Gout updat

Prof. Chit Soe
MBBS, MMed.Sc, MRCP(UK), Dr. Med.Sc,
FRCP (Edin), FRCP (Thai)
Dip.Med.Ed
Gout Update 2015

Gout…in 1799…
21.2.152 Gout-cs

Flare: Classic Description
The victim goes to bed and sleeps in good
health. About two o’clock in the morning he is
awakened by a severe pain in the great toe;
more rarely in the heel, ankle, or instep. The
pain is like that of a dislocation, and yet the
parts feel as if cold water were poured over
them . . . Now it is a violent stretching and
tearing of the ligaments – now it is a gnawing
pain, and now a pressure of tightening. So
exquisite and lively meanwhile is the feeling of
the part affected, that it cannot bear the weight
of the bedclothes nor the jar of a personSydenham, T: The Works of Thomas Sydenham, London, New Sydenham Soc. 1850 (translation)21.2.153 Gout-cs

Not Uncommon
King of the Diseases Disease of the Kings
21.2.15Gout-cs4
 Most common
inflammatory arthritis
in US
 Rise in prevalence by
fourfold in past half
century

Total Population of Several Rheumatic
Conditions in the United States
8.3
Million*
7.1
Million
†
5.0
Million
‡
2.7
Million
§
1.3
Million
‡
*Based on patient-reported data from NHANES 2007-2008.
†Estimated from 1997 NHIS and 2005 US Census Bureau data.
‡Estimated from 2005 US Census Bureau data.
§Based on 1988 NHIS data.
0
1
2
3
4
5
6
7
8
9
Gout Activity-limiting
Back Pain
Fibromyalgia Carpal Tunnel
Syndrome
Rheumatoid
Arthritis
TotalPopulation(Millions)
21.2.155 Gout-cs

Who May Be the Patient With Hyperuricemia and
Gout?
Demographics Comorbidities
• Advanced age
• Male
• Postmenopausal women
• Hypertension
• Cardiovascular disease
• Chronic kidney disease
• Diabetes mellitus
• Dyslipidemia
• Metabolic syndrome
Commonly Used Medications Lifestyle
• Diuretics
• Low-dose aspirin (eg, <325 mg)
• Cyclosporine
• Niacin
• Obesity (high BMI)
• Diet rich in meat and seafood
• High alcohol intake
• Frequent consumption of
high-fructose corn syrup
21.2.156 Gout-cs

ACR Guideline 2012
21.2.15Gout-cs7

Definition
21.2.15Gout-cs8
 Gout is a disorder that manifests as a spectrum of
clinical and pathologic features built on a
foundation of an excess body burden of uric acid,
manifested in part by hyperuricemia, which is
variably defined as a serum urate level greater
than 360umol/l (6.8mg%)

Definition
 The term gout is derived from the latin word
'guta' meaning a drop, and originally may
have referred to a drop of poison or evil
humor.
 a group of diseases characterized by
hyperuricaemia and uric acid crystal
formation.
21.2.159 Gout-cs

21.2.15Gout-cs11
 Gout is a disease in which tissue deposition of
monosodium urate (MSU) crystals occurs due
to hyperuricemia (MSU supersaturation of
extracellular fluids)
 Occur at >360umol/l concentration

These clinical syndromes include
 Asymptomatic hyperuricaemia
 Acute gouty arthritis,
 tophaceous gout,
 uric acid nephrolithiasis, and
 gouty nephropathy.
In its more narrow and perhaps more commonly
used definition, gout refers to arthritis caused by
uric acid crystals.
21.2.1512 Gout-cs

Acute Gouty Attack
21.2.1514 Gout-cs

Gout-cs15
CHARACTERISTICS OF AN ACUTE
ATTACK OF GOUT
 Early episodes of acute gouty arthritis are
typically monoarticular (85%) and begin abruptly,
often during the night or early morning.
 The affected joint becomes exquisitely painful,
warm, red, and swollen.
 A low -grade fever may be present.
 The periarticular erythema and swelling may
progress to resemble a cellulitis termed gouty
cellulitis.
21.2.15

