Gouthy Arthritis

Lita Diah
Rheumatology, Internal Med.
Dr. Soetomo Hospital
Airlangga Med School
Case presentation
•55 y/o male
•12 hours “pain in my big toe & ankle”
•went to bed last night feeling fine
•felt as if had broken toe this morning
•PMH of similar problems in right ankle & left
wrist
Case presentation
•can barely walk (due to pain)
•right elbow swollen
•exam shows left first MTP joint & left ankle
to be red, swollen & tender to touch
•right elbow also swollen
Case presentation
•lab studies
serum uric acid = 11.5 mg/dl
24-hour uric acid excretion = 300 mg
•left foot X-rays show bony erosion with
overhanging edge, medial side of first
metatarsal head
Case presentation

What does he have?

What can do we do about it?

Gout - acute arthritis

acute synovitis,
ankle & first MTP
joints
Gout - acute bursitis

acute olecranon
bursitis
Gouty arthritis - characteristics
• sudden onset • recurrent episodes
• middle aged males • influenced by diet
• severe pain • bony erosions on Xray
• distal joints
• Intense inflammation
What Happens To Gout
Patients & Why?
Gout - acute arthritis

arthrocentesis

acute synovitis,
ankle & first MTP
joints
 Monosodium urate crystals

needle shape

negative
birefringence

polarized light red compensator

Crystal-induced inflammation
hyperuricemia inflammation

crystal deposition crystals engulfed PMN is critical

component of
crystal-induced
protein binding influx of PMN’s
inflammation

receptor binding cytokine release

Gouty arthritis - characteristics
• sudden onset • recurrent episodes
• middle aged males • influenced by diet
• severe pain • bony erosions on Xray
• distal joints • hyperuricemia
• intense inflammation
Hyperuricemia

hyperuricemia results when production exceeds excretion

Hyperuricemia

net uric acid loss results when excretion exceeds production

 Nature of Gout

Chronic heterogeneous disorder of urate metabolism

Results in deposition of monosodium urate crystals in
the joints and soft tissues, with accompanying
inflammation and degenerative This disorder can be
progressive through four stages if undertreated
1.Asymptomatic hyperuricemia
2.Acute gout
3.Intercritical gout
4.Chronic tophaceous gout
Chronic tophaceous gout

tophus = localized deposit of

monosodium urate crystals
Gout - tophus

classic location of
tophi on helix of ear
Gout - X-ray changes

DIP joint destruction

phalangeal bone cysts

Gout - X-ray changes

bony erosions
Gout - cardinal manifestations

arthritis tophi

acute &
chronic
HYPERURICEMIA

nephrolithiasis nephropathy
The Role of Uric
Acid in Gout
Hyperuricemia & gout

Serum Uric Annual 5-Year

Acid Level Incidence Prevalence
> 10 mg/dl 70 30%
< 7 mg/dl 0.9 0.6%
Serum uric acid levels & age
13.0
12.0
11.0
10.0 Gouty Male
9.0
Normal Male
8.0
Gouty Female
7.0
6.0 Normal Female
5.0
4.0
3.0
10 20 30 40 50 60
Age (years)
Uric acid metabolism
dietary intake purine bases cell breakdown

xanthine oxidase hypoxanthine

catalyzes
hypoxanthine to
xanthine & xanthine
xanthine to uric
acid
uric acid
 Renal handling of uric acid

•glomerular filtration
•tubular reabsorption
•tubular excretion
•post-secretory
reabsorption
•net excretion
Hyperuricemia - mechanisms

excessive inadequate
production excretion

hyperuricemia
Hyperuricemia - mechanisms

overproducers underexcretors

hyperuricemia
Classifying hyperuricemia
•serum uric acid level
•urine uric acid excretion (24-hour)

overproduction underexcretion
serum uric acid high high
urine uric acid high normal/low
Gout - problems
•excessive total body levels of uric acid

•deposition of monosodium urate crystals in

joints & other tissues

•crystal-induced inflammation
Drug therapy of gout

What Drugs Are Available

For Treating Gout?
Treating acute gouty arthritis
•colchicine
•NSAID’s
•steroids
•rest, analgesia, ice, time
Drugs used to treat gout

Acute Arthritis Drugs Urate Lowering Drugs

colchicine allopurinol

steroids probenecid

NSAID’s febuxostat?

rest + analgesia + time

Benjamin Franklin (1706 - 1790)

suggests gout sufferers use

l’Eau Medicinale d'Husson
(secret French medicine
containing colchicine)
Colchicine - plant alkaloid

colchicum
autumnale
(autumn crocus or
meadow saffron)
Colchicine
•“only effective in gouty arthritis”
•not an analgesic
•does not affect renal excretion of uric acid
•does not alter plasma solubility of uric acid
•neither raises nor lowers serum uric acid
Colchicine
•mechanism of action poorly understood
•reduces inflammatory response to deposited
crystals
•diminishes PMN phagocytosis of crystals
•blocks cellular response to deposited
crystals
Crystal-induced inflammation
hyperuricemia inflammation

crystal deposition crystals engulfed PMN is critical

component of
crystal-induced
protein binding influx of PMN’s
inflammation

receptor binding cytokine release

Colchicine - indications

Dose Indication

high treatment of acute gouty arthritis

low prevention of recurrent gouty arthritis

Colchicine - toxicity
•gastrointestinal (nausea, vomiting,
cramping, diarrhea, abdominal pain)
•hematologic (agranulocytosis, aplastic
anemia, thrombocytopenia)
•muscular weakness
adverse effects dose-related & more common when
patient has renal or hepatic disease
Gout - colchicine therapy
•more useful for daily prophylaxis (low dose)
prevents recurrent attacks
colchicine 0.6 mg qd - bid

