Diapositiva 1

1
Gout and comorbidities
2
Background

• Gout is an inflammatory disease caused by the
  deposition of monosodium urate (MSU) crystalsin
  joints and other tissues
• Hyperuricaemia (serum uric acid gt7.0 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 20108820-23. Lukas E,
et al. Eur J Heart Fail 20024403-410. Richette
P, et al. Lancet 2010375318-328.
3
Gout and comorbidities

• Kidney disease
• Cardiovascular disease
• Metabolic syndrome
• Hypertension
• Obesity
• Dyslipidaemia
• Type 2 diabetes

Weaver Al, et al. Cleve Clin J Med
200875(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
20079251-257. Maalouf NM, et al. Curr Opin
Nephrol Hypertens 200413181-189.
6
Uric acid nephrolithiasisrisk 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 2006367333-344. Avram Z,
Krishnan E.Rheumatology (Oxford) 200847960-964.
7
Uric acid nephrolithiasis
treatment

• Increase urinary output
• Alkalinisation of urine
• Xanthine oxidase inhibitors

Moe OW. Lancet 2006367333-344.
8
Kidney disease

• Gout-related nephropathy
• Uric acid nephrolithiasis
• Acute uric acid nephropathy
• Chronic urate nephropathy

9
Pathogenesis of uric acid nephropathy
Shimada, et al. Nephrol Dial Transplant
2009242960-2964.
10
Clinical appearance of uric acid nephropathy

• Acute renal failure
• Rarely flank pain
• Uric acid levels gt15 mg/dl (900 µmol/l)
• Urinalysis sometimes shows uric acid cristals
• Uric-acid/creatinine ratio gt1

By kind permission of L. Punzi, Rheumatology
Unit, University of Padua
Conger JD. Med Clin North Am 1999074(4)859-871.
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 2008359(17)1811-182
1.
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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 2008359(17)1811-182
1.
14
Uric acid increases the risk of kidney disease
n13,338, ARIC and Framingham, follow-up 8.5 years
Weiner DE, et al. J Am Soc Nephrol
2008191204-1211.
15
Effect of allopurinol on progression of chronic
kidney disease
Prospective, randomised open label study of
allopurinol 100 mg vs placebo, mean follow up
23.4 months
Goicoechea M, et al. Clin J Am Soc Nephrol
201051388-1389.
16
Effect of allopurinol on progression of chronic
kidney disease and urinary albumin excretion
Goicoechea M, et al. Clin J Am Soc Nephrol
201051388-1389.
17
Gout and comorbidities

• Kidney diseases
• Metabolic syndrome
• Cardiovascular disease risk
• Hyperuricaemia?
• Gout?
• Both?

By kind permission of L. Punzi, Rheumatology
Unit, University of Padua
Feig DI, et al. N Engl J Med 2008359(17)1811-182
1.
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 2008359(17)1811-182
1.
19
Gout and cardiovascular risk factors
Prevalence of cardiovascular risk factors in
rheumatic patients anda sample of the general
population
72
68
62
57
Patients ()
30
26
21
17
Adapted from Meek IL, et al. Rheumatology 2012
Jul 30. Epub ahead of print
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 200921132-137.
Perlstein TS, et al.
Hypertension 2006481031-1036. Krishnan E, et
al. Hypertension 200749298-303.
21
Uric acid mediated hypertension
Feig DI, et al. N Engl J Med 20083591811-1821.
22
Survival from total cardiovascular disease
mortality, by sUA levels
Females (n48,514)
Males (n41,879)
Chen JH, et al. Arthritis Rheum
200961(2)225-232.
23
Hazard ratios of hyperuricaemia on
cardiovascular mortality(1) and all-cause
mortality(2)
(1)
(2)
Chen JH, et al. Arthritis Rheum
200961(2)225-232.
24
Cardiovascular disease mortality with increasing
serum uric acid levels
Chen JH, et al. Arthritis Rheum
200961(2)225-232.
25
Gout is an independent risk factor for all-cause
and cardiovascular mortality
Kuo CF, et al. Rheumatology (Oxford)
201049141-146.
26
Risk of myocardial infarction among patients
with gout
2.5 2 1.5 1 0.5 0
plt0.001 (Log rank test)
1000 patient-years
Kuo CF, et al, Rheumatology  2012 Jul 10. Epub
ahead of print
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
200921132-137. Choi HK, Ford ES. Am J Med
2007120442-447.
28
Prevalence of metabolic syndrome according to the
presence of gout
Choi HK, et al. Arthritis Care Res
200757109-115.
29
Prevalence of individual components of the
metabolic syndrome according to the presence of
gout
Choi HK, et al. Arthritis Care Res
200757109-115.
30
Comorbid conditions in two European populations
of patients with gout
UK population
German population
Annemans, et al. Ann Rheum Dis 200867960-966.
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 2005165742-748.
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 implications1

1. Yoo HG, et al. Rheumatol Int 2009.
33
Cod. MCI2961404
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
2013151049-55.
34
Cod. MCI2961404
The first evaluation of urate-lowering therapy
in gout patients with and without
diabetes (post-hoc analysis)
CONFIRMS TRIAL n2,269 patients with serum uric
acid 8 mg/dl
Patients with diabetes N312
Patients without diabetes N1,1957
Febuxostat 40 mg (n668)
Febuxostat 40 mg (n89)
Febuxostat 80 mg (n113)
Febuxostat 80 mg (n643)
Allopurinol 300/200 mg (n110)
Allopurinol 300/200 mg (n646)
Febuxostat 40 mg is not registered in EU
Becker MA, et al. Diabetes Obes Metab
2013151049-55.
35
Cod. MCI2961404
Achievement of sUA target levels in gout patients
with and without diabetes
Adapted from Fig. 2a in Becker MA, et al.
Diabetes Obes Metab 2013151049-55.
36
Cod. MCI2961404
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 2013151049-55.
37
Cod. MCI2961404
Adverse events of urate-lowering therapy in
diabetic and non-diabetic patients
Graphic processing of the text in Becker MA, et
al. Diabetes Obes Metab 2013151049-55.
38

Gout management of comorbidities
Hypertension, obesity, diabetes,
dyslipidaemia must be recognized and
treated (some treatments lower serum uric acid
levels)

• Hypertension
• Stop diuretics
• Hyperlipidaemia
• Diet
• Stop smoking
• Diabetes
• Improve insulin sensitivity
• Weight reduction
• Exercise

Zangh W, et al. Ann Rheum Dis 2006651312-1324.