Clinical Course of Classic Gout
21.2.1517 Gout-cs

Chronic Tophiceous gout with
flare
21.2.1518 Gout-cs

Tophi in multiple joints
21.2.1519 Gout-cs

Pathophysiology
 uric acid is an end product of purine
biosynthesis.
 Hyperuricaemia is a necessary but not a
sufficient condition for the development of
gout;
 and although the mechanisms of excess uric
acid accumulation are well defined, the
subsequent phases of crystal formation and
release into tissues remain less well
characterized.
21.2.1521 Gout-cs

Purine metabolism
Purines are derived from two sources.
(1) ingested in food
(2) generated via a complex de novo synthetic pathway.
Components of the purine ring are complexed to the
donor substrate phosphoribosylpyrophosphate (
PRPP).
These are then taken through a 10-step process
culminating in purine nucleotide formation.
PRPP is also used as a substrate for pyrimidine and
pyridine synthesis. Thus, the first committed step in
purine synthesis is catalysed by the enzyme
amidophosphoribosyl transferase ( amidoPRT).
The de novo synthetic pathway requires heavy
energy
21.2.1522 Gout-cs

Uric acid metabolism
 Uric acid is ultimately formed from purine nucleotides
through the intermediate compounds xanthine,
hypoxanthine, and guanine by the enzyme xanthine
oxidase.
 It is a terminal product as no mammalian uricase
exists.
 Uric acid is made primarily in the liver.
 The average pool size is 1200 mg in men and 600 mg in
women.
In both men and women, about two-thirds of the total uric
acid pool is turned over each day. 21.2.1524 Gout-cs

 Uric acid pools in patients with gout are always
larger than normal, usually in the range of 2000 to 4000
mg.
In patients with tophi, uric acid burdens can be as
high as
30 000 mg. Two-thirds of uric acid is renally excreted.
The remainder is degraded by gut bacteria via
the process of 'intestinal uricolysis‘
 The renal handling of uric acid is complex and
not fully understood. It entails a four-step
process beginning with glomerular filtration,
followed by active reabsorption in the proximal
tubule, tubular secretion at some distal site, and21.2.1525 Gout-cs

causes of hyperuricaemia associated with
gout devided into three catagories:
Mechanisms of hyperuricaemia in primary
gout
 Primary gout is simply defined by the absence
of any identifiable underlying disease causing
hyperuricaemia.
• the largest group of patients with gout.
• Most of these patients are older men and
• 80 to 85 per cent are hyperuricaemic on the
basis of
underexcretion of uric acid.
•most patients - have low fractional uric acid
excretion rates 21.2.1527 Gout-cs

 A minority of patients with primary gout have high
urinary uric acid levels and excessive de novo purine
synthesis.
The best evidence to date supports a role for increased
PRPP availability or decreased purine nucleotide
concentrations (thus diminishing feedback inhibition of
the synthetic enzymes) in patients with primary gout who
overproduce.A recent study of purine metabolism in women with
primary gout showed similar abnormalities to men
with primary gout.
21.2.1528 Gout-cs

Causes of secondary gout
(1) Overproduction of uric acid, such as tumour
lysis syndrome, myeloproliferative disease,
haemolytic amaemia, and psoriasis.
All of these conditions are characterized by
increased cell turnover with a subsequent increase
in purine synthesis and catabolism.
(2) Undersecretion of uric acid
 such as renal failure and many drugs
 Lead exposure is a cause of secondary gout.
Saternine gout, which is associated with heavy lead
exposures (often from the ingestion of lead-laden
whisky), is rare today.
21.2.1529 Gout-cs

