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Gout: background and clinical aspects

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

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Gout: background and clinical aspects

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  1. Gout: background and clinical aspects

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

  3. 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.

  4. Prevalence of gout in different countries

  5. Increasing prevalence of gout over time Wallace KL, et al. J Rheumatol 2004;31:1582-1587.

  6. Annual gout prevalence stratified by age Wallace KL, et al. J Rheumatol 2004;31:1582-1587.

  7. Gout prevalence is increasing globally UK 1970 1990 0.3% 1.0% USA China • 2008 • Zero 1.14% • 1999 • 2.1% 4.1% New Zealand 1966 1992 10% 14% 2% 6% 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. Maori Caucasian

  8. 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.

  9. Gout: a disabiling disease • 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 concern Schumacher 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.

  10. Gout and disability Clinical 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. 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.

  11. 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.

  12. Uric acid: the protagonist in gout • 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 Uric acid (2,6,8 three oxypurine) • When urate concentrations exceed 380 μmol/l, the risk of monosodium urate crystal formation and precipitation increases. Richette P, et al. Lancet 2010;375:318-328. Johnson RJ, et al. Nephrol 2005;25:3-8.

  13. Dietary purine intake Urinary urate excretion URATE LEVEL Urinary urate reabsorption Endogenous purine synthesis Uric acid formation Choi HK, et al. Ann Intern Med 2005;143(7):499-516.

  14. Purine synthesis, salvage and degradation Ribose 5 phosphate (RP) PRPP synthetase Nucleic acids Nucleic acids PRPP AMP IMP GMP HGPRT APRT PRPP PRPP Adenosine Guanosine Inosine Hypoxanthine Adenine Guanine Xanthine Xanthine oxidase Uric acid Renal excretion Choi H,et al. Ann Int Med 2005;143(7):499-516.

  15. Glomerular filtration 100% Proximal convoluted tubule Early tubular reabsorption 2% 98% 50% Active tubular secretion Post-secretory tubular reabsorption 40% 8-12% Excretion Renal excretion of uric acid Riches PL, et al. Hum Mol Genet 2009;18:R177-R184. Gutman AB, et al. Trans Assoc Am Physicians 1961;74:353-365.

  16. Mutations in renal urate transporters associated with gout Terkeltaub R. Nat Rev Rheumatol 2010;6(1):30-8.

  17. Drugs potentially inducing hyperuricaemia by 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

  18. Mechanisms of hyperuricaemia and gout Renal impairment Diuretics Dietary purine intake Urinary urate excretion HYPERURICAEMIA Endogenous purine synthesis Urinary urate reabsorption CRYSTAL FORMATION Alcohol SLC2A9 SLC22A11 SLC22A11 SLC16A9 SCL17A3 ABCG2 Purine breakdown Glycogen storage diseases Ethanol Purine salvage HGPRT PRPPS GOUT ATTACK Bleyer AJ, et al. Adv Chron Kidney Dis 2006;13:124-130.

  19. Asymptomatic hyperuricaemia Urate levels Cation concentration Temperature Intra-articular dehydration pH MSU crystalisation Nucleating agents Collagen Chondroitin sulphate Non-aggregating proteoglycans Other molecules Dissolution Promoters and inhibitors MSU crystal growth Tissue MSU crystal deposition Inflammation Rapid changes in urate levels Microcrystal release after local trauma Changes in MSU-crystal protein coating Susceptibility to phagocytes, mast cells Hyon K, et al. Ann Intern Med. 2005;143:499-516.

  20. 8 5 7 6 Neutrophil recruitment Release of pro-inflammatory mediators Endothelium Mechanisms of acute inflammation induced by urate crystals Busso N, Arthritis Res Ther 2010;12(2):206.

  21. Proposed model of MSU-induced acute inflammation and resolution Martin WJ, et al. Immunol Cell Biol 2010;88(1):15-19.

  22. Clinical phases of gout • Asymptomatic hyperuricaemia • Acute attack • Chronic arthritis Doherty M . Rheumatology 2009;48:ii2-ii8.

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

  24. 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.

  25. From acute attacks to chronic gout Progression depends on serum urate levels, local factors and lifestyle: • The acute attack may beonly 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 By kind permission of L. Punzi, Rheumatology Unit, University of Padua Wrist Elbow Liotè F, et al. Rheum Dis Clin North Am 2006;32:295-311.

  26. Chronic gout • Polyarticular • Low grade inflammation • Bone destruction and joint deformity • Associated with tophi • Possible visceral involvement By kind permission of L. Punzi, Rheumatology Unit, University of Padua Richette P, et al. Lancet 2010;375:318-328.

  27. Tophaceous gout Chronic depositions of monosodium urate (MSU) crystals aggregate to form macroscopicnodules 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.

  28. Tophaceous gout Helix of ear Toe Finger Elbow By kind permission of L. Punzi, Rheumatology Unit, University of Padua

  29. Tophaceous gout By kind permission of L. Punzi, Rheumatology Unit, University of Padua With the addition of a red compensator MSU crystals in a tophus observed by polarising microscope

  30. DIP PIP Big toes Radiographic features of gout By kind permission of L. Punzi, Rheumatology Unit, University of Padua

  31. New imaging techniques: ultrasonography NORMAL GOUT 1st MTP joint Grassi W, et al. Semin Arthritis Rheum 2006;36:197-202.

  32. New imaging techniques: computed tomography By kind permission of L. Punzi, Rheumatology Unit, University of Padua Perez-Ruiz F. Arthritis Res Ther 2009;11(3):232.

  33. 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.

  34. 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.

  35. Remember! MSU crystals are central in gout inflammation and provide an unequivocal diagnosis of gout By kind permission of L. Punzi, Rheumatology Unit, University of Padua Dalbeth N, et al. Rheumatology 2005;44(9):1090-1096.

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