GOUT

















  • 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




  • 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
  • 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




  • 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










  • 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®)


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






  • 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.





  • 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






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

Duration: 6 months
Outcome Peg biweekly Peg monthly Placebo Comparisons
Primary outcome 42% 35% 0% p<0.001 for 1 or 2 vs 3
Gout flare (months 1 - 3) 75% 81% 53% 1 vs 3 p=0.02 | 2 vs 3 p=0.002
Discontinue due to adverse event 18% 19% 2% N/A
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.