Kelley’s Rheumatology 9th
21.2.15Gout-cs30

Urate crystal formation
 Urate is present in two forms in the body.
 At neutral and alkaline pH (7.4), the monosodium salt (
MSU) predominates.
 At acidic pH, such as in urine, the primary form is uric
acid.
 Both forms are relatively insoluble, although uric acid
is less soluble than its salt.
 A solution is supersaturated with monosodiumurate at
37°C at concentrations greater than 6.8 mg/dl
.(360umol/l) Cooler temperatures and acidic pH
decrease urate solubility, thus predicting the
21.2.1531 Gout-cs


Crystal formation
 In vitro studies of crystallogenesis have
yielded conflicting results in regard to the
influences of serum, synovial fluid, and many
individual plasma proteins, including albumin
and proteoglycans, on crystal formation.
 Crystal formation is probably enhanced by
IgG and type I collagen.
 In addition, urate crystals themselves
initiate further crystal formation.
21.2.1532 Gout-cs

Pathogenesis of the acute attack
 Once monosodium urate crystals form in the joint,
they may induce an acute attack of gouty arthritis.
Urate crystals clearly cause inflammation; although
unable to explain why they are present in synovial
fluids from asymptomatic uninflamed joints.
The type and quantity of protein coating the crystals
may affect their ability to induce inflammation.
 IgG is found in association with MSU crystals and
increases cell activation .
 a role for the lipoprotein apoE in inhibiting crystal-
induced inflammation 21.2.1533 Gout-cs

 MSU enter the CD14 cell via TLR2/4
NLRP3 inflammasome (multimolecular
complex,NOD like receptor family, pyrin
domain 3 ) was formed
interleukin 1 ( IL1-b), IL-6, TNF , IL-18 and
IL33 which initiate a vigorous inflammatory
response.
 Recruited polymorphonuclear leucocytes
release proteases, superoxides, leukotrienes,
and interleukins when exposed to MSU
crystals..
 MSU crystals activate complement via the
classical pathway. They also promote the
21.2.1534 Gout-cs

 Effects of these lipoproteins are likely to play
a role in the self-limited nature of acute
gout.
 The role of the kinin and complement systems in
acute gout is unclear.
 The inflammatory potential of MSU crystals
is reduced (anti-inflammary) when
lipoproteins, particularly those containing
apolipoprotein B (ApoB), are allowed to bind
to them before injection in animal models.
21.2.1538 Gout-cs

SPONTANEOUS RESOLUTION —
 Even without treatment, a typical attack of acute
gout resolves within a few weeks.
 There are many feedback mechanisms that tend
to limit inflammatory states - inactivation of
inflammatory mediators; death, deactivation, or
differentiation of inflammatory cells;
- upregulation of anti-inflammatory mediators,
such as transforming growth factor-beta (TGF-beta),
IL-1 receptor antagonist (IL-1ra), and peroxisome
proliferator-activated receptor gamma (PPAR
gamma).
 These are likely to play a role in limiting the
duration of an acute attack of gout 21.2.1539 Gout-cs

Tophus formation
 Tophi are soft tissue deposits of urate.
 known little about how and why they form.
 Palmer et al. (1989) proposed that tophi are urate-
lowering organs.
 Based on histological studies, they proposed that
acini of macrophages develop in areas of high
local urate concentrations. These organized cells
actively transport urate from the interstitial fluid to
the centre of the acinus. They grow to a certain size
and then fuse with other acini, eventually forming
tophi.
21.2.1540 Gout-cs

 Tophi are deposits of MSU crystals surrounded by
granulomatous inflammation.
 found in numerous tissues besides joint and skin,
including the larynx, kidney, and heart valve.
 the tophus is a complex but organized chronic
inflammatory response to urate crystal deposition, in
which both innate and adaptive immunity participate.
In Tophi, macrophages continue to produce low level
cytokines and proteases facilitating cartilage and bone
destruction 21.2.1541 Gout-cs

