ADDRESSING

HYPERURICAEMIA & GOUT

EFFECTIVELY AT PRIMARY
CARE LEVEL
 DISCLOSURE

• NOVUGEN
 CONTENT

• INTRODUCTION
• CLINICAL FEATURES
• DIAGNOSIS
• MANAGEMENT
• COMORBIDITY
• TAKE HOME MESSAGE
Gout is a disease caused by monosodium urate (MSU) crystal
deposition.
GOUT
• With any of the following clinical presentations (current or prior):
 gout flare, chronic gouty arthritis, or subcutaneous tophus

Gout is the most common inflammatory arthritis worldwide.

Globally, gout ranges from 0.1% to 6.8% in prevalence and 0.58 to

2.89 per 1,000 person-years in incidence.

Clinical Practice Guidelines: Management of Gout (Second Edition - 2021) MOH/P/PAK/466.21(GU)-e

 Serum uric acid
Hyperuricemia is an HYPERURICEMIA
concentrations greater than
6 mg/dL for females,
abnormally high level of uric
7 mg/dL for men, and
acid in the blood.
5.5 mg/dL for youth (under
18 years old)

However, not all individuals

Prolonged hyperuricaemia is
with hyperuricaemia develop
the major risk factor for
MSU crystal deposition or
developing gout.
gout
RECOGNISING GOUT: 4 CLINICAL PHASES
1. Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician. 1999;59(4):925-934.
PHASE I: ASYMPTOMATIC
Asymptomatic; may remained RAISED SERUM
Incidental URIC
findings of raised
serum uric acid (SUA) level
for 10-30 years. ACID LEVEL via laboratory screening

Rx: Lifestyle modifications &

Increased incidences of future
identify to treat potential
development of gouty arthritis
treatable causes (Under-
with persistent raised SUA >
excretion 95%,
6.8 mg/dL (>400 µmol/L)
Overproduction 5%)
 Sun HL et al., Frontiers in Pharmacology. 2021 Jul 14;12:667753.

# Urate is a by-product of the purine degradation pathway (10-20 % from high purine diet, 80-90% from cellular
metabolism of nuclear acid).
# Normally 2/3 urate excreted from kidney, 1/3 from gut intestine.
# UA is freely filtered from kidney, but 90% reabsorbed back into system to maintain SUA 3.3-6.8mg/dL.
Hyperuricaemia from Under-excretion (95%)
URIC ACID UNDER-EXCRETION (95%)

• Decreased renal funtion

• Certain drugs (thiazides, frusemide,
cyclosporine, pyrazinamide, low dose
aspirin)
• Lead nephropathy
• Hyperparathyroidism
• Obesity
Sun HL et al., Frontiers in Pharmacology. 2021 Jul 14;12:667753.
Hyperuricaemia from Over-excretion (5%)

Sun HL et al., Frontiers in Pharmacology. 2021 Jul 14;12:667753.

Acute onset of arthritis – maximal intensity within 24 hours

Usually asymmetrical; lower limbs > upper limbs

PHASE II: ACUTE GOUTY ARTHRITIS
Usually monoarticular (one joint): If attack at MTPJ1 (podagra), other joints can also
be affected – midfoot, ankles, knees, elbows, wrists, DIPJ fingers
Severe intense, cannot touch, difficulty to stand & walk

May be associated with fever, chills, malaise

Acute episode not more than 2 weeks

Improved earlier if started medications eg painkillers, anti-inflammatory

Why and when the first gout flare occurs in susceptible (hyperuricaemic) persons
remains a mystery.

Identifiable precipitating factors / risks observed: trauma, infection, alcohol, diet,

WHAT TRIGGERS THIS ACUTE FLARE?
dehydration, stress, drugs (include XOI)

In some individuals, the SUA may remain normal during flare.

