  • GERD - 2.7%, P - 0.8%
  • Valproic acid - DO NOT COMBINE. Valproic acid is an epoxide hydrolase inhibitor. Epoxide hydrolase inhibitors may block the metabolism of lesinurad.
  • Epoxide hydrolase inhibitors - DO NOT COMBINE. Epoxide hydrolase inhibitors may block the metabolism of lesinurad. Lesinurad should not be given with epoxide hydrolase inhibitors.
  • CYP2C9 inhibitors and inducers - lesinurad is a sensitive CYP2C9 substrate. CYP2C9 inhibitors may increase blood levels of lesinurad and CYP2C9 inducers may decrease blood levels. Use caution when combining.
  • CYP3A4 substrates - lesinurad is weak inducer of CYP3A4. Blood levels of CYP3A4 sensitive substrates may be reduced when taken with lesinurad.
  • Hormone contraceptives - hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when taken with lesinurad. Backup forms of contraception should be used.
  • Aspirin - Aspirin at doses > 325 mg/day may decrease the effectiveness of lesinurad. Doses ≤ 325 mg/day do not decrease the efficacy of lesinurad.
  • Sildenafil - in studies, lesinurad reduced plasma concentrations of sildenafil, a CYP3A4 substrate
  • Amlodipine - in studies, lesinurad reduced plasma concentrations of amlodipine, a CYP3A4 substrate
  • CYP2C9 poor metabolizers - lesinurad is a CYP2C9 sensitive substrate. Poor CYP2C9 metabolizers may have increased exposure to lesinurad. Use caution in these patients.
  • Tumor lysis syndrome - DO NOT USE
  • Lesch-Nyhan syndrome - DO NOT USE
  • Renal events - in trials, more patients on lesinurad had increases in serum creatinine than patients on placebo. Creatinine elevations 1.5 to < 2 X baseline occurred in 3.9% of lesinurad-treated patients and 2.3% of placebo-treated patients. Creatinine elevations ≥ 2 X baseline occurred in 1.8% of lesinurad-treated patients and 0% of placebo-treated patients. In 90% of patients, the elevations resolved with continued treatment. Renal function should be evaluated before treatment and periodically thereafter. Patients with CrCl < 60 ml/min, and those with increases in serum creatinine after starting therapy should be monitored more frequently. Treatment should be held if serum creatinine rises above 2 X the baseline value.
  • Kidney stones - lesinurad increases the urinary excretion of uric acid which can increase the risk of both uric acid stones and calcium stones. Use caution in susceptible patients.
  • Acute gout attack - when initiating lesinurad, the risk of an acute gout attack is increased. This may be due to the mobilization of uric acid from tissue deposits which causes fluctuations in uric acid levels. The ACR recommends prophylactic therapy when initiating uric acid-lowering therapy - see gout flare prophylaxis for more.
  • Liver disease
    • Mild to moderate (Child-Pugh A/B): no dose adjustment necessary
    • Severe (Child-Pugh C): has not been studied. Not recommended.
  • Kidney disease
    • CrCl ≥ 45 ml/min - no dose adjustment necessary
    • CrCl < 45 ml/min - DO NOT USE

Drug Dosage form Dosage Generic/Price Other Mechanism of Action/
FDA-approved indications
Side Effects
P = % of patients on placebo
who experienced side effect
Drug/Lab Interactions Precautions/
Contraindications
Pegloticase

(Krystexxa®)
Vial
  • 8 mg single use vial
Hyperuricemia in gout
  • Dosing: 8 mg via IV infusion every 2 weeks
  • Pegloticase should only be used in patients who cannot tolerate or did not respond to other urate-lowering 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 effectiveness is associated with an increased risk of anaphylaxis and infusion reactions.
  • Consider discontinuing if uric acid levels rise above 6 mg/dl, particularly on 2 consecutive levels
  • Prophylactic gout attack therapy should be initiated 1 week before starting pegloticase and continue for at least 6 months. See ACR recommendations for more.
Pegloticase (Krystexxa®)
NO/$$$$
  • Unopened vials should be refrigerated

  • Infuse over no less than 2 hours

  • Patients should be premedicated before infusions. In trials, the following was given: fexofenadine 60 mg the evening before and again before infusion; acetaminophen 1000 mg + hydrocortisone 200 mg IV immediately before infusion. [15]

  • Infusions should be done in a healthcare setting. Patients should be observed for one hour after infusion.

  • It is not necessary to stop pegloticase during a gout flare
Mechanism of action
  • The uricase enzyme is found in many animals but not in humans. Uricase converts uric acid to allantoin, a highly soluble, easily eliminated purine metabolite. Pegloticase is a recombinant version of uricase.