AMP
ATPLactate
Pyruvate
Fructose 1-
Phosphate
Fructose Intake and Urate Excretion
 Dominant dietary source – high-fructose corn syrup (HFCS)
 High concentration of fructose causes rapid accumulation of AMP
 Increases the body pool of purines
 Lactic acid is a by-product of fructose metabolism
 Lactate decreases urate excretion
HFCS
Fructose
Uric Acid
Purine
Catabolism
21.2.1542 Gout-cs

Diagnosis
21.2.15Gout-cs43
 Clinical course and clinical feature

Monoarthritis and urate crystal
in synovial aspirate
Gout-cs 21.2.1545

Radiographic Hallmarks of Gout
 Overhanging edges
 Punched out lesions with sclerotic borders.
 Preservation of joint space (till late)
 Degenerative changes
21.2.1548 Gout-cs

Diagnostic criteria
21.2.15Gout-cs51

The “Double Contour Sign” of Gout.
Filippucci E, Grassi W
Department of Rheumatology, University of Ancona, Italy
21.2.1552 Gout-cs

“Gout is Like Matches”
 NSAID – puts out the fire
 Colchicine prophylaxis – keeps matches damp
 Xanthine oxidase inhibitors and uricosurics –
removes the matches
21.2.1554 Gout-cs

 Urate crystals clearly cause
inflammation…..
 A solution is supersaturated with
monosodium urate at 37°C at
concentrations greater than 6.4 mg/dl.
Cooler temperatures decrease urate
solubility,………
21.2.1555 Gout-cs

Urate-lowering therapy
 The aim of urate-lowering therapy is to maintain
urate
concentration below the saturation point for
monosodium
urate.
 This therapy dissolves crystal deposits and cures
gout while it is maintained.
EULAR128 guidelines
recommend that plasma urate should be maintained
at a
concentration less than 360 μmol/L, and
the British guidelines less than 300 μmol/L.
Even lower concentrations than these can be 21.2.1556 Gout-cs

 Urate-lowering therapy is indicated for
• recurrent gout attacks,
• chronic arthropathy,
• tophi, and
• gout with uric acid stones.
 Therapy should be continued indefinitely, because
gout usually recurs a few years after treatment stops.
21.2.1560 Gout-cs

Allopurinol
 lowers uricaemia through inhibition of
xanthine oxidase activity, and is used as first-
line urate-lowering therapy.
 Side-eff ects are rare and include
cutaneous intolerance, which develops in
roughly 2% of patients,
 Severe allopurinol-induced toxic eff ects
arise in less than 2% of patients but can be
life-threatening,
21.2.1561 Gout-cs

Uricase,
Febuxostat
Off –label monthly infusions of
rasburicase
Pegylated
uricase
(a novel xanthine oxidase inhibitor)
Uricosuric drugs - probenecid,
- sulfi npyrazone, and
- benzbromarone
as second-line therapy for patients
with underexcretion of uric acid.
21.2.1562 Gout-cs

FDA-Approved
Urate-Lowering Agents
Drug Action Dose Range
First-Line (Uricostatic)
Allopurinol Xanthine Oxidase 100-800 mg daily (decrease
inhibitor dose in renal impairment)
Febuxostat Xanthine Oxidase 40-80 mg daily
inhibitor
Second-Line (Uricostatic)
Probenecid URAT1 and GLUT9 500-2000 mg daily (carefully
inhibitor adjust dose to 3000 mg
maximum)
For Severe, Treatment-Refractory Disease (Uricostatic)
Pregloticase IV Recombinant, 8 mg IV every 2 weeks
PEGylated uricase
21.2.1563 Gout-cs

Allopurinol
21.2.15Gout-cs64
 The starting dosage of allopurinol should be no
greater than 100 mg/day
 and less than that in moderate to severe chronic
kidney disease (CKD), followed by gradual
upward titration of the maintenance dose,
 which can exceed 300 mg daily even in patients
with CKD.

