Management of Hyperuricemia

in gout patients

KONKER PAPDI 2021

 Uric acid – hyperuricemia - gout
• Uric acid is a waste product
created during the normal
breakdown of purines, naturally
occurring substance from
certain foods. Normally 70% of
uric acid cleaned out from the
body along with the urine. Uric
acid is insoluble in plasma and
at high concentration can be
deposited in the joint and tissue
• Hyperuricemia is defined as an
elevated plasma uric acid
concentration in the blood
greater than either 6.8 or 7.0
mg/dL (ACR 2012)
ACR 2012 – American College of Rheumatology 2012
 SPECTRUM OF THE DISEASE
European Journal of Internal Medicine 80 (2020) 1–11

Hyperuricemia is a predictive factor for the development of hypertension, metabolic syndrome, CVD and kidney disease
Definition:

Gout is a clinical disease associated with

hyperuricemia and caused by the deposition of
monosodium urate (MSU) crystals in and
around the tissues, resulting in one or more
the following manifestations:
I- Acute gouty arthritis
II - Tophaceous gout
III- Gouty nephropathy
IV- Uric acid stones
Clinical course
 25 in 100 will have hyperuricemia
1in100 will have gouty arthritis
50 of 100 gout patients have complications

Salido EO. et al. PJIM 2008; 46: 273-6. Manahan L. et al Rheum Int 1985. Dans LF.
et
al J Rheum 1997. Dans LF. et al. PJIM 2006. Roberto LC, et al. Poster. PRA 2007
Prevalence
of gout
Gout Across regions
Joint affliction
in gout
Metabolism of uric acid and risk
factors for gout:
Pathophysiology:
Management
Management
 “Gout is Like Matches”
NSAID – puts out the fire
Colchicine prophylaxis – keeps matches damp
Xanthine oxidase inhibitors and uricosurics –
removes the matches

19 Gout-cs 21.2.15
The fundamental aims of gout treatment
:

Improve outcomes by
short-term suppression
long-term elimination of gout flares
induce durable resolution of tophi
identify and effectively manage
comorbidities
 Pharmacologic treatment for acute and prevention of gout flare
US Pharmacist. 2017;42(3):33-38.

ACUTE GOUT CHRONIC GOUT

XANTIN OXIDASE
NSAID COLCHICINE STEROIDS URICOSURIC INHIBITOR
URICASE* THERAPY

ALLUPURINOL

FEBUXOSTAT

* Uricase : enzyme that converst uric acid into allantoin soluble form of uric acid
Management of
hyperuricemia

Edward Roddy, and Michael Doherty Clin Med 2013;13:400-403

ACR 2020 Gout flare
ACR Guideline 2020 ULT and prophylaxis
Recommendation for the patients
GUIDELINE US ACR 2020 EUROPE UK(BSR) 2017 EUROPE EULAR 2016 TAIWAN TUA 2016
Therapeutic ≤ 5 mg/dL (severe gout) ≤ 6 mg/dL
≤ 6 mg/dL ≤ 5 mg/dL
Goal ≤ 6 mg/dL
Strong for gout with :
• Frequent attack (≥2 / yr) ULT is indicated :
Gout, especially with :
• Tophus • Reccurent flares Diagnosis of gout with :
• Chronic arthritis
• radiographic damage (any • Tophi • Frequent attacks
• Recurring attacks
modality) attributable to • Urate arthropaty and/or • Tophus
Indication for • Tophus
gout renal stone • Past urolithiasis
Pharmacological • Joint damage
• Gout with comorbidities
ULT • Renal impairement
Conditionally for : Especially : and sUA ≥ 9 mg/dL
• Past urolithiasis
• Infrequent flares • Young age ≤ 40 yrs • Gout without comorbidities
• Diuretics use
(previously frequent) • Baseline sUA ≥ 8mg/dL and sUA ≥ 10 mg/dL
• Young age
• First flare CKD ≥ 3, SU >9 and/or comorbidities
mg/dl, urolithiasis
Recommended if :
Treatment with
1. sUA ≥ 9mg/dL with
ULT for
Not recommended Not recommended Not recommended comorbidities
asymptomatic
hyperuricemia
2. sUA ≥ 10 mg/dL without
comorbidities
1st line : allopurinol • Allopurinol
1st line: allopurinol (XOI)
2nd line : febuxostat 1st line: allopurinol • Benzbromarone
If target not achieve switch to
ULT Drugs 3rd line : sulfinpyrazone/ 2nd line : Febuxostat / • Febuxostat
febuxostat over combination
probenecid/ uricosuric • Sulfinpyrazone
with uricosuric
benzbromarone

Start low dose (≤100 mg allopurinol and lower in patients with CKD stage ≥ 3 or ≤40 mg of febuxostat) then titration
INDONESIA GUIDELINE
Pasien Gout
Cek Kadar Asam Urat Serum

Bila > 6 mg/ dL

Edukasi tentang penyakit gout, meliputi: modifikasi gaya hidup,

skrining penyakit komorbid, dan evaluasi obat yang dapat
menyebabkan hiperurisemia.

Mulai terapi pencegahan dengan terapi penurun kadar serum urat:

mulai dengan alopurinol 100 mg dititrasi perlahan hingga dosis
maksimum, perhatikan dosis pada pasien gangguan fungsi
ginjal

Febuxostat
Target Tercapai? Tidak atau
urikosurik
Ya

Target Tercapai?
Lanjutkan Tidak
Ya
Pertimbangkan kombinasi
penghambat xantin oksidase Lanjutkan
dengan urikosurik
 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
S econd-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

34 Gout-cs 21.2.15
 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,

35 Gout-cs 21.2.15
 Allopurinol
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.

36 Gout-cs 21.2.15
 Approximate Prevalance of the Human Leukocyte Antigen
(HLA) Allele HLA-B*5801 in Various Geographic Regions
of the World

Unshaded areas represent regions where prevalence

of the gene has not been determined.
66 Gout-cs 21.2.15
Middleton D, et al. Tissue Antigens.2003;61(5):403-407
 Febuxostat and Allopurinol
Febuxostat Allopurinol
CH3 H
O
Structure H3C N N
N
N
NC HN
CH3
S
CO2H O

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

38 Gout-cs 21.2.15
 Uricase Enzymes
Uricase Uricase

H2O + O2 H2O2 + CO2

OH
N
N
OH
HO N N
H
OH OH

N N N N
OH OH
HO N N HO N N
H H

Uric acid Allantoin

Uricase (uric acid oxidase) catalyzes the eventual conversion of uric acid
75 toGaolulat-ncstoin,a more soluble, readily renally excreted form. 21.2.15
 Uric Acid Production
About two-thirds of uric acid is generated
endogenously by the body, while one-third
comes from purines in the diet

Urate
Xanthine Xanthine Oxidase
Oxidase Oxidase (Uricase)

Purine
Catabolism2-5

Hypoxanthine Xanthine Uric Acid Allantoin

End product for humans, End product for the

higher primates, reptiles, majority of mammals
birds, and some mammals
Gout-cs
40 21.2.15
 Pegloticase
Pegloticase is appropriate for patients with severe gout disease
burden and refractoriness to, or intolerance of, appropriately dosed
oral ULT options.

Gout-cs
41 21.2.15
ACR 2020 nonpharmacologic approach
Summary
• The management of hyperuricemia in gout patients should include:
• Urate lowering agent that most appropriate with patient condition
• Inform patient that ULT / US should be taken indefinitely
• Treat to target approach
• Switching between ULT when necessary

• Flare prevention
• Keep an eye on side effects of ULT
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