gout: background and clinical aspects

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Gout: background and clinical aspects. Background. Gout is an inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints and other tissues Gout is not a minor disease since it may induce disability, severe nephropathy and increases cardiovascular risk - PowerPoint PPT Presentation

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Page 1: Gout: background  and clinical aspects

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Gout: background and clinical aspects

Page 2: Gout: background  and clinical aspects

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• Gout is an inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints and other tissues

• Gout is not a minor disease since it may induce disability, severe nephropathy and increases cardiovascular risk

• Hyperuricaemia (serum uric acid >7.0 mg/dl or 420 mol/l) is a crucial prerequisite for gout

Background

Liu-Bryan R. Imm Cell Biol 2010;88:20-23. Spieker LE, et al. Eur J Heart Fail 2002;4:403-410.

Richette P, et al. Lancet 2010;375:318-328.

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Epidemiology

• Gout is the most common form of inflammatory arthritis in men(1,2)

• The incidence and prevalence is rising in post-menopausal women(1)

• 1-2% of adults are affected by gout(3-5)

• The prevalence of gout increases with age, being 7% in men over 65 years and 3% in women over 85 years(3)

1.VanItallie TB. Metabolism 2010;59(Suppl 1):S32-6. 2. Lawrence RC, et al. Arthritis Rheum 1998;41:778-799.3. Zhang E et al. Ann Rheum Dis 2006;65:1301-1311. 4. Mikuls TR, et al. Ann Rheum Dis 2005;64:267-272.

5. Annemans L et al. Ann Rheum Dis 2008;67(7):960-6.

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Author Country Prevalence/100

Gardner et al (1982) UK M 3.9-8.4

Boyer et al (1988) Alaskan Inupiat EskimoM 0.5W 0.1

Harris et al (1995) UK(>65 years) M 5

W 1

Klemp et al (1997) New ZealandM 13.9 (Maori)

5.8 (Europeans)

Cou and Lai (1998) TaiwanM 26.2

W 1

Chang et al (2001) TaiwanM 15.2 (aborigines) and 0.3 (non-aborigines)

W 2.1 (general population)

Adams et al (2003) US NHIS 1996

2.2 (45-64 years)3.2 (65-74 years)45 years: M 4.6

W 2

Wallace et al (2004) US NHANES3.1 (65-74 years)4.1 (>75 years)

Mikuls et al (2005) UK1.4

7 (M >65)

Prevalence of gout in different countries

Page 5: Gout: background  and clinical aspects

5Wallace KL, et al. J Rheumatol 2004;31:1582-1587.

Increasing prevalence of gout over time

Page 6: Gout: background  and clinical aspects

6Wallace KL, et al. J Rheumatol 2004;31:1582-1587.

Annual gout prevalence stratified by age

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New Zealand

Maori

Caucasian

1966 1992

10% 14%

2% 6%

China 1980 2008

Zero 1.14%

USA

1990 1999

2.1% 4.1%

UK

1970 1990

0.3% 1.0%

Wallace K et al. J Rheumatol 2004;31:1582-1587.Harris CM et al. J Clin Epidemiol 1995;48:1153-1158.Miao Z et al. J Rheumatol 2008;35:1859-1864.Klemp P et al. Ann Rheum Dis 1987;56:22-26.

Gout prevalence is increasing globally

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Causes of the changing epidemiology of gout

• Rising levels of serum urate

• Ageing population/multiple pathologies

• Worldwide epidemic of obesity

• Six-fold increase in the prevalence of the metabolic syndrome from the 3rd to 7th decade

Roddy E, et al. Nat Clin Pract Rheumatol 2007:443-449.

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• Recurrent attacks of gouty arthritis more often tend to be polyarticular, prolonged, and increasingly disabling

• Patients may develop bone erosions and joint deformities and may progress to chronic gouty arthropathy

• Long-term urate-lowering therapy is usually required to prevent recurrences and treat chronic gouty arthropathy

• Non-adherence to long-term use of urate-lowering therapy is an important issue in patients with gout, as is physicians’ failure to adhere to clinical practice guidelines

• Despite the seemingly increasing interest in the debilitating consequences of gout and the severity of this disease, patients still frequently experience trivialization of the impact of their condition

• Work disability seems to be a major concernSchumacher HR, et al. J Rheumatol 2009; 36(10):2342-5.Ten Klooster PM, et al. Curr Opin Rheumatol 2012;24(2):139-44.

Doherty M, et al. Ann Rheum Dis. 2012;71(11):1765-70.

Gout: a disabiling disease

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Strand V, et al. Ann Rheum Dis 2009; 68(12):1800-4.Becker MA, et al, J Rheumatol 2009; 36(5):1041-8.

Lindsay K, et al, J Clin Rheumatol 2011;17:1-6. Kleinman NL, et al, Value Health 2007; 10(4):231-7.