Seen in 1/3 of cases

Thus, when SUA levels are low, might misdiagnosed flares as infection/septic arthritis,
cellulitis or reactive arthritis – we should be careful not to miss.
MOH CPG
Management of gout –
2nd edition (2021)
 Internally, the MSU
Initially, these acute
Phase between initial crystals gradually
PHASE arthritis attacks resolvePERIOD
arthritis flare with III: INTERCRITICAL accumulates, will lead
& patient is
subsequent ones to next acute arthritis
asymptomatic.
attack

Lasted from weeks to Later on, patients Move into complicated

months/ years – experience chronic low phase where tophi
duration becomes grade pain & swelling continue to get bigger
shorter with due to persistent with more erosive
subsequent attacks inflammation. deformities.
Any joints can be affected
UsuallyPHASE
more than IV: RECURRENCE
one joint; OF mid-tarsals,
involving (lower limbs) ACUTE ARTHRITIS
ankles, knees →
(upper limbs) fingers, wrists, elbows, shoulders, sternoclavicular joints
Chronicity course

More frequent attacks

Longer attacks – may extend beyond 14 days

More intense

More joints involvement (progressed)

Chronic Gouty Arthritis

● Defined as persistent joint inflammation

induced by MSU crystals.
● Characterized by chronic arthritis, with
or without tophi, functional disability,
structural joint destruction, deformity
and repeated flares.

MOH CPG Management of gout – 2nd edition (2021)

 COMORBIDITIES
Gout is an independent risk factor for mortality due to coronary
heart disease
Screening for comorbidities (CHD)
associated withand
goutkidney
include: disease
• 1. Hypertension
• 2. Diabetes Mellitus
• 3. Hyperlipidaemia
• 4. Coronary Heart Disease
• 5. Renal disease including urolithiasis
 Gout can lead to CKD:
GOUT IS ASSOCIATED WITH
nephrocalcinosis,
CKD Issue: Safety of
treatment options
CKD can lead to gout nephrolithiasis,
(acute flare & urate
concomitant comorbid
lowering Tx)
(DM,HPT), gout
treatment related
(NSAIDs)
 Diagnosis

● Demonstration of MSU (negative

birefringent) crystals in synovial fluid
(SF) or tophus aspirate is the gold
standard for the diagnosis of gout.

● If confirmation of presence of MSU

crystals is not possible, the diagnosis
may be made based on typical clinical
manifestations.

MOH CPG Management of gout – 2nd edition (2021)

Erosion with overhanging edge

Sclerotic borders (cookie-cutter, punched-out)

Soft PLAIN
tissue tophi
RADIOGRAPH
Joint space narrowing
 ULTRASOUND FINDINGS OF GOUTY ARTHRITIS:

A) hyperechoic spots in synovial tissues

& synovial space making ‘snowstorm
appearance’ in first MTPJ
B) Hyperechoic band around the surface
of hyaline cartilage of metatarsal head,
named ‘double contour sign’
C) a defect in the surface of subchondral
bone margin (erosion)
D) Circumscribed, heterogeneous
aggregations with thin anechoic rim (tophi)
– ‘wet clumps of sugar’
ACR-EULAR 2015 Gout Classification Criteria

MOH CPG Management of gout – 2nd edition (2021)

MOH CPG Management of gout – 2nd edition (2021)
 NON-PHARMACOLOGICAL
TREATMENT OF GOUT

• Health education and behavioral intervention should be offered.

• The following lifestyle modifications should be encouraged:
• Weight reduction / maintain ideal weight
• Limit intake of
 purine-rich food especially of animal origin (except omega-3
polyunsaturated fatty acid-rich fish)
 All types of alcohol (beer, wine and liquor)
 High-fructose corn syrup
MOH CPG Management of gout – 2nd edition (2021)
MOH CPG Management of gout – 2nd edition (2021)
 Diet
●Foods to avoid ●Foods to eat

Alcohol and gout risk: beer OR 2.5, liquid OR 1.6, wine OR 1.0
Sugary drink / fruit increase risk of gout (OR 1.85)
TREATMENT OF GOUT FLARE

● In gout flare, the following monotherapy may be used:

1- Colchicine 0.5mg tds to 0.5mg bd or od dosing depending on renal function
2- Nonsteroidal anti-inflammatory drugs/cyclooxygenase-2 inhibitors
3- Corticosteroids
4- Combination of the above may be used in gout flare if response to
monotherapy is insufficient.
5- Ice pack
 GOUT FLARE:

Colchicine:
• Start 1mg stat dose, followed by 0.5mg one hour later. No further tablets
should be taken for 12 hours.
• After 12 hours, treatment can be resumed if necessary with a maximum
dose of 0.5mg every 8 hours until symptoms are relieved.

