For Hussien Ararsa

1. Gout and hyperuricemia
1
Gobezie T,

2. Learning objectives
• Upon completion of this session, the students will
be able to:
– Explain the pathophysiologic mechanisms
underlying gout and hyperuricemia.
– Recognize major risk factors for developing
gout.
– Assess the signs and symptoms of an acute
gout attack.
– List the treatment goals for a patient with gout.
– Describe the treatment modalities of gout
2

3. 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.
• associated with hyperuricemia, defined as a serum
uric acid (SUA) level of > 7 mg/dL for men and > 6
mg/dL for women.
• not all patients with hyperuricemia demonstrate
symptoms
3

4. Epidemiology
• Gout is the most common inflammatory
arthritis in men
• male to female incidence of about 4:1
• incidence increases with age
4

5. Risk factors
• Diet
– Eating a diet rich in meat and seafood and drinking beverages
sweetened with fruit sugar (fructose) increase levels of uric acid,
which increase your risk of gout.
– Alcohol consumption, especially of beer, also increases the risk of
gout.
• Obesity
– If you're overweight, your body produces more uric acid & your
kidneys have a more difficult time eliminating uric acid.
• Medical conditions
– Certain diseases and conditions such as untreated high blood
pressure and chronic conditions such as diabetes, metabolic
syndrome, and heart and kidney diseases. increase your risk of gout
• Certain medications
– The use of thiazide diuretics, niacin, pyrazinamide and low-dose
aspirin also can increase uric acid levels.
5

6. Risk factors
• 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.
– aspirin in analgesic doses (325–650 mg several
times per day) should be avoided: inhibits uric acid
excretion
– The very low aspirin doses (75–81 mg/day) used for
heart attack or stroke prevention do not substantially
alter uric acid levels
6

7. Risk factors
• Family history of gout.
– If other members of your family have had gout, you're
more likely to develop the disease.
• Age and sex.
– Gout occurs more often in men, primarily because
women tend to have lower uric acid levels.
– After menopause, however, women's uric acid levels
approach those of men..
• Recent surgery or trauma.
– Experiencing recent surgery or trauma has been
associated with an increased risk of developing a gout
attack.
7

8. Pathophysiology
• Gout is caused by an abnormality in uric acid
metabolism.
• Uric acid is a waste product of the breakdown
of purines contained in the DNA of degraded
body cells & dietary protein.
• Uric acid is water soluble & excreted primarily
by the kidneys although some is broken down
by colonic bacteria and excreted via the GIT
8

9. Pathophysiology
• The solubility of uric acid depends on
concentration and temperature.
• At high serum concentrations, lower body
temperature causes the precipitation of
monosodium urate crystals.
• Collections of these crystals (called microtophi)
can form in joint spaces in the distal extremities.
• Larger tophi may take 10 years or longer to
develop.
9

10. Pathophysiology
• Free urate crystals can activate several pro-
inflammatory mediators, including TNF-α, IL-1 & IL-
8.
• Activation of these mediators signals chemotactic
movement of neutrophils into the joint space that
ingest MSU crystals via phagocytosis.
• These neutrophils then are lysed & release proteolytic
enzymes that trigger the clinical manifestations of an
acute gout attack such as pain & swelling.
• These inflammatory mechanisms in gout, especially in
untreated disease, can lead to cartilage & joint
destruction
10

11. Pathophysiology
• increased serum uric acid either:
• under-excretion of uric acid (80% of patients)
or its overproduction.
• Primary gout
–unknown
11

12. Complications
• Uric acid nephrolithiasis
–can occur in up to 25% of patients with
persistently acidic urine and hyperuricemia.
• In severe cases, uric acid stones can cause
nephropathy and renal failure
• joint destruction
• tophi
12

13. Clinical Presentation of Acute Gouty Arthritis
• Acute inflammatory monoarthritis.
• Patients are usually in acute distress
• severe pain and swelling in the affected joint(s).
• Symptoms reach maximal intensity within 6-12
hours.
• attack is usually monoarticular
• most common site is the metatarsophalangeal joint.
.
13

