Diagnosis and Management of Gout

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Diagnosis and Management of Gout

• The best medicine I know for rheumatism is to
  thank the Lord that it ain't gout. Josh Billings

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Objectives

• To review the etiology and pathophysiology of
  gout
• To recognize predisposing factors for gout
• To review diagnostic criteria and evaluation for
  gout
• To select appropriate treatment for a patient
  presenting with gout

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Definition

• Gout is a heterogeneous disorder that results in
  the deposition of uric acid salts and crystals in
  and around joints and soft tissues or
  crystallization of uric acid in the urinary
  tract.
• Uric acid is the normal end product of the
  degradation of purine compounds.
• Major route of disposal is renal excretion
• Humans lack the enzyme uricase to break down uric
  acid into more soluble form.
• Metabolic Disorder underlying gout is
  hyperuricemia.
• Defined as 2 SD above mean usually 7.0 mg/dL.
  This concentration is about the limit of
  solubility for (monosodium urate) MSU in plasma.
  At higher levels, the MSU is more likely to
  precipitate in tissues.

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Epidemiology

• Most common of microcrystalline arthropathy.
  Incidence has increased significantly over the
  past few decades.
• Affects about 2.1million worldwide
• Peak incidence occurs in the fifth decade, but
  can occur at any age
• Gout is 5X more common in males than
  pre-menopausal females incidence in women
  increases after menopause. After age 60, the
  incidence in women approaches the rate in men.
• People of South Pacific origin have an increased
  incidence.

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Classification of Hyperuricemia

• Uric acid overproduction
• Accounts for 10 of hyperuricemia
• Defined as 800mg of uric acid excreted
• Acquired disorders
• Excessive cell turnover rates such as
  myleoproliferative disorders, Pagets disease,
  hemolytic anemias
• Genetic disorders derangements in mechanisms
  that regulate purine neucleotide synthesis.
• Deficiency HGPRT, or superactivity PRPP
  synthetase
• Uric acid underexcretion
• Accounts for gt90 of hyperuricemia
• Diminished tubular secretory rate, increased
  tubular reabsorption, diminished uric acid
  filtration
• Drugs, other systemic disease that predispose
  people to renal insufficiency

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Predisposing Factors

• Heredity
• Drug usage
• Renal failure
• Hematologic Disease
• Trauma
• Alcohol use

• Psoriasis
• Poisoning
• Obesity
• Hypertension
• Organ transplantation
• Surgery

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Stages of Classic Gout

• Asymptomatic hyperuricemia
• Very common biochemical abnormality
• Defined as 2 SD above mean value
• Majority of people with hyperuricemia never
  develop symptoms of uric acid excess
• Acute Intermittent Gout (Gouty Arthritis)
• Episodes of acute attacks. Symptoms may be
  confined to a single joint or patient may have
  systemic symptoms.
• Intercritical Gout
• Symptom free period interval between attacks. May
  have hyperuricemia and MSU crystals in synovial
  fluid
• Chronic Tophaceous Gout
• Results from established disease and refers to
  stage of deposition of urate, inflammatory cells
  and foreign body giant cells in the tissues.
  Deposits may be in tendons or ligaments.
• Usually develops after 10 or more years of acute
  intermittent gout.

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Pathogenesis of Gouty Inflammation

• Urate crystals stimulate the release of numerous
  inflammatory mediators in synovial cells and
  phagocytes
• The influx of neutrophils is an important event
  for developing acute crystal induced synovitis
• Chronic gouty inflammation associated with
  cytokine driven synovial proliferation, cartilage
  loss and bone erosion

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Presenting Symptoms

• Systemic fever rare but patients may have fever,
  chills and malaise
• Musculoskeletal Acute onset of monoarticular
  joint pain. First MTP most common. Usually
  affected in 90 of patients with gout. Other
  joints knees, foot and ankles. Less common in
  upper extremities
• Postulated that decreased solubility of MSU at
  lower temperatures of peripheral structures such
  as toe and ear
• Skin warmth, erythema and tenseness of skin
  overlying joint. May have pruritus and
  desquamation
• GU Renal colic with renal calculi formation in
  patients with hyperuricemia

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Differential Diagnosis

• Trauma
• Infections
• septic arthritis, gonococcal arthritis,
  cellulitis
• Inflammatory
• Rheumatic arthritis, Reiters syndrome,
  Psoriatic arthritis
• Metabolic
• pseudogout
• Miscellaneous
• Osteoarthrtis

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Diagnosis

• Definitive diagnosis only possible by aspirating
  and inspecting synovial fluid or tophaceous
  material and demonstrating MSU crystals
• Polarized microscopy, the crystals appear as
  bright birefringent crystals that are yellow
  (negatively birefringent)