Edwards NL, et al, J Med Econ 2011;14(1):10-5.

Gout and disabilityClinical evidences

• In a USA population, Strand et al. demonstrated that health-related quality of life scores of patients with gout, including physical functioning, were much lower than those of the matched normal subjects and comparable to those of patients with debilitating rheumatoid arthritis or active systemic lupus erythematosus.

• Becker et al. found that patients with chronic gout with a mean age of 59 yearshad physical functioning scores analogous to people aged at least 75 yearsin the general population.

• In a recent qualitative study, patients with chronic gout indicated that gout had a direct impact on their ability to work, resulting in work absence and reduced productivity.

• A large study among USA employees with all types of gout showed that they had4.6 more days of absence per year than those without gout (14.4 vs 9.8 days, respectively). A more recent prospective study in the USA found even higher absence rates, with the mean annual workday loss for gout patients being 25.1 days.

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The history of gout• Hippocrates (469-399 BD) (aphorisms): women do

not suffer from gout while they have their menses, nor do boys before they initiate sexual activity

• Galen (129-216 AD): described tophi

• Paracelsus (1490-1541): calcareous material deposits in the joints

• Anton van Leeuwenhoek (1632-1723)

• William Wollaston (1766-1828): tophi are made of urate

• Alfred Baring Garrod (1819-1907): gouty patients have hyperuricaemia

• Folin & Denis (1913): first reliable method of measuring uric acid

• JL Hollander (1910-2000): Perceived the presence of what he thought were crystals in the synovial fluid of gouty patients

• Daniel J McCarthy (1960): Identified CPPD and MSU crystals, which are always present in synovial fluid samples obtained at the time of attacks

The inventor of the microscope was the first to

describe crystals from a gouty tophus

Nuki G et al. Arthritis Res Ther 2006;8 Suppl 1:S1. Epub 2006 Apr 12 .

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Uric acid(2,6,8 three oxypurine)

• Uric acid is the final metabolite of endogenous and dietary purine metabolism

• Purines are heterocyclic aromatic organic compounds, consisting of a pyrimidine ring fused to an imidazole ring

• It is a weak acid with a pKa of 5.75 (pH at which uric acid and urate concentrations are equal)

• At a physiological pH of 7.4 in the extracellular compartment, 98% of uric acid is in the ionised form of urate

• Because of the high concentration of sodium in the extracellular compartment, urate is largely present as monosodium urate (MSU), with a low solubility limit of about 380 μmol/l

• When urate concentrations exceed 380 μmol/l, the risk of monosodium urate crystal formation and precipitation increases.

Uric acid: the protagonist in gout

Richette P, et al. Lancet 2010;375:318-328. Johnson RJ, et al. Nephrol 2005;25:3-8.

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Uric acid formation

URATELEVEL

Dietary purine intake

Urinary urateexcretion

Endogenous purinesynthesis

Urinary uratereabsorption

Choi HK, et al. Ann Intern Med 2005;143(7):499-516.

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Purine synthesis, salvage and degradationRibose 5 phosphate (RP)

PRPP

PRPP synthetase

GMP

Guanosine

Guanine

Inosine

Nucleic acids

IMP

PRPP

HGPRT

AMP

Adenosine

Adenine

Nucleic acids

PRPP

APRT

Uric acid

XanthineXanthine

Hypoxanthine

Xanthine oxidase

Renal excretionChoi H,et al. Ann Int Med 2005;143(7):499-516.

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Renal excretion of uric acid

100% Glomerularfiltration

98%Early tubular reabsorption

2%

50%Active tubular

secretion

40% Post-secretorytubular reabsorption

8-12%

Proximal convoluted

tubule

Excretion Riches PL, et al. Hum Mol Genet 2009;18:R177-R184. Gutman AB, et al. Trans Assoc Am Physicians 1961;74:353-365.

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Mutations in renal urate transporters associated with gout

Terkeltaub R. Nat Rev Rheumatol 2010;6(1):30-8.

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Drugs potentially inducing hyperuricaemiaby a reduction of renal excretion (CAN’T LEAP)

Cyclosporine

Alcohol

Nicotinic acid

Thiazides

Lasix (furosemide) or other loop diuretics

Ethambutol

Aspirin (low dose)

Pyrazinamide

Andrew JK, et al. Am J Manag Care 2005;11:S435-S442. Underwood M. BMJ 2006;332:1315-9

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HYPERURICAEMIA

SLC2A9 SLC22A11 SLC22A11

SLC16A9 SCL17A3

ABCG2

Alcohol

Renal impairment Diuretics

Purine breakdown

Glycogen storage diseases Ethanol

Purine salvage

HGPRT PRPPS

Mechanisms of hyperuricaemia and gout

CRYSTAL FORMATION

GOUT ATTACK

Urinary urate excretionDietary purine intake

Endogenous purine synthesis Urinary urate reabsorption

Bleyer AJ, et al. Adv Chron Kidney Dis 2006;13:124-130.