  • See pathology for more

FDA-approved indications
  • Hyperuricemia in gout - for use in patients who are refractory to other treatments
NOTE: Only side effects that occurred at an incidence of ≥ 5% are listed

  • Gout flare - 77%, P - 81%
  • Infusion reactions - 26%, P - 5%
  • Nausea - 12%, P - 2%
  • Bruising - 11%, P - 5%
  • Nasopharyngitis - 7%, P - 2%
  • Constipation - 6%, P - 5%
  • Chest pain - 6%, P - 2%
  • Anaphylaxis - 5%, P - 0%
  • Vomiting - 5%, P - 2%
  • No known reactions
  • Because anti-pegloticase antibodies appear to bind to the PEG portion of the drug, there may be potential for binding with other PEGylated products. The impact of anti-PEG antibodies on patients’ responses to other PEG-containing therapeutics is unknown.
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency - DO NOT USE. Patients with G6PD deficiency are at increased risk of pegloticase-induced hemolysis and methemoglobinemia. Patients at high risk for G6PD deficiency (e.g. African or Mediterranean ancestry) should be screened for G6PD deficiency before initiating pegloticase.
  • Anaphylaxis - in trials, anaphylaxis occurred in 6.5% of patients treated with pegloticase. All patients were premedicated before infusions so the actual incidence may be higher. Anaphylaxis may occur with any infusion and generally manifests within 2 hours of an infusion. Patients should be premedicated before infusions. In trials, the following regimen was given: fexofenadine 60 mg the evening before and again before infusion; acetaminophen 1000 mg + hydrocortisone 200 mg IV immediately before infusion. [15]
  • Infusion reactions - in trials, infusion reactions occurred in 26% of patients. Common reactions included urticaria (10.6%), dyspnea (7.1%), chest discomfort (9.5%), chest pain (9.5%), erythema (9.5%), and pruritus (9.5%). 91% of reactions occurred at the time of infusion. Some reactions were abated by slowing the infusion and/or stopping the infusion and restarting at a slower rate.
  • Loss of pegloticase efficacy - patients who lose their response to pegloticase are at higher risk for anaphylaxis and infusion reactions. This is due to the development of anti-pegloticase antibodies. If uric acid levels rise above 6 mg/dl, particularly on 2 consecutive readings, consideration should be given to stopping pegloticase. Other uric acid-lowering therapies should not be given with pegloticase because they may mask a loss of efficacy.
  • Anti-pegloticase antibodies - in trials, 92% of pegloticase-treated patients developed anti-pegloticase antibodies compared to 28% of placebo-treated patients. High antibody titers were associated with a loss of efficacy and an increase in anaphylaxis and infusion reactions.
  • Anti-PEG antibodies - in trials, 42% of pegloticase-treated patients developed antibodies to the PEG portion of the drug. The impact of anti-PEG antibodies on patients’ responses to other PEG-containing therapeutics is unknown.
  • Acute gout attack - when initiating pegloticase, the risk of an acute gout attack is increased. This may be due to the mobilization of uric acid from tissue deposits which causes fluctuations in uric acid levels. Prophylactic gout attack therapy should be initiated 1 week before starting pegloticase and continue for at least 6 months. See ACR recommendations for more.
  • Heart failure - in trials, heart failure exacerbations occurred in a small number of pegloticase-treated patients. Use caution in susceptible patients.
  • Retreatment with pegloticase - the safety of retreating patients with pegloticase after stopping therapy for ≥ 4 weeks is unknown. Because of the high incidence of anti-pegloticase antibodies in treated patients, the risk of hypersensitivity reactions may be increased in patients who are retreated. Use caution in these patients.
  • Liver disease - has not been studied
  • Kidney disease - no dose adjustment necessary



  • GOUT STUDIES

    • Pegloticase vs placebo, JAMA (2011) [PubMed abstract]
      • A study in the JAMA enrolled 225 patients with gout and a 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
      • Patients were randomized to 1 of 3 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 infusion; 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.
      • After 6 months, the following was seen:
        • Primary outcome: Group 1 - 42%, Group 2 - 35%, Group 3 - 0% (p<0.001 for Group 1 and 2 vs Group 3)
        • Gout flare (months 1 - 3): Group 1 - 75%, Group 2 - 81%, Group 3 - 53% (Group 1 vs 3 p=0.02, Group 2 vs 3 p=0.002)
        • Discontinued treatment due to adverse event: Group 1 - 18%, Group 2 - 19%, Group 3 - 2%
        • Infusion reactions: Group 1 - 26%, Group 2 - 42%, Group 3 - 5%
        • Anti-pegloticase antibodies developed in 89% of patients in Group 1 and 2



  • PRICING

    • $ = 0 - $50
    • $$ = $51 - $100
    • $$$ = $101 - $150
    • $$$$ = > $151

    • Pricing based on one month of therapy at standard dosing in an adult
    • Pricing based on survey of GoodRX.com®, HEB®, and Costco®, [accessed 8/2015]
    • Pricing may vary by region and availability


  • References:

  • 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