450 0,55 Hyperuricemia Males 400 Hyperuricemia Female Gout ... · 05/11/2016 1 Giovambattista...
15
05/11/2016 1 Giovambattista Desideri UO Geriatria Università degli Studi dell’Aquila L’iperuricemia cronica nell’anziano con o senza deposito di urati: cause e trattamento Tophi and Frequent Gout Flares Are Associated With Impairment to Health Related Quality of Life SF-6D Health Utilities Khanna P et al. Health and Quality of Life Outcomes 2012, 10:117 0,627 0,688 0,635 0,685 0,4 0,45 0,5 0,55 0,6 0,65 0,7 0,75 0,8 RA OA SLE Gout Epidemiology of gout and hyperuricaemia (SUA >6 mg/dL) in Italy during the years 2005–2009 Trifirò G, et al. Ann Rheum Dis (2011). 0 50 100 150 200 250 300 350 400 450 18-34 35-44 45-54 55-64 65-74 75-84 over 85 Hyperuricemia Males Hyperuricemia Female Gout Males Gout Females Prevalence per 1000 inhabitants Human urate homeostasis Uricase Oxidative stress Humans and higher primates Rest of mammals Hediger MA et al. Physiology (Bethesda). 2005 Apr;20:125-33.
Transcript of 450 0,55 Hyperuricemia Males 400 Hyperuricemia Female Gout ... · 05/11/2016 1 Giovambattista...
05112016
1
Giovambattista Desideri
UO Geriatria
Universitagrave degli Studi dellrsquoAquila
Lrsquoiperuricemia cronica
nellrsquoanziano con o senza
deposito di urati cause e
trattamento
Tophi and Frequent Gout Flares Are Associated With Impairment to Health Related Quality of Life
SF
-6D
Hea
lth
Uti
liti
es
Khanna P et al Health and Quality of Life Outcomes 2012 10117
0627
0688
0635
0685
04
045
05
055
06
065
07
075
08
RA OA SLE Gout
Epidemiology of gout and hyperuricaemia (SUA gt6 mgdL) in Italy during the years 2005ndash2009
Trifirograve G et al Ann Rheum Dis (2011)
0
50
100
150
200
250
300
350
400
450
18-34 35-44 45-54 55-64 65-74 75-84 over 85
Hyperuricemia Males
Hyperuricemia Female
Gout Males
Gout Females
Pre
va
len
ce p
er 1
00
0 i
nh
ab
ita
nts
Human urate homeostasis
Uricase
Oxidative stress
Humans and higher primates
Rest of mammals
Hediger MA et al Physiology (Bethesda) 2005 Apr20125-33
05112016
2
Prevalence of gout in men in New Zealand (Maori)
compared with men of European descent
Klemp P et al Ann Rheum Dis 19975622ndash6
Roddy E et al Rheumatology 2007461441ndash4 Lennane GA et al Ann Rheum Dis 196019 120ndash5
Associations of purine-rich food groups with gout from
the Health Professionals Follow-up Study (HPFS)
Choi HK et al N Engl J Med 2004350 1093-
1103
Associations of alcoholic beverages with gout from
the Health Professionals Follow-up Study (HPFS)
Choi HK et al Lancet 20043631277-1281
Summary of the effects of beer liquor and wine on
SUA or gout by study
MacFarlane LA et al Rheum Dis Clin North Am 2014 November 40(4) 581ndash604
05112016
3
Sugar Sweetened Beverages and Serum Uric Acid
levels in Adolescents
Nguyen S et al J Pediatr 2009 June 154(6) 807ndash813
Vitamin C Intake and Serum Uric Acid
Concentration in Men
Gao X et al J Rheumatol 2008 September 35(9) 1853ndash1858
Age- and sex-adjusted serum uric acid levels
according to categories of coffee tea and caffeine
intake NHANES-III
Choi HK et al Arthritis Rheum 2007 Jun 1557(5)816-
21
Summary of the effects of diet on risk of gout
Beer liquor wine
Meat
Seefaood
Fructosesugar-sweetened beverages
Vegetable proteins
Dairy
Coffe
Vitamin C
cherries
MacFarlane LA et al Rheum Dis Clin North Am 2014 November 40(4) 581ndash604
SUA
LEVELS
SUA
LEVELS
05112016
4
Dose-Response Association and CVD risk factors
with Hyperuricemia
Juraschek SP et al PLoS One 20138(2)e56546
Drugs that lower
serum uric acid
Drugs that raise
serum uric acid
Effects on Uric Acid Metabolism of the Drugs
Moriwaki J Bioequiv Availab 2014 61
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
05112016
5
Gout The Fashionable Disease
the disease of kingsrdquo
rich mans diseaserdquo Ann Rheum Dis 2006651301ndash1311
Likelyhood ratio for various features in the diagnosis of gout - EULAR
Gout in the elderly (a)tipical features
Gout is one of the most painful type of arthritis
However gout in the elderly tend to be more indolent while gout flares tend to be more polyarticular
Given the chronicity of gout elderly patients tend to have an increased incidence of tophi especially of the elbows and hands
Gout in the Elderly can be mistaken for changes that are usually attributed to OA or RA
The presence of tophi in the hands and the upper extremities can be mistaken for rheumatoid nodules
Tophi can supervene on Heberdenʼs and Bouchardʼs nodes
05112016
6
Musculoskeletal US can be able to visualize intraarticular crystal deposits with a characteristic hyperechoic enhancement of the outer surface of the hyaline cartilage known as the ldquodouble contour signrdquo
Asymptomatic articular damage in hyperuricemia
Pineda et al
Arthritis Research amp Therapy 2011
Asymptomatic articular damage in hyperuricemia
High Serum Uric Acid
Hyperuricemia and gout time for a new staging system
Dalbeth N et al Ann Rheum Dis 2014
A proposed revised staging system for
hyperuricaemia and gout based on the American
Heart Association heart failure staging system
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
05112016
7
Epidemiology of gout and hyperuricaemia (SUA gt6 mgdL) in Italy during the years 2005ndash2009
Trifirograve G et al Ann Rheum Dis (2011)
0
50
100
150
200
250
300
350
400
450
18-34 35-44 45-54 55-64 65-74 75-84 over 85
