This document provides information on gout and hyperuricemia. It discusses the pathophysiology of gout, including how uric acid crystals form in the joints and cause inflammation. It also covers risk factors, clinical presentation, diagnosis, and treatment approaches. Treatment involves acute relief of gout attacks with medications like NSAIDs or colchicine, as well as long-term urate-lowering therapy with drugs like allopurinol or febuxostat to prevent future attacks by lowering uric acid levels.

1. Gout and Hyperuricemia
Mariam D. (B.Pharm, M.Sc.)

2. Quiz
1. What is osteoporosis
2. List at least four classes of drugs used for treatment of osteoporosis
3. How does being menopausal women results in osteoporosis

4. Introduction
• Gout is an inflammatory
condition of the arthritis type that
results from deposition of uric
acid crystals in joint spaces.
• Leads to an inflammatory
reaction that causes
• Intense pain
• Erythema
• Joint swelling

5. Epidemiology
• Gout is the most common
inflammatory arthritis in men
(M:F incidence – 4:1)
• Incidence increases with age
• Also rising in part due to a
larger number of patients with
risk factors for gout

6. 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 and dietary
protein.
• Uric acid is water soluble and excreted primarily by the kidneys,
although some is broken down by colonic bacteria and excreted
via the gastrointestinal (GI) tract

7. Cont´d…
• The solubility of uric acid depends on concentration and
temperature.
• At high serum concentrations, lower body temperature causes
the precipitation of monosodium urate (MSU) 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.
• Free urate crystals can activate several proinflammatory
mediators, including tumor necrosis factor (TNF-a), interleukin
1 (IL-1), and IL-8.

8. Cont´d…
• Activation of these mediators signals chemotactic movement of
neutrophils into the joint space that ingest MSU crystals via
phagocytosis.
• These neutrophils then are lysed and release proteolytic
enzymes that trigger the clinical manifestations of an acute gout
attack such as pain and swelling.
• These inflammatory mechanisms in gout, especially in
untreated disease, can lead to cartilage and joint destruction

9. • The increased SUA involves either the underexcretion of uric
acid (80% of patients) or its overproduction. The cause of
overproduction or underexcretion of uric acid in most gout
patients is unknown; this is referred to as primary gout.
• The reference range for SUA is 3.6 to 8.3 mg/dL (214– 494
μmol/L). The risk of gout increases as the SUA concentration
increases.
• Approximately 30% of patients with levels greater than 10
mg/dL (595 μmol/L) develop symptoms of gout within 5 years.
Cont´d…

10. Risk factors
Dietary risk factors
Ingestion of animal purines, fructose, and alcohol (especially beer)
Male gender
Obesity
Hypertension
Dyslipidemia
Metabolic syndrome
T2DM, CKD and CAD
Drugs

11. Cont´d…
• Some drugs can cause hyperuricemia and precipitate gout,
such as thiazide & loop diuretics, niacin, pyrazinamide,
calcineurin inhibitors, and, occasionally, aspirin.
• These drugs block uric acid secretion in the kidney.
• The effect of aspirin on uric acid is dose dependent
• At very high dose (4000 mg/day) - increased uric acid excretion
• Small doses (325–650 mg/day) – elevate serum uric acid levels
• very low doses (75–81 mg/day) – do not alter uric acid levels

12. Clinical
presentation

13. Diagnosis
• Presenting symptoms + laboratory tests + other diagnostic tests
• Severe joint pain, swelling, tenderness, and erythema that
rapidly peak are highly suggestive of, but not specific for,
gout.
• Gout is a reasonably accurate clinical diagnosis in patients
with recurrent podagra and hyperuricemia.

14. Cont´d…
• 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.
• The peripheral WBC count may be only mildly elevated.
• Other laboratory markers of inflammation (eg, increased
erythrocyte sedimentation rate) are often present.

15. Definitive Dx
• Aspiration of affected joint fluid or tophus
is essential for definitive diagnosis.
• Needle-shaped negatively birefringent MSU
crystals in the aspirate confirm the diagnosis
• Joint fluid may also have an elevated white
blood cell (WBC) count with neutrophils
predominating

16. Cont´d…
• Radiographs of affected joints – indicate characteristic cystic
changes, punched-out lytic lesions with overhanging bony
edges, and soft-tissue calcified masses.
• These signs not apparent with the first acute gout attack.
• Reserved for patients with long-standing disease.
• A 24-hour urine collection – to determine whether the patient is
an overproducer (>800mg or 4.8mmol) or an underexcretor
(<600mg/day or 3.6mmol/day) of uric acid.
• Rarely performed test

17. Treatment of acute gouty arthritis
 TREATMENT OF GOUT INVOLVES
Acute relief of a gouty arthritis attack with
 Topical application of ice
 Drug therapy including NSAIDs, colchicine, corticosteroids or
combination
Long-term prophylactic treatment with urate-lowering therapy
(ULT) to prevent subsequent attacks.

