Gout. Hospital practice

1. GOUT

HOSPITAL PRACTICE
SUBMITTED TO- Prof. IGOR YATSKOV
SUBMITTED BY- KAIS AHAMAD
GROUP – LA2 –CO-173(2)

2. 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
consequences
• Most common form of inflammatory joint disease in men aged ≥40
years
• This disorder can be progressive through four stages if undertreated
1.
2.
3.
4.
Asymptomatic hyperuricemia
Acute gout
Intercritical gout
Chronic tophaceous gout

3. Hallmarks of Gout

• Group of conditions which may be
characterized by
–
An elevation of serum uric acid (usually)
–
Recurrent attacks (flares) of an acute inflammatory
arthritis with monosodium urate crystals
demonstrated in synovial fluid leukocytes
–
Bone and joint destruction in some cases
–
Aggregates of uric acid crystals (tophi) in and
around joints, soft tissues, and various organs
–
Tophus in bone leading to erosions in some cases
–
Kidney disease and stones

4. Hyperuricemia

Biologically significant hyperuricemia (≥6.8 mg/dL) is less than
laboratory defined hyperuricemia (≥8.0 mg/dL)
The Hyperuricemia Cascade
Tissue
nucleic acids
Dietary
purines
Endogenous
Overproduction
purine synthesis
Urate
Underexcretion
Hyperuricemia ≥6.8 mg/dL
Silent
tissue
deposition
Gout
Renal
manifestations
Associated
cardiovascular events
and mortality

5. Hyperuricemia and Gout

Initial urate
Distribution, %
35
30
25
20
15
10
Males
Females
Urate crystallizes at
a level of 6.8 mg/dL
Many patients fit
biological definition
for hyperuricemia
5
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Cumulative incidence of gout, %
30
40
25
n
≥9.0
94
7.0-8.9
666
<7.0
898
20
15
10
5
0
1
2
3
4
5
Years
Serum urate, mg/dL
Serum urate levels in 1515 men and 1670
women aged ≥30 in Taiwan 1991-1992
Over time, high serum urate levels lead to gout
Normative Aging Study:1858 previously healthy men
(average initial age 42) followed for 14.9 years
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6. Evolution from Hyperuricemia to Gout

stores, advancing the severity of the disease
– Flares last longer
– Flares occur more often
– Intercritical segments (flare free periods) decrease
– Persistent pain and stiffness occur
Pain Levels
Evolution from Hyperuricemia to
Gout
Over time, untreated, chronic hyperuricemia increases body urate
Time:
3. Painless intercritical
segments
Body
Urate
Pool
1. Asymptomatic
hyperuricemia
2. Acute flares
4. Chronic
polyarthropathy
with tophus
formation

7. Properly Lowering Serum Urate s Acute Flares

Properly Lowering Serum Urate s Acute Flares
100.0
90.0
80.0
Incidence of
recurrent
gouty attacks
> 1 year
after each
patient visit, %
70.0
60.0
50.0
40.0
Observed
Logistic regression
30.0
20.0
10.0
0.0
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
Average serum urate during the whole investigation period, mg/dL
.
86% (71/81) of patients who had serum urate <6.0 mg/dL did not
experience an acute flare during the study period

8. Podagra

9. Common Sites of Acute Flares

Olecranon Bursa
Elbow
Gout can occur
in bursae, tendons,
and joints
Wrist
Fingers
Knee
1st MTP
(eventually affected in ~90%
of individuals with gout)
Ankle
Subtalar
Midfoot

10. Intervals Between 1st & 2nd Acute Flares

Intervals Between 1st & 2nd Acute Flares
Majority experience second acute flare within
1 year of first gout flare
Within 1 yr
4%
7%
1-2 yrs
5%
2-3 yrs
6%
3-5 yrs
16%
62%
After 10 yrs
No 2nd in more than
10 yrs

11. Advanced Chronic Tophaceous Gout

• Tophi can be seen clinically, with
obvious deformity demonstrated in
hands and foot
• Tophi may be associated with bony
destruction as seen on the x-ray on right

12. Largely Non-Specialist Care

The majority of individuals with gout
are treated by primary care physicians,
not specialists
Distribution of Office Visits
(1999-2003)
• Frequent Low Back Pain
Rheumatologist (3%)
Provider or PCP (74%) Other (22%)
Many gout-related visits are based on
acute exacerbations of the disease
• Osteoarthritis
Rheumatologist (7%)
(52%) Other (40%)
The diagnostic terms “acute gout” and
“chronic gout” with and without “tophi”
are commonly documented in primary
care medical records
• Osteoporosis
Rheumatologist (5%)
(79%) Other (15%)
PCP
• Gout
Rheumatologist (12%)
Other (8%)
PCP (80%)
• Rheumatoid Arthritis
Rheumatologist 52%)
(31%) Other (17%)
Primary Care
/
PCP
PCP