Hyperuricemia Males
Hyperuricemia Female
Gout Males
Gout Females
Pre
va
len
ce p
er 1
00
0 i
nh
ab
ita
nts
AS
YM
PT
OM
AT
IC H
YP
ER
UR
ICE
MIA
Hyperuricemia and CV disease
High Serum Uric Acid
Hypertension 20016
Determinants of Hyperuricemia
Xanthine
oxydase
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
05112016
8
Determinants of Hyperuricemia
Xanthine
oxydase
excretion
production
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
Lrsquoiperuricemia induce lo sviluppo di arteriolosclerosi in
modo indipendente dalla pressione arteriosa
Mazzali et al AJP Renal Physiol 2002
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
05112016
9
Chaudhary K et al Cardiorenal Med 20133208ndash220
Hyperuricemia and Cardiorenal Metabolic Syndrome
Alexander the great Darwin Harvey Newton Sydenham hellip This association cannot be mere co-incidencehellip
Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in
Normal Healthy Adults
Patil U et al International Journal of Recent Trends in Science And Technology 2013
100 medical students in the age group of 17 to 20 years
Lessons from comparative physiology could uric acid represent a physiologic alarm signal gone
awry in western society
Johnson RJ et al J Comp Physiol B 2009 179(1) 67ndash76
Uric acid having similar structure to that of caffeine and theobromine acts as a cerebral stimulant and thought to be responsible for better development of brain and more intelligence1
Uric acid can increase locomotor activity in rats2
Uric acid increases with emotional or physical stress3
1 Orowan E Nature 1955175683ndash684
2 Barrea CM et al Pharmacol Biochem Behav198933367ndash369
3 Rahe RH et al Psychosom Med 197436258ndash268
caffeine
05112016
10
Ruggiero C et al Dement Geriatr Cogn Disord 200927382ndash389
Uric Acid and Dementia in Community-Dwelling Older Persons The InChianti Study
Adjusted for UA tertile OR p
age sex BMI
education
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
234 (087ndash624)
306 (110ndash852)
-
00895
00323
+ alchohol energy intake smoking
chol plasma vit E
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
273 (096ndash775)
363 (122ndash1077)
-
00585
00199
+ renal function hypertension
CVD CBVD
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
262 (091ndash752)
332 (106ndash1042)
-
01465
00262
+ MMSE basal score
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
1102 (169ndash7200)
1889 (204ndash17467)
-
00122
00096
1016 elderly subjects (age 7438plusmn758 years)
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age 599plusmn189 mgdL
Serum UA 45plusmn14 mgdL
Vannorsdall TD et al Stroke 2008393418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Could uric acid directly promote neuronal dysfunction andor damage
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
2
Prevalence of gout in men in New Zealand (Maori)
compared with men of European descent
Klemp P et al Ann Rheum Dis 19975622ndash6
Roddy E et al Rheumatology 2007461441ndash4 Lennane GA et al Ann Rheum Dis 196019 120ndash5
Associations of purine-rich food groups with gout from
the Health Professionals Follow-up Study (HPFS)
Choi HK et al N Engl J Med 2004350 1093-
1103
Associations of alcoholic beverages with gout from
the Health Professionals Follow-up Study (HPFS)
Choi HK et al Lancet 20043631277-1281
Summary of the effects of beer liquor and wine on
SUA or gout by study
MacFarlane LA et al Rheum Dis Clin North Am 2014 November 40(4) 581ndash604
05112016
3
Sugar Sweetened Beverages and Serum Uric Acid
levels in Adolescents
Nguyen S et al J Pediatr 2009 June 154(6) 807ndash813
Vitamin C Intake and Serum Uric Acid
Concentration in Men
Gao X et al J Rheumatol 2008 September 35(9) 1853ndash1858
Age- and sex-adjusted serum uric acid levels
according to categories of coffee tea and caffeine
intake NHANES-III
Choi HK et al Arthritis Rheum 2007 Jun 1557(5)816-
21
Summary of the effects of diet on risk of gout
Beer liquor wine
Meat
Seefaood
Fructosesugar-sweetened beverages
Vegetable proteins
Dairy
Coffe
Vitamin C
cherries
MacFarlane LA et al Rheum Dis Clin North Am 2014 November 40(4) 581ndash604
SUA
LEVELS
SUA
LEVELS
05112016
4
Dose-Response Association and CVD risk factors
with Hyperuricemia
Juraschek SP et al PLoS One 20138(2)e56546
Drugs that lower
serum uric acid
Drugs that raise
serum uric acid
Effects on Uric Acid Metabolism of the Drugs
Moriwaki J Bioequiv Availab 2014 61
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
05112016
5
Gout The Fashionable Disease
the disease of kingsrdquo
rich mans diseaserdquo Ann Rheum Dis 2006651301ndash1311
Likelyhood ratio for various features in the diagnosis of gout - EULAR
Gout in the elderly (a)tipical features
Gout is one of the most painful type of arthritis
However gout in the elderly tend to be more indolent while gout flares tend to be more polyarticular
Given the chronicity of gout elderly patients tend to have an increased incidence of tophi especially of the elbows and hands
Gout in the Elderly can be mistaken for changes that are usually attributed to OA or RA
The presence of tophi in the hands and the upper extremities can be mistaken for rheumatoid nodules
Tophi can supervene on Heberdenʼs and Bouchardʼs nodes
05112016
6