•declining use in acute gout (high dose)

Drugs used to treat gout

Acute Arthritis Drugs Urate Lowering Drugs

colchicine allopurinol

steroids probenecid

NSAID’s febuxostat?

rest + analgesia + time

Hyperuricemia - mechanisms

excessive inadequate
production excretion

hyperuricemia
Urate-lowering drugs

block enhance
production excretion

net reduction in total body pool of

uric acid
Gout - urate-lowering therapy
•prevents arthritis, tophi & stones by lowering
total body pool of uric acid
•not indicated after first attack
•initiation of therapy can worsen or bring on
acute gouty arthritis
•no role to play in managing acute gout
Drug therapy of gout

Drugs That Block

Production of Uric Acid
Uric acid metabolism
dietary intake purine bases cell breakdown

xanthine oxidase hypoxanthine

catalyzes
hypoxanthine to
xanthine & xanthine
xanthine to uric
acid
uric acid
Allopurinol
•inhibitor of xanthine oxidase
•effectively blocks formation of uric acid
•how supplied - 100 mg & 300 mg tablets
•pregnancy category C
allopurinol
Chemical structures

N N
N
N N N HO N NH

HN N
NH O N

O allopurinol OH

hypoxanthine xanthine
Uric acid metabolism
dietary intake purine bases cell breakdown

oxypurinol
hypoxanthine

allopurinol
inhibits xanthine xanthine allopurinol
allopurinol
oxidase

uric acid
Allopurinol effect
allopurinol lowers serum uric acid levels

Component Serum Level

Hypoxanthine

Xanthine

Uric acid
Allopurinol

What are the clinical

consequences of
blocking production of
uric acid?
Allopurinol
•90% absorption from the gut
•metabolized to oxypurinol
•once daily dosing
•lowers serum uric acid levels
•lowers urine uric acid levels
•side effects rare, but potentially lethal
Allopurinol - usage indications
•management of hyperuricemia of gout
•management of hyperuricemia associated
with chemotherapy
•prevention of recurrent calcium oxalate
kidney stones
Allopurinol – black box warning
THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT
RECOMMENDED FOR THE TREATMENT OF
ASYMPTOMATIC HYPERURICEMIA

ALLOPURINOL SHOULD BE DISCONTINUED AT

THE FIRST APPEARANCE OF SKIN RASH OR
OTHER SIGNS OF AN ALLERGIC REACTION
Allopurinol - common reactions
•diarrhea, nausea, abnormal liver tests
•acute attacks of gout
•rash
Allopurinol - serious reactions
•fever, rash, toxic epidermal necrolysis
•hepatotoxicity, marrow suppression
•vasculitis
•drug interactions (ampicillin, thiazides,
mercaptopurine, azathioprine)
•death
Stevens-Johnson syndrome

target skin lesions

mucous membrane
erosions
epidermal necrosis with
skin detachment
Allopurinol hypersensitivity
•extremely serious problem
•prompt recognition required
•first sign usually skin rash
•more common with impaired renal function
•progression to toxic epidermal necrolysis &
death
Febuxostat
•recently approved by FDA (not on market)
•oral xanthine oxidase inhibitor
•chemically distinct from allopurinol
•94% of patients reached urate < 6.0 mg/dl
•minimal adverse events
•can be used in patients with renal disease
Drug therapy of gout

Drugs That Enhance

Excretion of Uric Acid
 Renal handling of uric acid

•glomerular filtration
•tubular reabsorption
•tubular excretion
•post-secretory
reabsorption
•excretion
Uricosuric therapy
•probenecid
•blocks tubular reabsorption of uric acid
•enhances urine uric acid excretion
•increases urine uric acid level
•decreases serum uric acid level
Uricosuric therapy
•moderately effective
•increases risk of nephrolithiasis
•not used in patients with renal disease
•frequent, but mild, side effects
•some drugs reduce efficacy (e.g., aspirin)
Uricosuric therapy
•contra-indications
history of nephrolithiasis
elevated urine uric acid level
existing renal disease
•less effective in elderly patients
Choosing a urate-lowering drug

excessive inadequate
production excretion
xanthine
uricosuric
oxidase
agent
inhibitor
hyperuricemia
Urate-lowering therapy
•mild gout uricosuric
•renal disease allopurinol
•nephrolithiasis allopurinol
•high 24-hr UUA allopurinol
•elderly allopurinol
•tophaceous gout allopurinol
Treating acute gout

What is the role of urate-

lowering drugs like allopurinol
or probenecid in treating acute
gouty arthritis?
Urate-lowering therapy
•no anti-inflammatory activity
•can precipitate acute gout
•can prolong attack of gout
•advice?
Gout - rule #309
Concept
“Don’t mess with the uric acid level”

Don’t change your urate-lowering

therapy during an acute gout attack
Gout - therapeutic problems
•renal disease
•nephrolithiasis
•transplantation
•allopurinol allergy
Case presentation - therapy
NSAID NSAID

steroid

colchicine (high dose)

Allopurinol + colcichine low dose

days 1-10 days 11-365 days 365+

Terima Kasih