14. Clinical Presentation of Acute Gouty Arthritis
• In elderly patients, gouty attacks may be
atypical with insidious and poly-articular
onset, often involving hand or wrist joints
• Mild fever may be present.
• Tophi (usually on hands, wrists, elbows, or
knees) may be present in chronic, severe
disease.
14

15. Diagnosis
• Clinical features
• Laboratory Tests
–WBC count in peripheral blood may be only
mildly elevated.
–serum uric acid level often is elevated but
may be normal during an acute attack.
–markers of inflammation [e.g. Increased
ESR] are often present
15

16. Diagnosis
• Aspiration of affected joint fluid or a tophus is
essential for a definitive diagnosis.
• Needle-shaped MSU crystals in the aspirate
confirm the diagnosis
16

17. Management
• Goals of therapy
–To achieve rapid and effective pain relief
–To maintain joint function
–To prevent disease complications
–To avoid treatment-related adverse effects
–To provide cost-effective therapy
–to improve quality of life.
17

18. Non-pharmacologic Therapy
• play an adjunctive role and usually 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
• Abstinence from Alcohol
– Consumption can increase serum urate levels by
increasing uric acid production.
• Dietary modification
– Decrease in dietary purine-meat and sea food.
– Dairy and vegetables do not seem to affect uric acid
18

19. Pharmacologic Therapy
• NSAIDs
• colchicine
• corticosteroids
• Xanthine oxidase inhibitors
• Uricosoric agents
19

20. 20
Algorithm for management of an acute gout attack.

21. 21
Figure: Treatment algorithm for
gout and hyperuricemia.
Renal insufficiency is defined as an
estimated CrCl <30 mL/minute. IA,
Intraarticular

22. 22

23. Pharmacologic Therapy
• Acute attacks
• NSAIDs, colchicine & corticosteroids are
considered first-line monotherapy options
• The earlier we employ, (ie, within 24 hours), the
better the outcome
• Opioid analgesics have little to no role in acute gout,
which results from overwhelming inflammation
23

24. Nonsteroidal Anti-Inflammatory Drugs
• have largely supplanted colchicine as the
treatment of choice
• most effective when given within the first 24
hours of the onset of pain.
• no one NSAID is preferred over another as
first-line treatment
• Usually continued at full doses until 24 hours
after symptoms subside
24

25. Nonsteroidal Anti-Inflammatory Drugs
• Only naproxen, indomethacin, and sulindac are FDA
approved for treatment of acute gout.
• Although indomethacin has been used traditionally, its
relative COX-1 selectivity increases its gastropathy
risk
• The patient’s overall clinical status should be
evaluated prior to NSAID initiation because adverse
effects include gastropathy (primarily peptic ulcers),
renal dysfunction, and fluid retention
25

26. Nonsteroidal Anti-Inflammatory Drugs
• NSAIDs should be avoided in patients
– at risk for peptic ulcers
–those taking anticoagulants
–those with renal insufficiency
–Uncontrolled hypertension, or heart failure.
26

27. Nonsteroidal Anti-Inflammatory Drugs
• COX-2–selective inhibitors produce results
comparable with those of traditional NSAIDs.
• However, cardiovascular safety concerns and
the high cost of COX-2 inhibitors argue
against their use for this disorder
27

28. Colchicine
• has a long history of successful use and was the
treatment of choice for many years.
• It is used less commonly today because of its
low therapeutic index and increased cost
• thought to exert its anti-inflammatory effects by
interfering with the function of mitotic spindles
in neutrophils by binding of tubulin dimers; this
inhibits phagocytic activity
28

29. Colchicine
• is not considered to be an analgesic
• most patients with acute gout respond favorably
if colchicine is given within the first 24 hours of
symptom onset
• absorbed rapidly from the GIT and metabolized
extensively in the liver
• reserved for patients who are at risk for NSAID-
induced gastropathy or who have failed NSAID
therapy
29

30. Colchicine
• Dose: 1.2 mg (two 0.6-mg tablets) at the onset
of an acute flare, followed by 0.6 mg 1 hour
later
• 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
30

31. Colchicine: side effects
• GI side effects (eg, nausea, vomiting, diarrhea &
abdominal pain) are most common
• more serious systemic toxicity, including myopathy &
bone marrow suppression (usually neutropenia)
• In the presence of severe renal impairment [CrCl] < 30
mL/min), dosing should be repeated no more than once
every 2 weeks.
• Dose reductions are required when co-administered
with p-glycoprotein or strong CYP3A4 inhibitors (eg,
clarithromycin, verapamil, ritonavir, cyclosporine)
31

32. Corticosteroids
• 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
32

33. Corticosteroids
• Dose: 0.5 mg/kg daily for 5-10 days, followed by
abrupt discontinuation, or
• full-dose therapy (30-40 mg/day given once daily
or in 2 divided doses) for 2-5 days with a 7- to 10-
day taper to discontinue
• 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
• may be used in combination with either an
NSAID, colchicine, or oral corticosteroid.
33

34. Corticosteroids: adverse effects
• fluid retention
• hyperglycemia
• CNS stimulation
• weight gain
• GI upset
• increased risk of infection
34

35. 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) are not
FDA approved for this purpose
• the American College of Rheumatology (ACR)
guidelines include off-label use as an option for
severe acute attacks or for patients refractory to
other agents
35

36. Combination Therapy
• In severe polyarticular attacks, particularly
attacks involving multiple large joints,
colchicine may be used in combination with an
NSAID or oral corticosteroid.
• Intraarticular corticosteroid injections may be
used in combination with any other first-line
agent (NSAID, colchicine, oral corticosteroid)
36

37. 37

38. Urate lowering therapy for gout prophylaxis
• Non-pharmacologic Therapy
– 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
38

39. Urate lowering therapy for gout prophylaxis
• Pharmacologic Therapy
–Prophylactic therapy with allopurinol,
febuxostat, probenecid, or pegloticase
–Patients with recurrent attacks (2 or more per
year), evidence of tophus or tophi, CKD stage
2 or worse, or past urolithiasis
–prophylactic therapy commonly involves
either decreasing uric acid production or
increasing its excretion
39

40. Urate lowering therapy for gout prophylaxis
• Drugs used to increase uric acid excretion
(uricosuric agents) generally are not as well
tolerated as drugs that decrease production
• uricosurics increase the risk of uric acid
nephrolithiasis
40

41. Urate lowering therapy (ULT)
• Xanthine oxidase inhibitor
– Allopurinol and febuxostat
– considered to be first-line urate lowering
agents
• Uricosuric agent
– Probenecid is an alternative first-line option
• Other Uricosuric Agents
– Pegloticase
• ULT should be continued in patients even during
acute flares.
41

42. Allopurinol
• The drug and its primary active metabolite,
oxypurinol, reduce SUA concentrations by
inhibiting the enzyme xanthine oxidase,
thereby blocking the two-phase oxidation of
hypoxanthine and xanthine to uric acid
42

43. Allopurinol
• well absorbed, with a short half-life of 2-3
hours
• The half-life of oxypurinol approaches 24
hours, allowing allopurinol to be dosed once
daily.
• Oxypurinol is cleared primarily by renal
mechanisms and can accumulate in patients
with reduced kidney function
43

44. Allopurinol
• Initial dose of allopurinol is based on the
patient’s renal function.
• If renal function is normal, an initial dose no
>100 mg daily is recommended.
• The initial dose should be reduced to 50 mg
daily in patients with a CrCl <30 mL/min
• However, the dose can be adjusted upward
every 2-5 weeks as needed and tolerated
44

45. Allopurinol
• SUA levels must be monitored every 2-5
weeks during titration, then every 6 months
after the target SUA is achieved
• The target SUA level is <6 mg/dL in all cases
and perhaps even <5 mg/dL in more severe
disease involving tophi
• The allopurinol dose should be titrated upward
(to a maximum of 800 mg/day)
45