Musculoskeletal US can be able to visualize intraarticular crystal deposits with a characteristic hyperechoic enhancement of the outer surface of the hyaline cartilage known as the ldquodouble contour signrdquo
Asymptomatic articular damage in hyperuricemia
Pineda et al
Arthritis Research amp Therapy 2011
Asymptomatic articular damage in hyperuricemia
High Serum Uric Acid
Hyperuricemia and gout time for a new staging system
Dalbeth N et al Ann Rheum Dis 2014
A proposed revised staging system for
hyperuricaemia and gout based on the American
Heart Association heart failure staging system
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
05112016
7
Epidemiology of gout and hyperuricaemia (SUA gt6 mgdL) in Italy during the years 2005ndash2009
Trifirograve G et al Ann Rheum Dis (2011)
0
50
100
150
200
250
300
350
400
450
18-34 35-44 45-54 55-64 65-74 75-84 over 85
Hyperuricemia Males
Hyperuricemia Female
Gout Males
Gout Females
Pre
va
len
ce p
er 1
00
0 i
nh
ab
ita
nts
AS
YM
PT
OM
AT
IC H
YP
ER
UR
ICE
MIA
Hyperuricemia and CV disease
High Serum Uric Acid
Hypertension 20016
Determinants of Hyperuricemia
Xanthine
oxydase
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
05112016
8
Determinants of Hyperuricemia
Xanthine
oxydase
excretion
production
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
Lrsquoiperuricemia induce lo sviluppo di arteriolosclerosi in
modo indipendente dalla pressione arteriosa
Mazzali et al AJP Renal Physiol 2002
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
05112016
9
Chaudhary K et al Cardiorenal Med 20133208ndash220
Hyperuricemia and Cardiorenal Metabolic Syndrome
Alexander the great Darwin Harvey Newton Sydenham hellip This association cannot be mere co-incidencehellip
Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in
Normal Healthy Adults
Patil U et al International Journal of Recent Trends in Science And Technology 2013
100 medical students in the age group of 17 to 20 years
Lessons from comparative physiology could uric acid represent a physiologic alarm signal gone
awry in western society
Johnson RJ et al J Comp Physiol B 2009 179(1) 67ndash76
Uric acid having similar structure to that of caffeine and theobromine acts as a cerebral stimulant and thought to be responsible for better development of brain and more intelligence1
Uric acid can increase locomotor activity in rats2
Uric acid increases with emotional or physical stress3
1 Orowan E Nature 1955175683ndash684
2 Barrea CM et al Pharmacol Biochem Behav198933367ndash369
3 Rahe RH et al Psychosom Med 197436258ndash268
caffeine
05112016
10
Ruggiero C et al Dement Geriatr Cogn Disord 200927382ndash389
Uric Acid and Dementia in Community-Dwelling Older Persons The InChianti Study
Adjusted for UA tertile OR p
age sex BMI
education
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
234 (087ndash624)
306 (110ndash852)
-
00895
00323
+ alchohol energy intake smoking
chol plasma vit E
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
273 (096ndash775)
363 (122ndash1077)
-
00585
00199
+ renal function hypertension
CVD CBVD
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
262 (091ndash752)
332 (106ndash1042)
-
01465
00262
+ MMSE basal score
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
1102 (169ndash7200)
1889 (204ndash17467)
-
00122
00096
1016 elderly subjects (age 7438plusmn758 years)
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age 599plusmn189 mgdL
Serum UA 45plusmn14 mgdL
Vannorsdall TD et al Stroke 2008393418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Could uric acid directly promote neuronal dysfunction andor damage
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
3
Sugar Sweetened Beverages and Serum Uric Acid
levels in Adolescents
Nguyen S et al J Pediatr 2009 June 154(6) 807ndash813
Vitamin C Intake and Serum Uric Acid
Concentration in Men
Gao X et al J Rheumatol 2008 September 35(9) 1853ndash1858
Age- and sex-adjusted serum uric acid levels
according to categories of coffee tea and caffeine
intake NHANES-III
Choi HK et al Arthritis Rheum 2007 Jun 1557(5)816-
21
Summary of the effects of diet on risk of gout
Beer liquor wine
Meat
Seefaood
Fructosesugar-sweetened beverages
Vegetable proteins
Dairy
Coffe
Vitamin C
cherries
MacFarlane LA et al Rheum Dis Clin North Am 2014 November 40(4) 581ndash604
SUA
LEVELS
SUA
LEVELS
05112016
4
Dose-Response Association and CVD risk factors
with Hyperuricemia
Juraschek SP et al PLoS One 20138(2)e56546
Drugs that lower
serum uric acid
Drugs that raise
serum uric acid
Effects on Uric Acid Metabolism of the Drugs
Moriwaki J Bioequiv Availab 2014 61
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
05112016
5
Gout The Fashionable Disease
the disease of kingsrdquo
rich mans diseaserdquo Ann Rheum Dis 2006651301ndash1311
Likelyhood ratio for various features in the diagnosis of gout - EULAR
Gout in the elderly (a)tipical features
Gout is one of the most painful type of arthritis
However gout in the elderly tend to be more indolent while gout flares tend to be more polyarticular
Given the chronicity of gout elderly patients tend to have an increased incidence of tophi especially of the elbows and hands
Gout in the Elderly can be mistaken for changes that are usually attributed to OA or RA
The presence of tophi in the hands and the upper extremities can be mistaken for rheumatoid nodules