Approximate Prevalance of the Human Leukocyte Antigen
(HLA) Allele HLA-B*5801 in Various Geographic Regions
of the World
Middleton D, et al. Tissue Antigens. 2003;61(5):403-407
Unshaded areas represent regions where prevalence
of the gene has not been determined.
21.2.1566 Gout-cs

HLA test
21.2.15Gout-cs67
 Prior to initiation of allopurinol, rapid polymerase
chain reaction–based HLA–B*5801 screening
should be considered as a risk management
component in subpopulations where both the
HLA–B*5801 allele frequency is elevated and the
HLA–B*5801–positive subjects have a very high
hazard ratio (“high risk”) for severe allopurinol
hypersensitivity reaction
 (e.g., Koreans with stage 3 or worse CKD and all
those of Han Chinese and Thai descent).
 ●

Febuxostat and Allopurinol
N
H
NN
HN
O
NC
O
S
N
CH3
CO2H
CH3
H3C
Febuxostat Allopurinol
Structure
Tablet Formulation 40 mg or 80 mg 100 mg or 300 mg
Dosing Range 40 mg-80 mg 100 mg-800 mg
Dosing Frequency Once daily Once daily for ≤300 mg
Divided doses for >300 mg
Drug Elimination Primarily hepatic Primarily renal
Dose adjustment in None Yes
Patients with mild to
moderate renal impairment
21.2.1568 Gout-cs

Febuxostat Efficacy:
APEX, Fact, and Confirms
42%
(n=610/145)
Allopurinol
300/200 mg
(n=242)
Allopurinol
300 mg
36%
(n=253/10)
Allopurinol
300/100 mg
39%
(n=253)
Febuxostat
80 mg
72%*
(n=249)
Febuxostat
80 mg
74%*
(n=756)
Febuxostat
80 mg
67%*†
(n=757)
Febuxostat
40 mg
45%
Proportion of Patients With sUA <6 mg/dL at Final Visit
APEX
(6 months)
FACT
(1 year)
80
70
60
50
40
30
20
10
0
Patients,%
CONFIRMS
(6 months)
*P<0.001 vs allopurinol; †P<0.001 vs Febuxostat 40 mg.
21.2.1569 Gout-cs

Confirms Efficacy in Patients With Mild to
Moderate Renal Impairment
*P≤0.05 vs allopurinol.
Proportion of Patients With Mild to Moderate
Renal Impairment with sUA <6 mg/dL at Final Visit
80
70
60
50
40
30
20
10
0
Patients,%
Confirms (6 months)
(n=479)
Febuxostat
40 mg
50%*
(n=503)
Febuxostat
80 mg
72%*
(n=356/145)
Allopurinol
300/200 mg
42%
Renal impairment was defined as baseline estimated ClCr ≥30 mL/min and <90 mL/min.
21.2.1570 Gout-cs

Febuxostat
21.2.15Gout-cs72
 Febuxostat is an orally administered nonpurine
analogue inhibitor of xanthine oxidase.
 In vitro studies have shown that febuxostat is an
inhibitor of both the oxidized and reduced forms
of xanthine oxidase; in contrast, allopurinol
weakly inhibits the oxidized form.

21.2.15Gout-cs73
 Febuxostat is metabolized mainly in the liver,
whereas allopurinol
 and its metabolites are excreted primarily by the
kidney.
 In a study of subjects with impaired renal
function, the ability of febuxostat to lower serum
urate levels was not altered in patients with mild-
to-moderate renal insufficiency.

21.2.15Gout-cs74
 59 percent of subjects receiving 120 mg of
febuxostat per day for 28 days
 Doses of febuxostat of 80 and 120 mg per day
were more effective in lowering serum urate
levels than was the fixed daily dose of 300 mg of
allopurinol.

Uricase Enzymes
Uricase (uric acid oxidase) catalyzes the eventual conversion of uric acid
to allantoin, a more soluble, readily renally excreted form.
OH
Uricase Uricase
H2O + O2 H2O2 + CO2
OH
OH
OH
HO
N
H
N
N
N
HO
N
N
OH
N
H
N
OH
HO
N
N
OH
N
H
N
Uric acid Allantoin
21.2.1575 Gout-cs

Uric Acid Production
 About two-thirds of uric acid is generated
endogenously by the body, while one-third
comes from purines in the diet
Purine
Catabolism2-5
Xanthine
Oxidase
Xanthine
Oxidase
Urate
Oxidase
(Uricase)
End product for humans,
higher primates, reptiles,
birds, and some mammals
End product for the
majority of mammals
Hypoxanthine Xanthine Uric Acid Allantoin
21.2.1576 Gout-cs

Pegloticase
21.2.15Gout-cs77
 Pegloticase is appropriate for patients with severe
gout disease burden and refractoriness to, or
intolerance of, appropriately dosed oral ULT
options.

Anakinra (Off-Label)
 Effective for acute attack in studies.
 Best in pts who cannot take steroids or
colchcine.
 Expensive but 1 week of treatment may be
affordable.
 Not for preventive use.
 Other interleukin-1 inhibitors currently in
trials (rilonacept & canakinumab)
21.2.1578 Gout-cs

Indication for ULT
21.2.15Gout-cs79
 The general indications for allopurinol therapy are
 failure of uricosuric drugs or contraindications to their
use,
 tophaceous gout,
 frequent attacks of gouty arthritis (three or more per
year),
 nephrolithiasis,
 decreased creatinine clearance, and
 Overproduction of urate.
 Indications for the use of febuxostat will probably be
the same as those for allopurinol.

Frequency and Tophi number
21.2.15Gout-cs80

21.2.15Gout-cs88
 Notably, the ACR recommended probenecid and
other agents with clinically significant uricosuric
effects, such as fenofibrate and losartan, as
therapeutically useful in a comprehensive ULT
program in refractory disease (evidence B).

21.2.15Gout-cs89
 Established pharmacologic urate-lowering
therapy should be continued, without interruption,
during an acute attack of gout.
 ● Nonsteroidal antiinflammatory drugs (NSAIDs),
 corticosteroids, or oral colchicine are appropriate
first-line options for treatment of acute gout,
 And certain combinations can be employed for
severe or refractory attacks.

21.2.15Gout-cs90
 Low-dose NSAID therapy is an appropriate
choice
 for first-line gout attack prophylaxis, unless there
 is a lack of tolerance or medical contraindication.

Severity, Duration and Joint
count
21.2.15Gout-cs91

Colchicine
21.2.15Gout-cs94
 loading dose of 1.2 mg of colchicine followed by
0.6 mg 1 hour later (evidence B)
 and this regimen can then be followed by gout
attack prophylaxis dosing 0.6 mg once or twice
daily (unless dose adjustment is required) 12
hours later, until the gout attack resolves
(evidence C)

Colchicine
21.2.15Gout-cs95
 Previous studies and common practice show that
prophylaxis with colchicine to prevent recurrent
attacks of gout is needed
 for as long as 6 to 12 months.

 Combination therapy of fenofibrate or losartan
 with anti-hyperuricaemic agents, which included
benzbromarone (50 mg once daily)
 or allopurinol (200 mg twice a day), significantly
reduced serum uric acid concentrations in
accordance with increased uric acid excretion.
21.2.1597 Gout-cs

Gout-cs99
Food and Gout
 Avoid sea food
 Avoid viscera & excess red meat
 Moderate beer and spirit, sweetened bevarages
 Take one cup of milk a day
 Take 3 fish meal a week
 Not much relation to eggs, bamboo shoot, berry
21.2.15

Take Home
21.2.15Gout-cs100
 Treatment threshold for gout is 360mg%
 Target is to reduce below 200mg%
 In mild to moderate activity, use single treatment
 In severe activity, use combination
 Aim to reduce pain 25% in 3 days
 If not reach target, can consider newer option
 Fabuxostat is more effective and safer than
allopurinol
 Colchicine can be used up to 12 months for
prophylaxis of acute attacks
 Diet therapy is important in gout

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