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Synovial Fluid Findings

• Needle shaped crystals of monosodium urate
  monohydrate that have been engulfed by
  neutrophils

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Diagnostic Studies

• Uric Acid
• Limited value as majority of hyperuricemic
  patients will never develop gout
• Levels may be normal during acute attack
• CBC
• Mild leukocytosis in acute attacks, but may be
  higher than 25,000/mm
• ESR
• mild elevation or may be 2-3x normal
• 24hr urine uric acid
• Only useful in patients being considered for
  uricosuric therapy or if cause of marked
  hyperuricemia needs investigation
• Trial of colchicine
• Positive response may occur in other types of
  arthritis to include pseudogout.

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Treatment Goals

• Gout can be treated without complications.
• Therapeutic goals include
• terminating attacks
• providing control of pain and inflammation
• preventing future attacks
• preventing complications such as renal stones,
  tophi, and destructive arthropathy

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Acute Gout Treatment

• NSAIDs
• Most commonly used.
• No NSAID found to work better than others
• Regimens
• Indocin 50mg po bid-tid for 2-3 days and then
  taper
• Ibuprofen 400mg po q4-6 hr max 3.2g/day
• Ketorolac 60mg IM or 30mg IV X1 dose in
  patientslt65
• 30mg IM or 15mg IV in single dose in patients
  gt65yo, or with patients who are renally impaired
• Continue meds until pain and inflammation have
  resolved for 48hr

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Acute Treatment

• Colchicine
• Inhibits microtubule aggregation which disrupts
  chemotaxis and phagocytosis
• Inhibts crystal-induced production of chemotatic
  factors
• Administered orally in hourly doses of 0.5 to
  0.6mg until pain and inflammation have resolved
  or until GI side effects prevent further use. Max
  dose 6mg/24hr
• 2mg IV then 0.5mg q6 until cumulative dose of 4mg
  over 24hr

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Acute treatment contd

• Corticosteriods
• Patients who cannot tolerate NSAIDs, or failed
  NSAID/colchicine therapy
• Daily doses of prednisone 40-60mg a day for 3-5
  days then taper 1-2 weeks
• Improvement seen in 12-24hr
• ACTH
• Peripheral anti-inflammatory effects and
  induction of adrenal glucocorticoid release
• 40-80IU IM followed by second dose if necessary
• Intra-articular injection with steroids
• Beneficial in patient with one or two large
  joints affected
• Good option for elderly patient with renal or PUD
  or other illness
• Triamcinolone 10-40mg or Dexamethasone 2-10mg
  alone or in combination with Lidocaine

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Non- Pharmacologic Treatments

• Immobilization of Joint
• Ice Packs
• Abstinence of Alcohol
• Consumption can increase serum urate levels by
  increasing uric acid production. When used in
  excess it can be converted to lactic acid which
  inhibits uric acid excretion in the kidney
• Dietary modification
• Low carbohydrates
• Increase in protein and unsaturated fats
• Decrease in dietary purine-meat and seafood.
  Dairy and vegetables do not seem to affect uric
  acid
• Bing cherries and Vitamin C

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Prophylaxis

• Frequent attacks gt3/year, tophi development or
  urate overproduction
• Avoid use of medications that contribute to
  hyperuricemia Thiazide and loop diuretics,
  low-dose salicylates, niacin, cyclosporine,
  ethambutol
• Losartan promotes urate diuresis and may even
  normalize urate levels. This action does not
  extend to other members of the ARB class.
• Useful in elderly with HTN and gout
• Colchicine
• Colchicine 0.6mg qd-bid
• Use alone or in combination with urate lowering
  drugs
• Prophylaxis without urate lowering drugs may
  allow tophi to develop

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Prophylaxis

• Urate Lowering drugs
• Used for documented urate overproduction
• Goal is for serum urate concentration to 6mg/dL
  or less
• Start of therapy can precipitate acute attack
  therefore, may need to use colchicine as a long
  as six months
• Xanthine oxidase inhibitors
• Allopurinol blocks conversion of xanthine to
  uric acid. works for underexcretors and
  overproducers.
• Start typically 300mg/day and titrate weekly
  100mg/day until optimal urate levels achieved.
• Start lower doses with renally impaired patients
• Uricosuric drugs
• Probenecid or Sulfinpyrazone increase renal
  clearance of uric acid by inhibiting tubular
  absorption
• Side effects may prohibit use-GI and kidney
  stones
• Need measurement of 24hr urine in anyone for whom
  Probenecid therapy is initiated