MOH CPG Management of gout – 2nd edition (2021)

 URATE LOWERING THERAPY (ULT)

●
Established indications to initiate ULT for gout patients are:
1.Recurrent gout flares (≥2 flares in 12 months) OR
2.Presence of ≥1 tophi OR
3.Presence of radiographic damage attributable to gout

MOH CPG Management of gout – 2nd edition (2021)

Patient with gout should be treated with urate-lowering therapy
when indicated

Allopurinol (Xanthine oxidase inhibitor) is the first-line therapy. It

should be started at low dose and increased gradually

Starting dose: 100mg 200mg (Max 900mg od)

URATE
# Renal impairment: starting dose: 50mg od or eod

LOWERING
When Allopurinol is contraindicated or not tolerated, febuxostat
or uricosuric agents (probenecid, Benzbromarone) may be
THERAPY
considered.
Uricosuric agents are contraindicated in patients with
urolithiasis and not recommended in severe renal impairment

ULT should be continued long-term in gout patients to prevent

recurrence of gout.
 The most serious AE with Allopurinol is severe cutaneous adverse reaction (SCAR)
which can be fatal.
ALLOPURINOL-SIDE EFFECT
Reported risk factors for Allopurinol Hypersensitivity Syndrome (AHS) include the
starting dose of allopurinol, presence of renal impairment and genetic allele HLA-
B*5801 (however, screening not recommended)

HLA B 5801 is the genetic marker for Allopurinol hypersensitivity (OR 580)

Frequency: up to 20% in Asia, esp Thailand and Taiwan (remarkable regional

differences of prevalent)
 FEBUXOSTAT

• FDA (2019) issued black-box warning: CV death risk in patient with pre-existing CVD
• Based on CARES (2018) study: controversial
• Other studies FAST (2020), FREED (2019) & CONFIRMS (2010) studies— no
increased CV events & mortality

• ACR 2020: For patients with gout taking febuxostat with a history of CVD or a new CV
event, we conditionally recommend switching to an alternative ULT agent if available
and consistent with other recommendations in this guideline. (Moderate evidence)

Reference: FAST, FREED, CARES, & CONFIRMS: A Run-Down on the Black-Box Blues of Febuxostat | RheumNow. 10 Nov. 2020, https://rheumnow.com/news/fast-
freed-cares-confirms-run-down-black-box-blues-febuxostat.
FEBUXOSTAT

• Starting dose: 40mg od (Max: 80-120mg )

• eGFR >30ml/min: no adjustment (80 to 120mg od)

• eGFR < 30ml/min: 40mg od

• Dialysis: no dosage adjustments provided (has not

been studied)
 Cardiovascular safety of febuxostat compared to allopurinol for
the treatment of gout: A systematic and meta-analysis 1

The present study suggests compared with allopurinol, the use of febuxostat results in a
significant decreased risks of urgent coronary revascularization and stroke 1
1. Gao L, Wang B, Pan Y, Lu Y, Cheng R. Cardiovascular safety of febuxostat compared to allopurinol for the treatment of gout: a systematic and meta‐analysis. Clinical cardiology. 2021 Jul;44(7):907-16.
 USAGE OF NSAID/ COLCHICINE IN CKD

1) NSAID, COXIBS: avoid in CKD

2) Colchicine: avoid if eGFR < 30 or renal adjustment dose if eGFR < 60
• Colchicine toxicity in renal impairment
• Bone marrow suppression and pancytopenia
• Neuromuscular toxicity & rhabdomyolysis

• Kidney impairment is a significant risk factor for the development of

colchicine-induced myotoxicity, even with short term use (eg 4 to 7 days)

(KUNCL 1987; WALLACE 1991; WILBUR 2004)

 FLARE PROPHYLAXIS
-Paradoxical increase in gout flares when starting ULA
(mobilization flare)

Prophylaxis for gout flares should The preferred choices are

be used for at least three to six stepwise dose increase of urate
months when initiating urate- lowering therapy and / or
lowering therapy. concomitant colchicine 0.5 mg od
WHAT CAUSES
MSU crystal are shed‘MOBILIZATION FLARE’
or mobilized from intra-articular deposits when
the SU falls, leading to interaction between crystals and resident
synoviocytes and initiation of the acute inflammatory response.