13. Changing Treatment Landscape

Current
• Allopurinol
In Development
• Uricosurics
• Uricosurics
• Selective xanthine oxidase
inhibitor
• Symptomatic relief
• Pegylated uricase enzyme
• IL-1 receptor antagonists
• URAT1 Transporter
Inhibitor
IL-1 = Lnterleukin-1
URAT1 = urate transporter 1

14. Synoviocytes phagocytose urate crystals and then secrete inflammatory mediators, which attract and activate polymorphonuclear

leukocytes (PMN) and mononuclear phagocytes
(MNP) (macrophages).
Drugs active in gout inhibit crystal phagocytosis and polymorphonuclear leukocyte and
macrophage release of inflammatory mediators. PG, prostaglandin; IL-1, interleukin-1; LTB4,
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leukotriene B4.

15.

Drugs Capable of Inducing Hyperuricemia
and Gout:
• Diuretics
• Ethanol
• Ethambutol
• Nicotinic acid
• Pyrazinamide
• Cytotoxic drugs
• Salicylates (<2 g/day)
• Levodopa
• Cyclosporine
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16. Signs and Symptoms

Acute attack:
• Acute arthritis
• The metatarsophalangeal joint of the first toe often involved
• Nocturnal excruciating pain, swelling, redness and tenderness
Chronic:
• Nonsymmetric synovitis
• Chronic gouty arthritis
• Periarticular tophaceous deposits
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17.

The aims of treatment are to:
1.Decrease the symptoms of an acute attack
2.Decrease the risk of recurrent attacks
3.Lower serum urate levels
The substances available for these purposes are:
1.Drugs that relieve inflammation and pain (NSAIDS, colchicine,
glucocorticoids,)
2.Drugs that prevent inflammatory responses to crystals (colchicine,
NSAIDS and Interleukin-1 inhibitors)
3.Drugs that act by inhibition of urate formation (allopurinol,
febuxostat) or to augment urate excretion (probenecid)
4.Converts uric acid to allantoin, which is then excreted (Pegloticase
and rasburicase )
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18.

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19. Treatment of acute gout

• Acute gouty attacks can result from a number of conditions,
including excessive alcohol consumption, a diet rich in purines, or
kidney disease.
• The mainstay of treatment during an acute attack is the
administration of anti-inflammatory drugs such as NSAIDs,
colchicine or glucocorticoids.
• NSAIDs are used most often in individuals without complicating
comorbid conditions.
• The most effective drugs are indomethacin, naproxen, ibuprofen,
diclofenac and celecoxib.
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20. Treatment of acute gout

• Acute gouty attacks can result from a number of conditions,
including excessive alcohol consumption, a diet rich in purines, or
kidney disease.
• Glucocorticoids is given i.m. or orally (prednisone).
• For a single joint or a few involved joints, intraarticular
triamcinolone acetonide or methyl prednisolone have been
effective and well tolerated.
Note: Aspirin is contraindicated, because it competes with uric acid
for the organic acid secretion mechanism in the proximal tubule
of the kidney.
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21. Treatment of chronic gout

• Treatment strategies for chronic gout include the use of uricosuric
drugs that increase the excretion of uric acid, thereby reducing its
concentration in plasma, and the use of allopurinol, which is a
selective inhibitor of the terminal steps in the biosynthesis of uric
acid.
• Uricosuric agents are first-line agents for patients with gout
associated with reduced urinary excretion of uric acid.
• Allopurinol is preferred in patients with excessive uric acid synthesis,
with previous histories of uric acid stones, or with renal
insufficiency.
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22. Colchicine

• Colchicine is currently used for prophylaxis of recurrent attacks
and will prevent attacks in more than 80 percent of patients.
Pharmacokinetics:
Colchicine is administered orally, followed by rapid absorption
from the GI tract.
• Colchicine is recycled in the bile and is excreted unchanged in the
feces or urine.
• Use should be avoided in patients with a creatinine clearance of
less than 50 mL/min.
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23.