Page 19: Gout: background  and clinical aspects

19Hyon K, et al. Ann Intern Med. 2005;143:499-516.

Asymptomatic hyperuricaemia

Urate levels Cation concentration Temperature Intra-articular dehydration pH

MSU crystalisation

Nucleating agents Collagen

Chondroitin sulphate Non-aggregating proteoglycans

Other molecules

MSU crystal growth

Dissolution

Tissue MSU crystal deposition

Rapid changes in urate levels Microcrystal release after local trauma

Changes in MSU-crystal protein coating Susceptibility to phagocytes,

mast cells

Inflammation

Promoters and inhibitors

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Release of pro-inflammatory

mediators

Neutrophil recruitmentEndothelium

76

85

Busso N, Arthritis Res Ther 2010;12(2):206.

Mechanisms of acute inflammation induced by urate crystals

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Proposed model of MSU-inducedacute inflammation and resolution

Martin WJ, et al. Immunol Cell Biol 2010;88(1):15-19.

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Clinical phases of gout

• Asymptomatic hyperuricaemia

• Acute attack

• Chronic arthritis

Doherty M . Rheumatology 2009;48:ii2-ii8.

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Acute gout

By kind permission of L. Punzi, Rheumatology Unit, University of Padua

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Factors triggering acute gout

• Alcohol intake

• Meat and seafood consumption

• Fasting

• Trauma

• Surgery

• Diuretics

• Initiation of urate lowering therapy

• Initiation of thyroxine replacement therapy

Choi HK, et al. N Engl J Med 2004;350:1093-1103.

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From acute attacks to chronic goutProgression depends on serum urate levels, local factors and lifestyle:

• The acute attack may be only an isolated episode

• A second attack may occur within 6 months to 2 years(periods between attacks are called inter-critical phases)

• Subsequent attacks frequently last longer than the first attack, and affect several joints

Wrist ElbowLiotè F, et al. Rheum Dis Clin North Am 2006;32:295-311.

By kind permission of L. Punzi, Rheumatology Unit, University of Padua

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Chronic gout

• Polyarticular

• Low grade inflammation

• Bone destruction and joint deformity

• Associated with tophi

• Possible visceral involvement

Richette P, et al. Lancet 2010;375:318-328.

By kind permission of L. Punzi, Rheumatology Unit, University of Padua

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Tophaceous gout

Chronic depositions of monosodium urate (MSU) crystals aggregate to form macroscopic

nodules called tophi

Tophi appear most frequently in the subcutaneous tissue, but also in intraarticular

and articular structures

Gutman AB. Arthritis Rheum 1973;16:431-445.Gerster JC, et al. Arthritis Rheum 1996;39(8):1406-1409.

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Tophaceous gout

Helix of ear ElbowToe Finger

By kind permission of L. Punzi, Rheumatology Unit, University of Padua

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Tophaceous gout

MSU crystals in a tophus observed by polarising microscope

With the addition of a red compensator

By kind permission of L. Punzi, Rheumatology Unit, University of Padua

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Radiographic features of gout

DIP

PIP Big toes

By kind permission of L. Punzi,Rheumatology Unit, University of Padua

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Grassi W, et al.Semin Arthritis Rheum 2006;36:197-202.

NORMAL

GOUT1st MTP joint

New imaging techniques: ultrasonography

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New imaging techniques:computed tomography

Perez-Ruiz F. Arthritis Res Ther 2009;11(3):232.

By kind permission of L. Punzi, Rheumatology Unit, University of Padua

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Magnetic resonance imaging

T2-weighted magnetic resonance imaging (MRI) scans.

(a) Coronal gradient echo T2-weighted MRI: two nodular images with an intermediate signal (tophi) under the external collateral ligament and inside the posterior cruciate ligament of the knee. An external meniscus tear may be seen close to urate deposition.

(b) Axial T2-weighted MRI: low signal intensity of both tophi, and marked hypointensity of synovium in a Baker’s cyst.

(c) Axial post-contrast (gadolinium) T1-weighted MRI: thickening and nodular enhancement of the synovium in the suprapatellar recess.

Perez-Ruiz F. Arthritis Res Ther 2009;11(3):232.

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MSU crystals deposit in unsuspected structures

9/68 gouty patients had images indicative of MSU deposits in the spine

Konatalapalli RM. J Rheumatol 2009;36(3):609-613.

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MSU crystals are central in gout inflammation and provide an unequivocal diagnosis of gout

Remember!

Dalbeth N, et al. Rheumatology 2005;44(9):1090-1096.

By kind permissionof L. Punzi,

Rheumatology Unit,University of Padua