46. Allopurinol: adverse effects
• typically well tolerated
• nausea and diarrhea occur uncommonly
• A generalized, maculopapular rash occurs in
about 2% of patients
46

47. Drug interactions
• Azathioprine and 6-mercaptopurine are purines
whose metabolism is inhibited by concomitant
allopurinol therapy
– The dose of these drugs must be reduced by
75% with allopurinol co-therapy
47

48. Febuxostat
• Non-purine xanthine oxidase inhibitor
structurally distinct from allopurinol
• approved for chronic hyperuricemia associated
with gout.
• The initial dose is 40 mg orally once daily.
• The dose may be increased to 80 mg orally
once daily if the SUA does not decrease to 6
mg/dL
48

49. Febuxostat
• No dosage adjustment is necessary in patients
with mild or moderate renal impairment (CrCl
30–89 mL/min
• not recommended in patient with severe renal
insufficiency (CrCl < 30 mL/min)
• Due to cost concerns, febuxostat should generally
be reserved for patients who do not tolerate
allopurinol or cannot achieve SUA levels ≤ 6
mg/dL despite maximal allopurinol therapy
49

50. Adverse effects of febuxostat
• nausea, arthralgias, rash & transient elevation
of hepatic transaminases.
• Periodic liver function tests are recommended
(eg, at baseline, 2 and 4 months after starting
therapy, and then periodically thereafter).
• Due to differences in chemical structure,
febuxostat would not be expected to cross-
react in patients with a history of allopurinol
hypersensitivity syndrome.
50

51. Probenecid
• uricosuric agent that blocks the tubular
reabsorption of uric acid, increasing its
excretion
• Because of its mechanism of action,
probenecid is not recommended for urate
overproducers
• contraindicated in patients with a history of
urolithiasis or urate nephropathy
51

52. Probenecid
• Probenecid loses its effectiveness as renal
function declines and should be avoided when
the CrCl is <50 mL/min
• Considered an alternate first-line agent if
xanthine oxidase inhibitor therapy is either not
tolerated or contraindicated
52

53. Probenecid: adverse effects
• generally well tolerated
• can cause GI side effects such as nausea as
well as fever, rash
• Rarely hepatic toxicity
• Patients should be instructed to maintain
adequate fluid intake and urine output to
decrease the risk of uric acid stone formation
53

54. Pegloticase
• Gout does not occur in most non-primate
mammals because these species produce the
enzyme uricase, which catalyzes oxidation of
uric acid into the more soluble compound
allantoin, which is readily excreted.
• Humans lack this enzyme, which allows uric
acid to accumulate, leading to gout in some
individuals
54

55. Pegloticase
• is a recombinant form of uricase (also known
as urate oxidase)
• FDA approved for treatment of chronic gout
refractory to other therapies.
• The approved dose of 8 mg by IV infusion
over at least 2 hours every 2 weeks rapidly
(within 6 hours) decreased SUA
55

56. Pegloticase
• limited to patients with severe gout with tophi or
nephropathy that has not responded to other agents due to:
– significant adverse effects, including gout flares, infusion
reactions, anaphylaxis (in up to 5% of patients) that
mandates pretreatment with antihistamines &
corticosteroids
– the inconvenience of IV therapy
– its high cost
– contraindicated in patients with G6PD deficiency due to
the risk of hemolysis and therefore, patients should be
screened prior to initiation of therapy.
56

57. 57

58. Outcome evaluation
• Acute Gout
–Monitor the patient for pain relief and
decreased swelling of the affected joint(s).
–Both parameters improve significantly
within 48 hours of starting therapy
58

59. Outcome evaluation
• Urate Lowering Therapy
–Monitor the SUA level every 2-5 weeks
during ULT initiation and titration.
–Adjust the dose of ULT to achieve a target
SUA level of <6 mg/dL
–Then continue measurements every 6
months thereafter
59