18. Nonpharmacologic Therapy
• Nondrug 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
NB : heat application may be detrimental.

19. Pharmacologic Therapy
 Nonsteroidal 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
• Patient factors such as comorbidities and renal function.

20. Cont´d…
• Each drug class has a unique safety and efficacy profile in gout that
should be considered carefully before choosing a specific agent.
• Generally, the earlier in the course of the arthritic attack these agents
are employed (ie, within 24 hours), the better the outcome.
• 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.

22. NSAIDs
• NSAIDs are 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.
• 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.

23. Cont´d…
• Only naproxen, indomethacin, and sulindac are FDA approved
for treatment of acute gout.
• Although indomethacin has been used traditionally, its relative
cyclooxygenase-1 (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.

24. • 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.
• 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.
Cont´d…

25. Colchicine
• Colchicine is used less commonly today because of its low
therapeutic index and more recently, increased cost.
• It exert its anti-inflammatory effects by interfering with the
function of mitotic spindles in neutrophils by binding of tubulin
dimers; this inhibits phagocytic activity.
• Colchicine is not considered to be an analgesic.
• About 2/3 of patients with acute gout respond favorably if
colchicine is given within the first 24 hours of symptom onset.
• Presently, colchicine is only indicated if given within 36 hours of attack
onset.

26. Cont´d…
• GI effects (eg, nausea, vomiting, diarrhea, and abdominal pain)
are most common and are considered a forerunner of more
serious systemic toxicity, including myopathy and bone marrow
suppression (usually neutropenia).
• Dose reductions required when coadministered with p-
glycoprotein or strong CYP3A4 inhibitors (clarithromycin
ritonavir, cyclosporine).
• Because of these problems, colchicine may be reserved for
patients who are at risk for NSAID-induced gastropathy or who
have failed NSAID therapy.

27. Cont´d…
• Colcrys is the only single-ingredient oral colchicine product FDA
approved for treatment of acute gout attacks.
• 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.
• 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 14 days.

28. 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.

29. ACR recommendation
• Initiate 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 2-5 days with a 7-10 day
taper to discontinue.
• .

30. Cont´d…
• 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 by arthrocentesis should be examined for
evidence of joint space infection and crystal identification.

31. Corticotropin (Adrenocorticotropic Hormone)
• Exogenous administration of IM adrenocorticotropic hormone
(ACTH) stimulates production of cortisol and corticosterone by
the adrenal cortex.
• 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.

32. 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
ACR guidelines include off-label use as an option for severe
acute attacks or for patients refractory to other agents.

33. 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).

35. Urate lowering therapy for gout prophylaxis
• Gout is an episodic disease, and the number of attacks varies
widely from patient to patient.
• 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.
• Asymptomatic hyperuricemia generally does not require
treatment.

36. Nonpharmacologic 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, HTN, DM).
• Low-purine diets, including avoiding organ meats, and limiting
beef, pork, and lamb are not well tolerated; instead, dietary
recommendations should focus on general nutrition principles.
• If clinically appropriate, drugs that may cause or aggravate
hyperuricemia should be discontinued.

37. 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.
• Since 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 significantly,
leaving less uric acid available for conversion to MSU crystals.

38. Cont´d…
• Selection of long-term prophylactic therapy involves determining
the cause of hyperuricemia (by analyzing a 24-hour urine
collection for uric acid) and tailoring therapy appropriately.
• If less than 600 mg (3.6 mmol) of uric acid is found in the 24-
hour sample, the patient is considered an underexcretor.
• However, this approach is not used commonly for several
reasons.
• The urine collection is inconvenient for patients and clinicians and
does not identify patients who may be both overproducers a &
underexcretors of uric acid.
• Drugs used to increase uric acid excretion (uricosuric agents) generally
are not as well tolerated as drugs that decrease production, and
uricosurics increase the risk of uric acid nephrolithiasis.

39. Cont´d…
• 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.

40. 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.

41. Cont´d…
• Guidelines recommend that all acute gout patients receive
prophylaxis when ULT is started with continuation of therapy for
at least 6 months or up to 3 to 6 months after no clinical
evidence of gout activity is apparent and the target SUA has
been achieved.

42. Cont´d…
• The initial dose of allopurinol is based on the patient’s renal function.
• If renal function is normal, an initial dose no greater than 100 mg
daily is recommended. The initial dose should be reduced to 50 mg
daily in patients with a CrCl less than 30 mL/ min (0.5 mL/s).
• The relationship between allopurinol dose and its most severe side
effects, including allopurinol hypersensitivity syndrome (AHS), is
controversial.
• However, the dose can be adjusted upward every 2 to 5 weeks as
needed and tolerated, even in patients with renal insufficiency
provided that they are monitored and educated appropriately.

