1 Gout and comorbidities

2 Background Gout is an inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints and other tissues Hyperuricaemia (serum uric acid >7.0 mg/dl or 420 μmol/l) is a crucial prerequisite for gout Gout is not a minor disease since it may induce disability, severe nephropathy and increases cardiovascular risk Ru L-B. Imm Cell Biol 2010;88: Lukas E, et al. Eur J Heart Fail 2002;4: Richette P, et al. Lancet 2010;375:

3 Gout and comorbidities Kidney disease Cardiovascular disease Metabolic syndrome –Hypertension –Obesity –Dyslipidaemia –Type 2 diabetes Weaver Al, et al. Cleve Clin J Med 2008;75(suppl5):S9-S12.

4 Kidney disease Gout-related nephropathy Uric acid nephrolithiasis Acute uric acid nephropathy Chronic urate nephropathy

5 Uric acid nephrolithiasis It is the most frequent type of gout-related nephropathy, arising in about 10-40% of patients In Europe and the US uric acid stones account for 5-10% of stones 80% of kidney stones in patients with gout are entirely composed of uric acid Men with gout have a two-fold higher risk of kidney stones than do patients without gout Calcium oxalate stones are 10- to 30-fold more prevalent in patients with gout than in persons without gout Liebman SE, et al. Curr Rheumatol Rep 2007;9: Maalouf NM, et al. Curr Opin Nephrol Hypertens 2004;13:

6 Uric acid nephrolithiasis: risk factors and pathogenesis Relatively high serum uric acid levels Low urinary pH Low fractional excretion of urate Treatment with uricosuric agents Uric acid kidney stones precede arthritis in 40% of patients Moe OW. Lancet 2006;367: Avram Z, Krishnan E.Rheumatology (Oxford) 2008;47:

7 Increase urinary output Alkalinisation of urine Xanthine oxidase inhibitors Uric acid nephrolithiasis: treatment Moe OW. Lancet 2006;367:

8 Kidney disease Gout-related nephropathy Uric acid nephrolithiasis Acute uric acid nephropathy Chronic urate nephropathy

9 Shimada, et al. Nephrol Dial Transplant 2009;24: Pathogenesis of uric acid nephropathy

10 Clinical appearance of uric acid nephropathy Acute renal failure Rarely flank pain Uric acid levels >15 mg/dl (900 μmol/l) Urinalysis sometimes shows uric acid cristals Uric-acid/creatinine ratio >1 Conger JD. Med Clin North Am 19990;74(4): By kind permission of L. Punzi, Rheumatology Unit, University of Padua

11 Kidney disease Gout-related nephropathy Uric acid nephrolithiasis Acute uric acid nephropathy Chronic urate nephropathy (gouty nephropathy)

12 Chronic urate nephropathy (gouty nephropathy) (I) Rare entity Kidney lesions in patients with gout are characterised by advanced arteriolosclerosis, glomerulosclerosis, and interstitial fibrosis, often with the presence of urate crystals in the outer medulla However, the responsibility of crystals is doubtful, since crystal deposition is focal and the lesions are diffuse and crystals could also be found in normal kidneys in the absence of inflammation Feig DI, et al. N Engl J Med 2008;359(17):

13 Chronic urate nephropathy (gouty nephropathy) (II) The most characteristic findings, such as advanced arteriolosclerosis and glomerulosclerosis, are indistinguishable from those observed with long-standing hypertension or age-related glomerulosclerosis and may simply reflect the fact that most patients with gout have hypertension and are older Both experimental and clinical studies suggest that an elevated level of uric acid itself can lead to kidney disease without the deposition of uric acid crystals. Experimental studies in rats have shown that raising uric acid levels can cause de novo kidney disease as well as accelerate existing kidney disease The principal lesions from increased uric acid in the rat are glomerulosclerosis, interstitial fibrosis, and arteriolar disease, conditions similar to those observed in “gouty” nephropathy, except for the absence of intrarenal urate crystals Feig DI, et al. N Engl J Med 2008;359(17):

14 Uric acid increases the risk of kidney disease n=13,338, ARIC and Framingham, follow-up 8.5 years Weiner DE, et al. J Am Soc Nephrol 2008;19:

15 Effect of allopurinol on progression of chronic kidney disease Goicoechea M, et al. Clin J Am Soc Nephrol 2010;5: Prospective, randomised open label study of allopurinol 100 mg vs placebo, mean follow up 23.4 months

16 Effect of allopurinol on progression of chronic kidney disease and urinary albumin excretion Goicoechea M, et al. Clin J Am Soc Nephrol 2010;5:

17 Gout and comorbidities Kidney diseases Metabolic syndrome Cardiovascular disease risk –Hyperuricaemia? –Gout? –Both? Feig DI, et al. N Engl J Med 2008;359(17): By kind permission of L. Punzi, Rheumatology Unit, University of Padua

18 Hyperuricaemia is associated with groups at increased cardiovascular risk Post-menopausal women Blacks Hypertension Metabolic syndrome Renal disease Feig DI, et al. N Engl J Med 2008;359(17):

19 Gout and cardiovascular risk factors Prevalence of cardiovascular risk factors in rheumatic patients and a sample of the general population Adapted from: Meek IL, et al. Rheumatology 2012 Jul 30. [Epub ahead of print] Patients (%) 68% 57% 72% 30% 17% 26% 21% 62%