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Newer Therapies

• Uricase
• Enzyme that oxidizes uric acid to a more soluble
  form
• Natural Uricase from Aspergillus flavus and
  Candida utilis under investigation
• Febuxostat
• New class of Xanthine Oxidase inhibitor
• More selective than allopurinol
• Little dependence on renal excretion
• Losartan
• ARB given as 50mg/dL can be urisuric. When given
  with HCTZ, it can blunt the effect of the
  diuretic and potentiate its antihypertensive
  action
• Fenofibrate
• Studies note when used in combo with Allopurinol
  produced additional lowering of the urate

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Complications

• Renal Failure
• ARF can be caused by hyperuricemia, chronic urate
  nephropathy
• Nephrolithiasis
• Joint deformity
• Recurrent Gout

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Case study 1

• 56yo postmenopausal female with sudden onset of
  acute pain in her right toe and knee . The
  patient reported that she has had 3 previous
  episodes of the same symptoms lasting 4-5 days
  and treated by ED physicians. PMHx HTN treated
  with thiazide diuretic and patient is trying to
  lose weight and currently on the Atkins diet. BP
  138/86 BMI 32 PE remarkable for swollen and
  tender right great toe and knee. UA 8.3mg/dL,
  aspiration of her knee demonstrated cell count of
  15K and presence of urate crystals.
• Treatment options for this patient include all of
  the folllowing except
• A. Starting Allopurinol at 300mg/day with an
  NSAID for acute pain control
• B. Discuss risk factors for gout to include
  obesity, stopping the Atkins diet but continue
  with weight loss and switching HTN meds.
• C. Start colchicine at 0.6mg bid and start
  anti-hyperuricemia therapy in 4 weeks
• D. Start therapy for acute pain with NSAIDs, but
  hold any anti-hyperuricemia meds until the
  results of the following labs have been reviewed
  24hr urine collection, Cr, lipid panel

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Answer Case Study 1

• A. Starting Allopurinol at 300mg/day with an
  NSAID for acute pain control
• Starting urate-lowering therapy during an acute
  attack will prolong the attack.

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Case Study 2

• 50yo AAM who presents for evaluation of his
  long-standing gouty arthritis. He states that he
  has several attacks a year but he usually can
  treat them with OTC NSAIDs. However, he states
  that the attacks have become more frequent and
  the NSAIDs are not controlling the pain as well.
  Only other medical problem is his HTN for which
  he takes captopril. On PE BP 135/85, BMI 31,
  temp nl. No gait abnormalities and exam
  remarkable for a small effusion over right knee
  and tophi noted over bilateral olecranons. Labs
  include UA 7.5mg/dL, ESR 23mm/hr and nl WBC
  count. X-rays of his knees noted narrowing of
  joint space with effusion on right side.
• Best treatment option for this patient is
• A. Start colchicine 0.6mg po bid and urate
  lowering therapy with allopurinol
• B. Advise patient to discontinue NSAID therapy
  and use low dose prednisone daily for prophylaxis
• C. Start colchicine 0.6mg po bid and uricosuric
  therapy with Probenecid
• D. Since patient is between attacks, just start
  urate lowering therapy.

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Answer Case Study 2

• A. Start colchicine 0.6mg po bid and urate
  lowering therapy with allopurinol.
• Meds for lower uric acid levels are indicated for
  patients who have frequent attacks a year and
  those who have tophi or erosive arthritis. As
  urate therapy can precipitate an attack, patients
  also needs prophylactic meds for several months.

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Case Study 3

• 60yo male presenting with persistent gouty
  symptoms despite taking allopurinol daily at
  100mg/day for the past year. He has a 20 year hx
  of gout usually manifested by mono- or
  oligoarthritis involving his lower extremities.
  Patient has been treated with NSAIDs for his
  acute flairs however, once the attacks became
  more common, he was placed on chronic NSAID
  therapy. PMHx significant for HTN and chronic
  renal insufficiency- last Cr 1.6. On PE BP
  125/73 BMI 34. no acute musculoskeletal symptoms
  but he has chronic synovial changes over wrists,
  and left first MTP. Tophi are noted over
  olecranon. UA 9.5mg/dL
• The best treatment options for this patient is
• A. Replace NSAIDs for chronic prophylaxis with
  prednisone starting at 30mg/day and then tape. Do
  not change allopurinol dose
• B. Continue to increase allopurinol despite his
  renal issues to a dose that keeps UA level below
  6.0mg/dL and replace NSAIDs with other
  prophylactic therapy.
• C. Continue NSAID therapy for prophylaxis.
  Counsel patient that long term NSAID use and HTN
  can contribute to increasing renal disease.
• D. Discontinue all current meds and replace them
  with Colchicine 0.6mg po bid
• E. None of the above

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Answer Case Study 3

• B. Continue to increase allopurinol despite his
  renal issues to a dose that keeps UA level below
  6.0mg/dL and replace NSAIDs with other
  prophylactic therapy.

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Questions?
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References

• Klippel, JH.Primer on Rheumatic Diseases. 12th
  ed. Arthitis Foundation 2001 307-323.
• Schumacher HR, Chen LX. Newer Therapeutic
  Approaches Gout. Rheumatic Disease Clinics of
  North America 200632.
• Pittman, JR, Bross, MH. Diagnosis and Management
  of Gout. American Family Physician 199959
• Monu JU, Pope TL. Gout a clinical and radiologic
  review. Radiologic Clinics of North America.
  200442
• Goldman. Cecil Textbook of Medicine. 22nd ed.
  W.B. Saunders Company 2004
• Shen S, Wolfe R. Gout. Emergency Medicine
  Clinical Reviews. 2004

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Review Question 1

• A 62yo male comes into your office with pain and
  swelling over left great toe at MTP joint. Exam
  shows it is erythematous, warm swollen, tender to
  touch. The patient has a history of DM controlled
  by diet and HTN. His medications include HCTZ
  25mg daily. A CBC and blood chemistry profile are
  normal except for uric acid level of 9.2 mg/dL(Nl
  3.6-8.5).
• Which of the following is true in this situation?
• A. This attack should resolve spontaneously in
  3-4 days
• B. Allopurinol therapy should be started
• C. The elevated uric acid level establishes
  diagnosis of gout
• D. Intra-articular injection should be avoided
• E. Stopping the HCTZ may control hyperuricemia

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Answer 1

• E. Stopping HCTZ may control hyperuricemia.

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Question 2A

• A 32 year-old male visits your office complaining
  of pain of 12 hr duration in the MTP joint of
  large left toe. He states that the joint is very
  tender to touch and denies history of trauma. He
  is on no meds. Exam is within normal limits
  except for large area of erythema over his left
  large toe and up onto the dorsum of his foot. No
  lymphangitis is noted.
• Tests which would help establish a definitive
  diagnosis include which of the following?
• A gram stain of the fluid aspirated from the
  joint
• 24hr urine collection for protein
• An X-ray of foot and ankle
• Microscopic examination for crystals in the
  synovial fluid aspirate
• Intravenous pyelography

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Question 2 Answer

• Tests which would help establish a definitive
  diagnosis include which of the following?
• T A gram stain of the fluid aspirated from the
  joint
• F 24hr urine collection for protein
• F An X-ray of foot and ankle
• T Microscopic examination for crystals in the
  synovial fluid aspirate
• F Intravenous pyelography

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Question 2B

• Appropriate drug choices for the initial
  management of this acute gout attack include
  which of the following?
• A. Colchicine
• B. Probenecid
• C. Nafcillin
• D. Prednisone
• E. Indocin
• F. Allopurinol

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Answer 2B

• Appropriate drug choices for the initial
  management of this acute problem include which of
  the following?
• T Colchicine
• F Probenecid
• F Nafcillin
• T Prednisone
• T Indocin
• F Allopurinol

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Question3

• You are able to aspirate synovial fluid from the
  joint, to establish diagnosis of gout, which of
  the following joint findings will establish the
  diagnosis of gout?
• A. Negatively birefringent needle shaped crystals
• B. Positively birefringent needle shaped crystals
• C. Snowball like aggregate crystals
• D. Dumbbell and octahedron shaped crystals

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Answer 3

• A. Negatively birefringent needle shaped crystals

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Gout

• Introduction
• Etiology
• Primary vs secondary gout
• Epidemiology
• Age, gender and race
• Pathophysiology
• Predisposing factors
• Associated conditions
• Presentation
• History, PE, Lab and Radiology work-up
• Differential Diagnosis
• Treatment Summary
• Pharmacologic
• Non-pharmacologic

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Pathophysiology

• Primary gout is caused by inborn defects in
  purine metabolism or inherited defects of the
  renal tubular secretion of urate.
• Secondary gout is caused by acquired disorders
  that result in increased turnover of nucleic
  acids, by defects in renal excretion of uric acid
  salts, and by the effects of certain drugs

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Associated Conditions

• Cardiovascular Disease
• Pagets disease
• Arthritis- rheumatoid and osteoarthritis
• Septic Arthritis
• Metabolic syndrome

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