Tophi can supervene on Heberdenʼs and Bouchardʼs nodes
05112016
6
Musculoskeletal US can be able to visualize intraarticular crystal deposits with a characteristic hyperechoic enhancement of the outer surface of the hyaline cartilage known as the ldquodouble contour signrdquo
Asymptomatic articular damage in hyperuricemia
Pineda et al
Arthritis Research amp Therapy 2011
Asymptomatic articular damage in hyperuricemia
High Serum Uric Acid
Hyperuricemia and gout time for a new staging system
Dalbeth N et al Ann Rheum Dis 2014
A proposed revised staging system for
hyperuricaemia and gout based on the American
Heart Association heart failure staging system
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
05112016
7
Epidemiology of gout and hyperuricaemia (SUA gt6 mgdL) in Italy during the years 2005ndash2009
Trifirograve G et al Ann Rheum Dis (2011)
0
50
100
150
200
250
300
350
400
450
18-34 35-44 45-54 55-64 65-74 75-84 over 85
Hyperuricemia Males
Hyperuricemia Female
Gout Males
Gout Females
Pre
va
len
ce p
er 1
00
0 i
nh
ab
ita
nts
AS
YM
PT
OM
AT
IC H
YP
ER
UR
ICE
MIA
Hyperuricemia and CV disease
High Serum Uric Acid
Hypertension 20016
Determinants of Hyperuricemia
Xanthine
oxydase
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
05112016
8
Determinants of Hyperuricemia
Xanthine
oxydase
excretion
production
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
Lrsquoiperuricemia induce lo sviluppo di arteriolosclerosi in
modo indipendente dalla pressione arteriosa
Mazzali et al AJP Renal Physiol 2002
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
05112016
9
Chaudhary K et al Cardiorenal Med 20133208ndash220
Hyperuricemia and Cardiorenal Metabolic Syndrome
Alexander the great Darwin Harvey Newton Sydenham hellip This association cannot be mere co-incidencehellip
Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in
Normal Healthy Adults
Patil U et al International Journal of Recent Trends in Science And Technology 2013
100 medical students in the age group of 17 to 20 years
Lessons from comparative physiology could uric acid represent a physiologic alarm signal gone
awry in western society
Johnson RJ et al J Comp Physiol B 2009 179(1) 67ndash76
Uric acid having similar structure to that of caffeine and theobromine acts as a cerebral stimulant and thought to be responsible for better development of brain and more intelligence1
Uric acid can increase locomotor activity in rats2
Uric acid increases with emotional or physical stress3
1 Orowan E Nature 1955175683ndash684
2 Barrea CM et al Pharmacol Biochem Behav198933367ndash369
3 Rahe RH et al Psychosom Med 197436258ndash268
caffeine
05112016
10
Ruggiero C et al Dement Geriatr Cogn Disord 200927382ndash389
Uric Acid and Dementia in Community-Dwelling Older Persons The InChianti Study
Adjusted for UA tertile OR p
age sex BMI
education
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
234 (087ndash624)
306 (110ndash852)
-
00895
00323
+ alchohol energy intake smoking
chol plasma vit E
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
273 (096ndash775)
363 (122ndash1077)
-
00585
00199
+ renal function hypertension
CVD CBVD
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
262 (091ndash752)
332 (106ndash1042)
-
01465
00262
+ MMSE basal score
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
1102 (169ndash7200)
1889 (204ndash17467)
-
00122
00096
1016 elderly subjects (age 7438plusmn758 years)
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age 599plusmn189 mgdL
Serum UA 45plusmn14 mgdL
Vannorsdall TD et al Stroke 2008393418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Could uric acid directly promote neuronal dysfunction andor damage
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
4
Dose-Response Association and CVD risk factors
with Hyperuricemia
Juraschek SP et al PLoS One 20138(2)e56546
Drugs that lower
serum uric acid
Drugs that raise
serum uric acid
Effects on Uric Acid Metabolism of the Drugs
Moriwaki J Bioequiv Availab 2014 61
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
05112016
5
Gout The Fashionable Disease
the disease of kingsrdquo
rich mans diseaserdquo Ann Rheum Dis 2006651301ndash1311
Likelyhood ratio for various features in the diagnosis of gout - EULAR
Gout in the elderly (a)tipical features
Gout is one of the most painful type of arthritis
However gout in the elderly tend to be more indolent while gout flares tend to be more polyarticular
Given the chronicity of gout elderly patients tend to have an increased incidence of tophi especially of the elbows and hands
Gout in the Elderly can be mistaken for changes that are usually attributed to OA or RA
The presence of tophi in the hands and the upper extremities can be mistaken for rheumatoid nodules
Tophi can supervene on Heberdenʼs and Bouchardʼs nodes
05112016
6
Musculoskeletal US can be able to visualize intraarticular crystal deposits with a characteristic hyperechoic enhancement of the outer surface of the hyaline cartilage known as the ldquodouble contour signrdquo
Asymptomatic articular damage in hyperuricemia
Pineda et al
Arthritis Research amp Therapy 2011
Asymptomatic articular damage in hyperuricemia
High Serum Uric Acid
Hyperuricemia and gout time for a new staging system
Dalbeth N et al Ann Rheum Dis 2014
A proposed revised staging system for
