Gout & Hyperuricemia

 Gout and Hyperuricemia:

 Gout is an inflammatory condition of the
arthritis type that results from deposition of
uric acid crystals in joint spaces, leading to an
inflammatory reaction that causes intense pain,
erythema, and joint swelling.

 It is associated with hyperuricemia, defined

as a serum uric acid (SUA) level of 6.8 mg/dL
(404 μmol/L) or greater, but not all patients
with hyperuricemia demonstrate symptoms.
 Patients should be evaluated for drug-induced
hyperuricemia before treatment.

 Some drugs can cause hyperuricemia and precipitate

gout, such as thiazide and loop diuretics, niacin,
pyrazinamide

 Diuretics are a common precipitating factor.

 In most cases, these drugs block uric acid secretion in the

kidney.

 Long-term consequences of gout and hyperuricemia

include joint destruction, tophi, nephrolithiasis, and
nephropathy.
 The effect of aspirin on uric acid is dose dependent.

 At very high doses (eg, 4000 mg/day), aspirin blocks uric

acid reabsorption by the kidneys, increasing uric acid
excretion.

 Smaller aspirin doses inhibit uric acid excretion and can

elevate serum uric acid levels.

 The very low aspirin doses (75–81 mg/day) used for heart
attack or stroke prevention do not substantially alter
uric acid levels.

 However, patients with hyperuricemia or gout and

cardiovascular risk factors should continue low-dose
aspirin for cardiovascular prophylaxis because the
 Clinical Presentation of Acute Gouty Arthritis
 Symptoms:
 There is severe pain and swelling in the affected joint(s).

 Symptoms reach maximal intensity within 6 to 12 hours.

 The attack is usually monoarticular; the most common site is the

metatarsophalangeal joint.

 In elderly patients, gouty attacks may be atypical with insidious

and polyarticular onset, often involving hand or wrist joints.

 Signs:
 Affected joint(s) are warm, erythematous, and swollen.

 Mild fever may be present.

 Tophi (usually on hands, wrists, elbows, or knees) may be present

in chronic, severe disease.
 Diagnosis
 A presumptive diagnosis is often based on presenting
symptoms and may be confirmed later with laboratory and
other diagnostic tests.

 Severe joint pain, swelling, tenderness, and erythema

that rapidly peak are highly suggestive of, but not
specific for, gout.

 The serum uric acid level often is elevated but may be

normal during an acute attack.

 In addition, an elevated SUA alone is not diagnostic for

gout.

 Increased erythrocyte sedimentation rate are often

 Aspiration of affected joint fluid or a tophus is essential for a
definitive diagnosis.

 Needle-shaped negatively MSU crystals in the aspirate

confirm the diagnosis.

 Joint fluid may also have an elevated white blood cell (WBC)
count with neutrophils predominating. If infection is
suspected, it is imperative to obtain the appropriate diagnosis
and treatment.

 Radiographs of affected joints may have characteristic cystic

changes, punched-out lytic lesions with overhanging bony
edges, and soft-tissue calcified masses.

 These signs may also appear in other arthropathies and are

 Therefore, radiographs are often reserved for patients
with long-standing disease.

 Although rarely performed, a 24-hour urine collection

can be obtained to determine whether the patient is an
overproducer or an underexcretor of uric acid.

 Individuals who excrete more than 800 mg (4.8 mmol)

of uric acid in this collection are considered
overproducers.

 Patients with hyperuricemia who excrete less than 600

mg/day (3.6 mmol/day) are classified as
underexcretors of uric acid.
 TREATMENT OF ACUTE GOUTY ARTHRITIS

 Treatment of gout involves:

 acute relief of a gouty arthritis attack with

topical application of ice and drug therapy
commonly including NSAIDs, colchicine,
corticosteroids or a combination there of in
some patients, long-term prophylactic
treatment with urate-lowering therapy (ULT)
to prevent subsequent attacks.
attacks
 Non-pharmacologic Therapy
 Non-drug modalities play an adjunctive
role and usually are not effective when
used alone.
 Immobilization of the affected extremity
speeds resolution of the attack.

 Applying ice packs to the joint also decreases

pain and swelling, but heat application may be
detrimental.
 Pharmacologic Therapy
 Non-steroidal anti-inflammatory drugs (NSAIDs), colchicine,
and corticosteroids are considered first-line monotherapy
options for acute attacks.

 Selection depends on number of joints affected,

presence/absence of infection, clinician/patient preference,
prior response, and patient factors such as comorbidities and
renal function

 Corticotropin (adrenocorticotropic hormone, ACTH) and IL-1

inhibitors are alternatives in select cases.

 Opioid analgesics have little to no role in acute gout, which

results from overwhelming inflammation.
 »» Non-steroidal Anti-inflammatory Drugs
 These agents are most effective when given within the first 24
hours of the onset of pain. Most studies have shown similar
results among agents, and no one NSAID is preferred over
another as first-line treatment.
 Doses at the higher end of the therapeutic range are often
needed.

 NSAIDs are usually continued at full doses until 24 hours after

symptoms subside.

 Clinicians may consider tapering the dose if a patient has

multiple comorbidities, including hepatic or renal failure.
failure

 Only naproxen, indomethacin, and sulindac are FDA

approved for treatment of acute gout. Although
 The patient’s overall clinical status should be evaluated
prior to NSAID initiation because adverse effects
include gastropathy (primarily peptic ulcers),
ulcers renal
dysfunction, and fluid retention.

 NSAIDs generally should be avoided in patients at risk

for peptic ulcers; those taking anticoagulants; and those
with renal insufficiency, uncontrolled hypertension, or
heart failure.

 Gastroprotective agents such as proton pump inhibitors

may protect against ulcer development in patients
receiving NSAIDs for acute gout.
 Cyclooxygenase-2 (COX-2)–selective inhibitors
(ie, celecoxib) produce results comparable with
those of traditional NSAIDs.

 However, the need for large COX-2 inhibitor

doses, cardiovascular safety concerns, and
high cost make the risk-benefit ratio unclear
for this disorder.
 »» Colchicine
 It is used less commonly today because of its low therapeutic
index and more recently, increased cost.

 About two-thirds of patients with acute gout respond

favorably if colchicine is given within the first 24 hours of
symptom onset.

 In the presence of severe renal impairment (creatinine

clearance [CrCl] < 30 mL/min [0.5 mL/s]), dosing should be
repeated no more than once every 2 weeks.

 Dose reductions are required when coadministered with p-

glycoprotein or strong CYP3A4 inhibitors (eg, clarithromycin,
verapamil, ritonavir, cyclosporine, ranolazine).

B f th bl l hi i b d
 The approved dosage regimen is 1.2 mg (two 0.6-mg
tablets) at the onset of an acute flare, followed by 0.6
mg 1 hour later.

 The ACR guidelines suggest it can then be continued

starting 12 hours later at a dose of 0.6 mg once or twice
daily (prophylaxis dosing) until the gout attack is
resolved.

 Dose adjustment is required for renal insufficiency.

 Colchicine should not be used for an acute attack if the

patient is currently prescribed colchicine for prophylaxis
and was previously treated with colchicine for an acute
attack within the last
l t 14 days
 »» Corticosteroids
 It is important to determine the number of joints affected
when considering a corticosteroid for first-line therapy.

 Systemic corticosteroids are a useful option in patients with

contraindications to NSAIDs or colchicine (primarily renal
impairment) or polyarticular attacks, especially in elderly
patients.

 The ACR recommends initiating oral prednisone or

prednisolone at a starting dose of at least 0.5 mg/kg daily
for 5 to 10 days, followed by abrupt discontinuation, or full
dose therapy for 2 to 5 days with a 7- to 10-day taper to
discontinue.

 Oral methylprednisolone and naproxen have been shown to

 When only one or two large joints are affected, an
intraarticular corticosteroid injection can provide rapid
relief with a relatively low incidence of side effects,
and it may be used in combination with either an
NSAID, colchicine, or oral corticosteroid.

 Joint fluid obtained should be examined for evidence

of joint space infection and crystal identification.

 If uric acid crystals are present and there is no

infection, intra-articular injection can proceed.
 Finally, an alternative regimen consisting of a single
intramuscular injection of a long-acting corticosteroid
such as triamcinolone acetonide, followed by oral
prednisone or prednisolone may also be used.

 Adverse effects from corticosteroids include fluid

retention, hyperglycemia, CNS stimulation, weight gain, GI
upset, and increased risk of infection.

 Patients with diabetes should have blood glucose levels

monitored carefully during the corticosteroid course,
and caution should be exercised when treating patients
with a history of peptic ulcer disease.
 »» Corticotropin (Adrenocorticotropic Hormone)

 Clinical studies have shown efficacy similar to

other agents for acute gout.

 Although not a first-line option (or FDA

approved for this use), the ACR supports its use
for patients unable to take medications orally.
 »» Interleukin-1 Inhibitors
 Several small clinical trials have demonstrated
efficacy of IL-1 inhibitors in inhibiting
inflammation associated with acute gout attacks.

 While their role is unclear and the available

products (anakinra and canakinumab)
canakinumab are not
FDA approved for this purpose, the ACR
guidelines include off-label use as an option for
severe acute attacks or for patients refractory
to other agents
 »» Combination Therapy
 In severe polyarticular attacks, particularly
attacks involving multiple large joints, colchicine
may be used in combination with an NSAID or
oral corticosteroid.

 Intra-articular corticosteroid injections may be

used in combination with any other first-line
agent (NSAID, colchicine, oral corticosteroid).
 URATE LOWERING THERAPY FOR GOUT PROPHYLAXIS

 Gout is an episodic disease, and the number of

attacks varies widely from patient to patient.

 Thus the benefit of long-term prophylaxis

against acute gout flares must be weighed
against the cost and potential toxicity of
therapy that may not be necessary in all
patients.
 Non-pharmacologic Therapy
 Patients should be educated to engage in regular exercise
to lose weight if obese, strictly limit or discontinue ethanol
consumption, maintain hydration, and manage other
comorbidities (eg, hypertension, diabetes).

 Low-purine diets, including avoiding organ meats, and

limiting sardines, shellfish, beef, pork, and lamb are not
well tolerated; instead, dietary recommendations should
focus on general nutrition principles.

 Some studies have shown that low-fat dairy products,

coffee, and vitamin C may confer a protective effect.
 Complementary therapies that are considered to be
inappropriate for gout due to insufficient evidence of
benefit include cherry juice/extract, willow bark extract,
ginger, flaxseed, charcoal, strawberries, black current,
burdock, sour cream, olive oil, horsetail, pears, and celery
root.

 Drugs that may cause or aggravate hyperuricemia should

be discontinued if clinically appropriate.

 Few patients adhere to lifestyle modifications long term,

and pharmacologic therapy usually is needed to treat
hyperuricemia adequately.
 Pharmacologic Therapy
 Patients with recurrent attacks (2 or more per year),
evidence of tophus or tophi, CKD stage 2 or worse, or
past urolithiasis are candidates for prophylactic
therapy with allopurinol, febuxostat, probenecid, or
pegloticase to lower SUA levels.

 Because hyperuricemia is the strongest modifiable risk

factor for acute gout, prophylactic therapy commonly
involves either decreasing uric acid production or
increasing its excretion.

 The goal of therapy is to decrease SUA levels

significantl leaving less uric acid available for
 Because allopurinol (which reduces uric acid
production) is effective in both overproducers and
underexcretors and is generally well tolerated, many
clinicians forego the 24-hour urine collection and
treat patients empirically with it.

 Both allopurinol and febuxostat are xanthine oxidase

inhibitors (XOIs) and are considered to be first-line
ULT agents.

 Probenecid, a uricosuric agent, is an alternative first

-line option, whereas pegloticase is generally
reserved for refractory cases