The greater the reduction in serum urate after starting ULT the greater
the risk of flare, thus the more gradual reduction in SU may be a/w
fewer gout flare.
TREAT-TO-TARGET
● Achieving SU target over time leads to suppression of gout flares as well
as reduction of tophi size and number.
● Treat-to-target strategy aiming for serum urate of <360 μmol/L should be
applied in the treatment of all gout patients.
● A lower SU target of <5 mg/dL (300 μmol/L) for faster dissolution of
crystals is recommended in severe gout (tophi, chronic arthropathy,
frequent flares).

MOH CPG Management of gout – 2nd edition (2021)

MONITORING
● Monitoring of patients with gout should include:

 Clinical outcomes
 Drug-related adverse events; notably allopurinol-induced
severe cutaneous adverse reaction
 Blood investigations for adverse effects of drugs
 Serum urate and comorbidity screening
ASYMPTOMATIC HYPERURICAEMIA

There is insufficient evidence from current studies to recommend ULT

(Urate-lowering therapy) in asymptomatic hyperuricemia to prevent gout,
disease progression in CKD or CV events.

MOH CPG Management of gout – 2nd edition (2021)

 Referral to a Rheumatologist
• Diagnostic indications:
 Unclear diagnosis with atypical clinical presentation ( premenopausal
woman, men with early onset at age < 30 years without predisposing risk
factors for gout.

• Therapeutic indications:
 Refractory to conventional therapy despite drug adherence
 Complicated gout with destructive joint changes
 Hypersensitivity or intolerance to allopurinol

• Special group indications: gout in pregnancy

 CASE STUDY

46/ Man
• PMH:
• Dyslipidemia (not on regular medication)
• DM with HbA1c of 6.9% (9/2023)

• Gout history:
• Gout attack for 3 years
• Joints involvement: both ankles
• Triggering factor: high purine diet
• Treatment: colchicine and arcoxia prn
 FIRST VISIT (23/3/3024)

• Blood test:
• CO: Right ankle pain and swelling x 3
days • Hba1c: 6.7%, FBS 5.4,
• UA 644
• Creat 120, eGFR 60
• MSK US:
• LDL 4.7, TG 2.9
• Subcutaneous edema
• Treatment:
• Double contour sign
• Tophi seen 1) Education and counselling
2) Gout: opted for febuxostat (40mg)
and colchicine 0.6mg od
3) DM: refused OHA
2nd visit on 20/4/2024 Review on 1/10/2024
• Blood test: • UA 335
• UA 644  397 • Treatment:
• FBS 5.5 • Maintain febuxostat 40mg od
• LDL 5.1, TG 5.3
• Colchicine prn
• Treatment:
• Keep febuxostat 40mg od and
colchicine 0.6mg od
• Add atorvastatin 20mg on
For affordable USFDA Quality by
Design medicine
Clinical Practice Guidelines: Management of Gout (Second Edition - 2021) MOH/P/PAK/466.21(GU)-e e-CPG_Management_of_Gout_(Second_Edition).pdf (moh.gov.my)
 TAKE HOME MESSAGE

• Gout and high UA are very common conditions with a rising global prevalence due to genetics
and lifestyles
• HLA-B 5801 genes is associated with allopurinol hypersensitivity especially in Asian
population.
• Key modifiable risk factors for gout and hyperuricemia include alcohol and sugar consumption,
obesity and the use of certain medications.
• Gout is primary clinically diagnosed, aided by the presence of MSU crystal and imaging tools
like x-ray and ultrasound.
• Comorbidity (DM / CKD and CV diseases frequently exist, complicating diagnosis,
management and worsening prognosis
• Treat to target : aim UA < 360, < 300 umol/L(tophi)
Thank You