hyperuricaemia and gout based on the American
Heart Association heart failure staging system
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
05112016
7
Epidemiology of gout and hyperuricaemia (SUA gt6 mgdL) in Italy during the years 2005ndash2009
Trifirograve G et al Ann Rheum Dis (2011)
0
50
100
150
200
250
300
350
400
450
18-34 35-44 45-54 55-64 65-74 75-84 over 85
Hyperuricemia Males
Hyperuricemia Female
Gout Males
Gout Females
Pre
va
len
ce p
er 1
00
0 i
nh
ab
ita
nts
AS
YM
PT
OM
AT
IC H
YP
ER
UR
ICE
MIA
Hyperuricemia and CV disease
High Serum Uric Acid
Hypertension 20016
Determinants of Hyperuricemia
Xanthine
oxydase
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
05112016
8
Determinants of Hyperuricemia
Xanthine
oxydase
excretion
production
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
Lrsquoiperuricemia induce lo sviluppo di arteriolosclerosi in
modo indipendente dalla pressione arteriosa
Mazzali et al AJP Renal Physiol 2002
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
05112016
9
Chaudhary K et al Cardiorenal Med 20133208ndash220
Hyperuricemia and Cardiorenal Metabolic Syndrome
Alexander the great Darwin Harvey Newton Sydenham hellip This association cannot be mere co-incidencehellip
Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in
Normal Healthy Adults
Patil U et al International Journal of Recent Trends in Science And Technology 2013
100 medical students in the age group of 17 to 20 years
Lessons from comparative physiology could uric acid represent a physiologic alarm signal gone
awry in western society
Johnson RJ et al J Comp Physiol B 2009 179(1) 67ndash76
Uric acid having similar structure to that of caffeine and theobromine acts as a cerebral stimulant and thought to be responsible for better development of brain and more intelligence1
Uric acid can increase locomotor activity in rats2
Uric acid increases with emotional or physical stress3
1 Orowan E Nature 1955175683ndash684
2 Barrea CM et al Pharmacol Biochem Behav198933367ndash369
3 Rahe RH et al Psychosom Med 197436258ndash268
caffeine
05112016
10
Ruggiero C et al Dement Geriatr Cogn Disord 200927382ndash389
Uric Acid and Dementia in Community-Dwelling Older Persons The InChianti Study
Adjusted for UA tertile OR p
age sex BMI
education
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
234 (087ndash624)
306 (110ndash852)
-
00895
00323
+ alchohol energy intake smoking
chol plasma vit E
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
273 (096ndash775)
363 (122ndash1077)
-
00585
00199
+ renal function hypertension
CVD CBVD
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
262 (091ndash752)
332 (106ndash1042)
-
01465
00262
+ MMSE basal score
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
1102 (169ndash7200)
1889 (204ndash17467)
-
00122
00096
1016 elderly subjects (age 7438plusmn758 years)
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age 599plusmn189 mgdL
Serum UA 45plusmn14 mgdL
Vannorsdall TD et al Stroke 2008393418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Could uric acid directly promote neuronal dysfunction andor damage
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
5
Gout The Fashionable Disease
the disease of kingsrdquo
rich mans diseaserdquo Ann Rheum Dis 2006651301ndash1311
Likelyhood ratio for various features in the diagnosis of gout - EULAR
Gout in the elderly (a)tipical features
Gout is one of the most painful type of arthritis
However gout in the elderly tend to be more indolent while gout flares tend to be more polyarticular
Given the chronicity of gout elderly patients tend to have an increased incidence of tophi especially of the elbows and hands
Gout in the Elderly can be mistaken for changes that are usually attributed to OA or RA
The presence of tophi in the hands and the upper extremities can be mistaken for rheumatoid nodules
Tophi can supervene on Heberdenʼs and Bouchardʼs nodes
05112016
6
Musculoskeletal US can be able to visualize intraarticular crystal deposits with a characteristic hyperechoic enhancement of the outer surface of the hyaline cartilage known as the ldquodouble contour signrdquo
Asymptomatic articular damage in hyperuricemia
Pineda et al
Arthritis Research amp Therapy 2011
Asymptomatic articular damage in hyperuricemia
High Serum Uric Acid
Hyperuricemia and gout time for a new staging system
Dalbeth N et al Ann Rheum Dis 2014
A proposed revised staging system for
hyperuricaemia and gout based on the American
Heart Association heart failure staging system
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
05112016
7
Epidemiology of gout and hyperuricaemia (SUA gt6 mgdL) in Italy during the years 2005ndash2009
Trifirograve G et al Ann Rheum Dis (2011)
0
50
100
150
200
250
300
350
400
450
18-34 35-44 45-54 55-64 65-74 75-84 over 85
Hyperuricemia Males
Hyperuricemia Female
Gout Males
Gout Females
Pre
va
len
ce p
er 1
00
0 i
nh
ab
ita
nts
AS
YM
PT
OM
AT
IC H
YP
ER
UR
ICE
MIA
Hyperuricemia and CV disease
High Serum Uric Acid
Hypertension 20016
Determinants of Hyperuricemia
Xanthine
oxydase
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
05112016
8
Determinants of Hyperuricemia
Xanthine
oxydase
excretion
production
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
Lrsquoiperuricemia induce lo sviluppo di arteriolosclerosi in
modo indipendente dalla pressione arteriosa
Mazzali et al AJP Renal Physiol 2002
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
05112016
9
Chaudhary K et al Cardiorenal Med 20133208ndash220
Hyperuricemia and Cardiorenal Metabolic Syndrome
Alexander the great Darwin Harvey Newton Sydenham hellip This association cannot be mere co-incidencehellip
Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in
Normal Healthy Adults
Patil U et al International Journal of Recent Trends in Science And Technology 2013
100 medical students in the age group of 17 to 20 years
Lessons from comparative physiology could uric acid represent a physiologic alarm signal gone
awry in western society
Johnson RJ et al J Comp Physiol B 2009 179(1) 67ndash76
Uric acid having similar structure to that of caffeine and theobromine acts as a cerebral stimulant and thought to be responsible for better development of brain and more intelligence1
Uric acid can increase locomotor activity in rats2
Uric acid increases with emotional or physical stress3
1 Orowan E Nature 1955175683ndash684
2 Barrea CM et al Pharmacol Biochem Behav198933367ndash369
3 Rahe RH et al Psychosom Med 197436258ndash268
caffeine
05112016
10
Ruggiero C et al Dement Geriatr Cogn Disord 200927382ndash389
Uric Acid and Dementia in Community-Dwelling Older Persons The InChianti Study
Adjusted for UA tertile OR p
age sex BMI
education
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
234 (087ndash624)
306 (110ndash852)
-
00895
00323
+ alchohol energy intake smoking
chol plasma vit E
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
273 (096ndash775)
363 (122ndash1077)
-
00585
00199
+ renal function hypertension
CVD CBVD
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
262 (091ndash752)
332 (106ndash1042)
-
01465
00262
+ MMSE basal score
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
1102 (169ndash7200)
1889 (204ndash17467)
-
00122
00096
1016 elderly subjects (age 7438plusmn758 years)
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age 599plusmn189 mgdL
Serum UA 45plusmn14 mgdL
Vannorsdall TD et al Stroke 2008393418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Could uric acid directly promote neuronal dysfunction andor damage
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
6
Musculoskeletal US can be able to visualize intraarticular crystal deposits with a characteristic hyperechoic enhancement of the outer surface of the hyaline cartilage known as the ldquodouble contour signrdquo
Asymptomatic articular damage in hyperuricemia
Pineda et al
Arthritis Research amp Therapy 2011
Asymptomatic articular damage in hyperuricemia
High Serum Uric Acid
Hyperuricemia and gout time for a new staging system
Dalbeth N et al Ann Rheum Dis 2014
A proposed revised staging system for
hyperuricaemia and gout based on the American
Heart Association heart failure staging system
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
05112016
7
Epidemiology of gout and hyperuricaemia (SUA gt6 mgdL) in Italy during the years 2005ndash2009
Trifirograve G et al Ann Rheum Dis (2011)
0
50
100
150
200
250
300
350
400
450
18-34 35-44 45-54 55-64 65-74 75-84 over 85
Hyperuricemia Males
Hyperuricemia Female
Gout Males
Gout Females
Pre
va
len
ce p
er 1
00
0 i
nh
ab
ita
nts
AS
YM
PT
OM
AT
IC H
YP
ER
UR
ICE
MIA
Hyperuricemia and CV disease
High Serum Uric Acid
Hypertension 20016
Determinants of Hyperuricemia
Xanthine
oxydase
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
05112016
8
Determinants of Hyperuricemia
Xanthine
oxydase
excretion
production
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
Lrsquoiperuricemia induce lo sviluppo di arteriolosclerosi in
modo indipendente dalla pressione arteriosa
Mazzali et al AJP Renal Physiol 2002
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
05112016
9
Chaudhary K et al Cardiorenal Med 20133208ndash220
Hyperuricemia and Cardiorenal Metabolic Syndrome
Alexander the great Darwin Harvey Newton Sydenham hellip This association cannot be mere co-incidencehellip
Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in
Normal Healthy Adults
Patil U et al International Journal of Recent Trends in Science And Technology 2013
100 medical students in the age group of 17 to 20 years
Lessons from comparative physiology could uric acid represent a physiologic alarm signal gone
awry in western society
Johnson RJ et al J Comp Physiol B 2009 179(1) 67ndash76
Uric acid having similar structure to that of caffeine and theobromine acts as a cerebral stimulant and thought to be responsible for better development of brain and more intelligence1
Uric acid can increase locomotor activity in rats2
Uric acid increases with emotional or physical stress3
1 Orowan E Nature 1955175683ndash684
2 Barrea CM et al Pharmacol Biochem Behav198933367ndash369
3 Rahe RH et al Psychosom Med 197436258ndash268
caffeine
05112016
10
Ruggiero C et al Dement Geriatr Cogn Disord 200927382ndash389
Uric Acid and Dementia in Community-Dwelling Older Persons The InChianti Study
Adjusted for UA tertile OR p
age sex BMI
education
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
234 (087ndash624)
306 (110ndash852)
-
00895
00323
+ alchohol energy intake smoking
chol plasma vit E
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
273 (096ndash775)
363 (122ndash1077)
-
00585
00199
+ renal function hypertension
CVD CBVD
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
262 (091ndash752)
332 (106ndash1042)
-
01465
00262
+ MMSE basal score
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
1102 (169ndash7200)
1889 (204ndash17467)
-
00122
00096
1016 elderly subjects (age 7438plusmn758 years)
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age 599plusmn189 mgdL
Serum UA 45plusmn14 mgdL
Vannorsdall TD et al Stroke 2008393418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Could uric acid directly promote neuronal dysfunction andor damage
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
7
Epidemiology of gout and hyperuricaemia (SUA gt6 mgdL) in Italy during the years 2005ndash2009
Trifirograve G et al Ann Rheum Dis (2011)
0
50
100
150
200
250
300
350
400
450
18-34 35-44 45-54 55-64 65-74 75-84 over 85
Hyperuricemia Males
Hyperuricemia Female
Gout Males
Gout Females
Pre
va
len
ce p
er 1
00
0 i
nh
ab
ita
nts
AS
YM
PT
OM
AT
IC H
YP
ER
UR
ICE
MIA
Hyperuricemia and CV disease
High Serum Uric Acid
Hypertension 20016
Determinants of Hyperuricemia
Xanthine
oxydase
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
05112016
8
Determinants of Hyperuricemia
Xanthine
oxydase
excretion
production
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
Lrsquoiperuricemia induce lo sviluppo di arteriolosclerosi in
modo indipendente dalla pressione arteriosa
Mazzali et al AJP Renal Physiol 2002
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
05112016
9
Chaudhary K et al Cardiorenal Med 20133208ndash220
Hyperuricemia and Cardiorenal Metabolic Syndrome
Alexander the great Darwin Harvey Newton Sydenham hellip This association cannot be mere co-incidencehellip
Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in
Normal Healthy Adults
Patil U et al International Journal of Recent Trends in Science And Technology 2013
100 medical students in the age group of 17 to 20 years
Lessons from comparative physiology could uric acid represent a physiologic alarm signal gone
awry in western society
Johnson RJ et al J Comp Physiol B 2009 179(1) 67ndash76
Uric acid having similar structure to that of caffeine and theobromine acts as a cerebral stimulant and thought to be responsible for better development of brain and more intelligence1
Uric acid can increase locomotor activity in rats2
Uric acid increases with emotional or physical stress3
1 Orowan E Nature 1955175683ndash684
2 Barrea CM et al Pharmacol Biochem Behav198933367ndash369
3 Rahe RH et al Psychosom Med 197436258ndash268
caffeine
05112016
10
Ruggiero C et al Dement Geriatr Cogn Disord 200927382ndash389
Uric Acid and Dementia in Community-Dwelling Older Persons The InChianti Study
Adjusted for UA tertile OR p
age sex BMI
education
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
234 (087ndash624)
306 (110ndash852)
-
00895
00323
+ alchohol energy intake smoking
chol plasma vit E
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
273 (096ndash775)
363 (122ndash1077)
-
00585
00199
+ renal function hypertension
CVD CBVD
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
262 (091ndash752)
332 (106ndash1042)
-
01465
00262
+ MMSE basal score
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
1102 (169ndash7200)
1889 (204ndash17467)
-
00122
00096
1016 elderly subjects (age 7438plusmn758 years)
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age 599plusmn189 mgdL
Serum UA 45plusmn14 mgdL
Vannorsdall TD et al Stroke 2008393418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Could uric acid directly promote neuronal dysfunction andor damage
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
8
Determinants of Hyperuricemia
Xanthine
oxydase
excretion
production
Modified from Rees F et al Nat Rev Rheumatol doi101038nrrheum201432
Lrsquoiperuricemia induce lo sviluppo di arteriolosclerosi in
modo indipendente dalla pressione arteriosa
Mazzali et al AJP Renal Physiol 2002
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
Inflammasome the missing link between gout and cardio-nephro-metabolic disorders
05112016
9
Chaudhary K et al Cardiorenal Med 20133208ndash220
Hyperuricemia and Cardiorenal Metabolic Syndrome
Alexander the great Darwin Harvey Newton Sydenham hellip This association cannot be mere co-incidencehellip
Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in
Normal Healthy Adults
Patil U et al International Journal of Recent Trends in Science And Technology 2013
100 medical students in the age group of 17 to 20 years
Lessons from comparative physiology could uric acid represent a physiologic alarm signal gone
awry in western society
Johnson RJ et al J Comp Physiol B 2009 179(1) 67ndash76
Uric acid having similar structure to that of caffeine and theobromine acts as a cerebral stimulant and thought to be responsible for better development of brain and more intelligence1
Uric acid can increase locomotor activity in rats2
Uric acid increases with emotional or physical stress3
1 Orowan E Nature 1955175683ndash684
2 Barrea CM et al Pharmacol Biochem Behav198933367ndash369
3 Rahe RH et al Psychosom Med 197436258ndash268
caffeine
05112016
10
Ruggiero C et al Dement Geriatr Cogn Disord 200927382ndash389
Uric Acid and Dementia in Community-Dwelling Older Persons The InChianti Study