43. Cont´d…
• Prior to initiating allopurinol, pharmacogenetic screening via
human leukocyte antigen (HLA)-B*5801 testing is
recommended for patients at an elevated risk for AHS (eg,
Koreans with stage 3 or worse CKD and all individuals of Han
Chinese and Thai descent).
• If results are positive, the patient should be provided with an
alternative to allopurinol. Patients with a history of AHS should
never again receive allopurinol (including desensitization) or
oxypurinol (which is available outside the United States).

44. Febuxostat
• Febuxostat is a nonpurine XOI structurally distinct from
allopurinol that is FDA 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 (357 μmol/L) or less after 2 weeks of
treatment.
• No dosage adjustment is necessary in patients with mild or
moderate renal impairment; however, febuxostat is not
recommended in patient with severe renal insufficiency (CrCl <
30 mL/min [0.5 mL/s]).

45. Cont´d…
• Adverse effects of febuxostat include nausea, arthralgias, rash,
and 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
• Due to cost concerns, febuxostat should generally be reserved
for patients who do not tolerate allopurinol and those who
cannot achieve SUA levels of 6 mg/dL (357 μmol/L) or less
despite maximal allopurinol therapy.

46. Probenecid
• Probenecid is a 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 and is contraindicated in
patients with a history of urolithiasis or urate nephropathy.
• Probenecid loses its effectiveness as renal function declines
and should be avoided when the CrCl is 50 mL/min (0.83 mL/s)
or less.

47. Cont´d…
• Probenecid is considered an alternate first-line agent if XOI
therapy is either not tolerated or contraindicated.
• It may also be added to XOI therapy that has been titrated to
the maximum dose without attainment of the target SUA level.
• Although generally well tolerated, probenecid can cause GI side
effects such as nausea as well as fever, rash, and rarely,
hepatic toxicity.

48. Other Uricosuric Agents
• Other medications with mild uricosuric effects may be appropriate
adjunctive therapy in some patients.
• Losartan increases both uric acid excretion and urine pH and may be
an option in hypertensive patients with gout.
• Fenofibrate is also uricosuric and may be appropriate in select
dyslipidemic patients with gout.
• Either one of these agents may be combined with a XOI in patients
who fail to achieve the target SUA level on maximized therapy.

49. Pegloticase
• Gout does not occur in most nonprimate 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.
• Pegloticase is a recombinant form of uricase (also known as urate
oxidase) conjugated to polyethylene glycol. It is 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 in subjects in
published trials.

50. Cont´d…
• However, pegloticase should be limited to patients with severe
gout with tophi or nephropathy that has not responded to other
agents because of significant adverse effects, including gout
flares, infusion reactions, anaphylaxis (in up to 5% of patients)
that mandates pretreatment with antihistamines and
corticosteroids, the inconvenience of IV therapy, and its high
cost.
• Pegloticase is contraindicated in patients with G6PD deficiency
due to the risk of hemolysis and methemoglobinemia; therefore,
patients should be screened prior to initiation of therapy.

51. Outcome evaluation …… acute gout
Monitor the patient for pain relief and decreased swelling of the
affected joint(s) (Improvement expected within 48 hours)
Assess the patient’s complaints and objective information for
adverse effects
 For NSAID therapy, be alert for new-onset epigastric pain, dark or tarry stools,
blood in vomitus, dizziness or lightheadedness, development of edema,
decreased urine output, or shortness of breath.
 For colchicine, monitor for nausea or vomiting, diarrhea, easy bruising, cold or
flu-like symptoms, lightheadedness, muscle weakness, or pain.
 Monitor patients receiving intraarticular corticosteroid injections for increased
swelling or pain at the injection site.
 Assess patients receiving systemic corticosteroids for mental status changes,
fluid retention, increased blood glucose, muscle weakness, or development of
new infections.

52. Urate Lowering Therapy
• Monitor the SUA level every 2 to 5 weeks during ULT initiation
and titration. Adjust the dose of ULT to achieve a target SUA
level of less than 6 mg/dL (357 μmol/L) or optionally less than 5
mg/dL (297 μmol/L) in more severe disease. Then continue
measurements every 6 months thereafter.
• Evaluate patients taking allopurinol for development of rash,
nausea, or new fever. These symptoms usually appear within
the first 3 months of therapy but can occur anytime.

53. Cont´d…
• Evaluate patients on pegloticase for development of gouty
flares and infusion reactions, which may include anaphylaxis.
The manufacturer recommends giving an antihistamine and
perhaps low-dose methylprednisolone before the infusion to
minimize reactions.

54. THE END
THANK YOU