20 Hyperuricaemia and hypertension The prevalence of hyperuricaemia in hypertensive patients is between 20 and 40% The prevalence of hypertension among gouty patients is between 25 and 50% Recent large epidemiological studies have found that serum urate levels predict the later development of hypertension The Normative Aging Study showed that the serum urate level independently predicted the development of hypertension The MRFIT study showed that normotensive men with hyperuricaemia at baseline had an 80% excess risk of developing hypertension compared to those who did not have hyperuricaemia Edwards NL. Curr Opin Rheumatol 2009;21: Perlstein TS, et al. Hypertension 2006;48: Krishnan E, et al. Hypertension 2007;49:

21 Feig DI, et al. N Engl J Med 2008;359: Uric acid mediated hypertension

22 Survival from total cardiovascular disease mortality, by sUA levels Males (n=41,879) Females (n=48,514) Chen JH, et al. Arthritis Rheum 2009;61(2):

23 Chen JH, et al. Arthritis Rheum 2009;61(2): Hazard ratios of hyperuricaemia on cardiovascular mortality(1) and all-cause mortality(2) (1) (2)

24 Chen JH, et al. Arthritis Rheum 2009;61(2): Cardiovascular disease mortality with increasing serum uric acid levels

25 Gout is an independent risk factor for all-cause and cardiovascular mortality Kuo CF, et al. Rheumatology (Oxford) 2010;49:

26 Risk of myocardial infarction among patients with gout Kuo CF, et al, Rheumatology 2012 Jul 10. [Epub ahead of print] p<0.001 (Log rank test) 1000 patient-years

27 Gout and metabolic syndrome Up to 76% of patients with gout have the metabolic syndrome Hyperuricaemia associated with the metabolic syndrome has been attributed to insulin resistance and hyperinsulinaemia However, recent studies have shown that hyperuricaemia precedes the development of obesity, diabetes and even hyperinsulinaemia In a study of non-obese patients who developed metabolic syndrome, those with hyperuricaemia had a 10-fold increased risk compared to those with normal uricaemia There is also some evidence suggesting that lowering serum urate levels can reverse features of the metabolic syndrome Edwards NL. Curr Opin Rheumatol 2009;21: Choi HK, Ford ES. Am J Med 2007;120:

28 Choi HK, et al. Arthritis Care Res 2007;57: Prevalence of metabolic syndrome according to the presence of gout

29 Choi HK, et al. Arthritis Care Res 2007;57: Prevalence of individual components of the metabolic syndrome according to the presence of gout

30 Annemans, et al. Ann Rheum Dis 2008;67: UK population German population Comorbid conditions in two European populations of patients with gout

31 Gout and obesity Increased body mass index is directly correlated with hyperuricaemia, and leptin may be a contributory factor Greater adiposity and weight gain are strong risk factors for gout, whereas weight loss is protective Increased adiposity and the insulin resistance syndrome are both associated with hyperuricaemia Body mass index, waist-to-hip ratio, and weight gain have all been associated with the risk of incident gout in men Choi HK, et al. Arch Int Med 2005;165:

32 Gout and insulin resistance Metabolic syndrome increases the risk for type 2 diabetes up to five times Insulin resistance contributes to the hyperuricaemia, but it is unclear whether insulin resistance inhibits the urinary excretion of uric acid or increases the production of uric acid Only some patients with hyperuricaemia develop attacks of gout and a direct association between gout and insulin resistance has not been proven Insulin senitivity in patients with gout is lower than that of healthy people, suggesting that insulin resistance and metabolic syndrome may be considered as an important pathogenic mechanism in gout and could have therapeutic implications 1 1. Yoo HG, et al. Rheumatol Int 2009.

33 Gout and diabetes There is a known association of gout with diabetes The mechanisms involved are still unclear Can diabetes and other co-morbidities influence the efficacy and/or safety of urate-lowering therapy in patients with gout? Becker MA, et al. Diabetes Obes Metab 2013;15: Cod. MCI

34 Becker MA, et al. Diabetes Obes Metab 2013;15: CONFIRMS TRIAL n=2,269 patients with serum uric acid ≥ 8 mg/dl Patients with diabetes N=312 Febuxostat 40 mg* (n=89) Febuxostat 80 mg (n=113) Allopurinol 300/200 mg (n=110) Febuxostat 40 mg (n=668) Febuxostat 80 mg (n=643) Allopurinol 300/200 mg (n=646) Patients without diabetes N=1,1957 The first evaluation of urate-lowering therapy in gout patients with and without diabetes (post-hoc analysis) * Febuxostat 40 mg is not registered in EU Cod. MCI

35 Adapted from Fig. 2a in: Becker MA, et al. Diabetes Obes Metab 2013;15: Achievement of sUA target levels in gout patients with and without diabetes Cod. MCI

36 Efficacy of urate-lowering therapy in diabetics and non-diabetics with moderate renal impairment Adapted from Fig. 2c in: Becker MA, et al. Diabetes Obes Metab 2013;15: Cod. MCI

37 Graphic processing of the text in: Becker MA, et al. Diabetes Obes Metab 2013;15: Adverse events of urate-lowering therapy in diabetic and non-diabetic patients Cod. MCI

38 Gout: management of comorbidities Hypertension –Stop diuretics Hyperlipidaemia –Diet Stop smoking Diabetes – Improve insulin sensitivity – Weight reduction – Exercise Hypertension, obesity, diabetes, dyslipidaemia must be recognized and treated (some treatments lower serum uric acid levels) Zangh W, et al. Ann Rheum Dis 2006;65: