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 person

walking in the room. The night is spent in

Sydenham, 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-limitingBack Pain

Fibromyalgia Carpal TunnelSyndrome

RheumatoidArthritis

To

tal

Po

pu

lati

on

(M

illi

on

s)

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

21.2.1510 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

21.2.1513 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.

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Gout-cs16 21.2.15

Clinical Course of Classic Gout

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Chronic Tophiceous gout with

flare

21.2.1518 Gout-cs

Tophi in multiple joints

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Pathophysiology

uric acid is an end product of purinebiosynthesis.

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

consumption in the form of ATP.

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, and

ending with postsecretory tubular reabsorption.

21.2.1525 Gout-cs

21.2.1526 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•The mechanism of underexcretion remains to be

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

association of gout with distal joints.

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

release of Hageman factor and the

21.2.1534 Gout-cs

21.2.15Gout-cs35

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21.2.1537 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.

Further work is necessary to confirm this theory.

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

FructoseUric Acid

Purine

Catabolism

21.2.1542 Gout-cs

Diagnosis

21.2.15Gout-cs43

Clinical course and clinical feature

21.2.1544 Gout-cs

Monoarthritis and urate crystal

in synovial aspirate

Gout-cs 21.2.1545

21.2.1546 Gout-cs

21.2.1547 Gout-cs

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

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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

Treatment

21.2.15Gout-cs53

“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

advised for severe gout because the rate of tophus

21.2.1556 Gout-cs

Gout

21.2.1557 Gout-cs

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21.2.1559 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.

21.2.15Gout-cs65

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 allopurinolhypersensitivity 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

Pa

tie

nts

, %

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

Pa

tie

nts

, %

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

21.2.15Gout-cs71

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

HONH

NN

N

HO

N

N

OH

NH

N

OH

HO

N

N

OH

NH

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

21.2.1581 Gout-cs

21.2.1582 Gout-cs

21.2.1583 Gout-cs

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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

21.2.15Gout-cs92

21.2.15Gout-cs93

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.

21.2.1596 Gout-cs

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

TLC

21.2.15Gout-cs98

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

21.2.15Gout-cs101