• Colchicine modulates multiple pro- and
antiinflammatory pathways associated with
gouty arthritis.
• Colchicine prevents microtubule assembly
and thereby disrupts inflammasome
activation, microtubule-based inflammatory
cell chemotaxis, generation of leukotrienes
and cytokines, and phagocytosis.
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24. Colchicine

Adverse effects:
• Nausea
• Vomiting
• Abdominal pain
• Diarrhoea
Chronic administration may lead to:• myopathy, neutropenia, aplastic anaemia and alopecia.
• The drug should not be used in pregnancy, and it should be used
with caution in patients with hepatic, renal, or cardiovascular
disease.
• The fatal dose has been reported as low as 7 to 10 mg.
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25. Uricosuric agents

• Both probenecid and sulfinpyrazone inhibit the secretion as well
as the reabsorption of urate and, if given in subtherapeutic doses,
can actually increase plasma urate concentrations.
• The maintenance of adequate urine flow and alkalinization of the
urine during the first several days of uricosuric therapy further
diminish the possibility of uric acid stone formation.
Note- In addition, probenecid can inhibit the tubular secretion of
other organic acids; thus, increased plasma concentrations of
penicillins, cephalosporins, sulfonamides, and indomethacin
can occur.
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26. Uricosuric agents

Adverse effects:
Contraindication:
• Gastrointestinal irritation
• Rash and hypersensitivity
• Precipitation of acute gouty
arthritis
• Stone formation.
Of the two agents, probenecid is
the most frequently used
uricosuric as sulfinpyrazone is
associated with more severe
adverse effects.
• Allergic to uricosuric drugs
• In patients with impaired
renal function (a creatinine
• Clearance <50 ml/min)
• A history of renal calculi
• In patients who are
overproducers of uric acid
For such patients,
allopurinol should be
used.
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27. Allopurinol

• Allopurinol inhibits xanthine oxidase and prevents the synthesis of
urate from hypoxanthine and xanthine.
• It is used to treat hyperuricemia in patients with gout and to
prevent it in those with hematological malignancies about to
undergo chemotherapy (acute tumor lysis syndrome).
• Even though underexcretion rather than overproduction is the
underlying defect in most gout patients, allopurinol remains
effective therapy.
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28.

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29. Allopurinol

Drug Interactions:
(a) Allopurinol inhibits the degradation of 6- mercaptopurine and
azathioprine: their doses should be reduced to 1/3rd, but not that
of thioguanine, because it follows a different metabolic
path(S-methylation).
(b) Probenecid given with allopurinol has complex interaction; while
probenecid shortens t1/2 of alloxanthine, allopurinol prolongs
t1/2 of probenecid.
(c) Allopurinol can potentiate warfarin and theophylline by inhibiting
their metabolism.
(d) A higher incidence of skin rashes has been reported when
ampicillin is given to patients on allopurinol.
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30. Allopurinol

Therapeutic Uses:
• Allopurinol is available for oral use and provides effective therapy
for the primary hyperuricemia of gout and the hyperuricemia
secondary to polycythemia vera, myeloid metaplasia, other blood
dyscrasias, or acute tumor lysis syndrome.
• In the management of gout, it is customary to antecede
allopurinol therapy with colchicine and to avoid starting
allopurinol during an acute attack of gouty arthritis.
• Fluid intake should be sufficient to maintain daily urinary volume
of more than 2 liters; slightly alkaline urine is preferred.
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31. Allopurinol

Adverse Effects:
Allopurinol is tolerated well by most patients.
• The most common adverse effects are hypersensitivity reactions
that may occur after months or years of medication.
• Cutaneous reaction: Predominantly, a pruritic, erythematous, or
maculopapular eruption. Occasionally, the lesion is urticarial or
purpuric.
• Rarely, toxic epidermal necrolysis or Stevens-Johnson
syndrome (SJS) occurs, which can be fatal.
– The risk for SJS is limited primarily to the first 2 months
of treatment.
Fever, malaise, and myalgias also may occur.
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32. Febuxostat

• Febuxostat is a non-purine-selective inhibitor of xanthine
oxidase. It works by non-competitively blocking the molybdenum
pterin center which is the active site on xanthine oxidase.
• It is used in the treatment of chronic gout and hyperuricemia.
• Side effects-nausea, diarrhea, arthralgia, headache, increased
hepatic serum enzyme levels and rash.
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33. Drugs Increasing Metabolism

• Urate oxidase (uricase) metabolizes insoluble uric acid to soluble
allantoin in the birds.
• This enzyme is absent in humans.
• Recombinant urate oxidase is now available as rasburicase.
• Pegloticase is another similiar drug that is pegylated to increase
duration of action.
• Pegloticase and rasburicase are administered by i.v. route and are
indicated only in patients with chronic gout refractory to other
treatments.
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34. Interleukin-1 inhibitors

• Drugs targeting the IL-1 pathway, such as anakinra, canakinumab,
and rilonacept, are used for the treatment of gout.
• These agents may provide a promising treatment option for acute
gout in patients with contraindications to, or who are refractory
to, traditional therapies like NSAIDs or colchicine.
• A recent study suggests that canakinumab, a fully human anti- IL1β monoclonal antibody, can provide rapid and sustained pain
relief at a dose of 150 mg subcutaneously
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35.

THANK YOU
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