Adjusted for UA tertile OR p
age sex BMI
education
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
234 (087ndash624)
306 (110ndash852)
-
00895
00323
+ alchohol energy intake smoking
chol plasma vit E
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
273 (096ndash775)
363 (122ndash1077)
-
00585
00199
+ renal function hypertension
CVD CBVD
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
262 (091ndash752)
332 (106ndash1042)
-
01465
00262
+ MMSE basal score
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
1102 (169ndash7200)
1889 (204ndash17467)
-
00122
00096
1016 elderly subjects (age 7438plusmn758 years)
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age 599plusmn189 mgdL
Serum UA 45plusmn14 mgdL
Vannorsdall TD et al Stroke 2008393418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Could uric acid directly promote neuronal dysfunction andor damage
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
9
Chaudhary K et al Cardiorenal Med 20133208ndash220
Hyperuricemia and Cardiorenal Metabolic Syndrome
Alexander the great Darwin Harvey Newton Sydenham hellip This association cannot be mere co-incidencehellip
Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in
Normal Healthy Adults
Patil U et al International Journal of Recent Trends in Science And Technology 2013
100 medical students in the age group of 17 to 20 years
Lessons from comparative physiology could uric acid represent a physiologic alarm signal gone
awry in western society
Johnson RJ et al J Comp Physiol B 2009 179(1) 67ndash76
Uric acid having similar structure to that of caffeine and theobromine acts as a cerebral stimulant and thought to be responsible for better development of brain and more intelligence1
Uric acid can increase locomotor activity in rats2
Uric acid increases with emotional or physical stress3
1 Orowan E Nature 1955175683ndash684
2 Barrea CM et al Pharmacol Biochem Behav198933367ndash369
3 Rahe RH et al Psychosom Med 197436258ndash268
caffeine
05112016
10
Ruggiero C et al Dement Geriatr Cogn Disord 200927382ndash389
Uric Acid and Dementia in Community-Dwelling Older Persons The InChianti Study
Adjusted for UA tertile OR p
age sex BMI
education
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
234 (087ndash624)
306 (110ndash852)
-
00895
00323
+ alchohol energy intake smoking
chol plasma vit E
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
273 (096ndash775)
363 (122ndash1077)
-
00585
00199
+ renal function hypertension
CVD CBVD
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
262 (091ndash752)
332 (106ndash1042)
-
01465
00262
+ MMSE basal score
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
1102 (169ndash7200)
1889 (204ndash17467)
-
00122
00096
1016 elderly subjects (age 7438plusmn758 years)
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age 599plusmn189 mgdL
Serum UA 45plusmn14 mgdL
Vannorsdall TD et al Stroke 2008393418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Could uric acid directly promote neuronal dysfunction andor damage
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
10
Ruggiero C et al Dement Geriatr Cogn Disord 200927382ndash389
Uric Acid and Dementia in Community-Dwelling Older Persons The InChianti Study
Adjusted for UA tertile OR p
age sex BMI
education
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
234 (087ndash624)
306 (110ndash852)
-
00895
00323
+ alchohol energy intake smoking
chol plasma vit E
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
273 (096ndash775)
363 (122ndash1077)
-
00585
00199
+ renal function hypertension
CVD CBVD
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
262 (091ndash752)
332 (106ndash1042)
-
01465
00262
+ MMSE basal score
1) 382plusmn053 mgdL
2) 505plusmn027 mgdL
3) 672plusmn124 mgdL
1 (reference)
1102 (169ndash7200)
1889 (204ndash17467)
-
00122
00096
1016 elderly subjects (age 7438plusmn758 years)
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age 599plusmn189 mgdL
Serum UA 45plusmn14 mgdL
Vannorsdall TD et al Stroke 2008393418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Could uric acid directly promote neuronal dysfunction andor damage
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
11
Ambivalenza
biologica
dellrsquoacido urico
The therapeutical management of chronic hyperuricemia in the third millennium
What we would like to treatprevent by urate
lowering treatment
Flares tophi nephrolithiasis and hellip
subclinical articular damage
Cardio-nephro-metabolic protection ()
How we can reduce serum uric acid
Lifestyle
Drugs
Patient education and appropriate lifestyle advice (healthy diet and reduced consumption of beverages containing fructose and alcohol beer especially) are core aspects of management Strength of recommendation (95 CI) 83 (75 91)
Charles Dickens wrote about gout in both Bleak House and The Pickwick Papers
In The Pickwick Papers the character Sam Weller warns his father that drinking will lead to gout
Manara M et al Reumatismo 2013 65 (1) 4-21
Therapeutic Approaches to Chronic Hyperuricemia and Gout
Desideri G et al High Blood Press Cardiovasc Prev (2014) 21243ndash250
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
12
Berry CE et al J Physiol 2004 555(Pt 3)589ndash6061
The purine degradation pathway
Allopurinol Febuxostat
80 ndash
70 ndash
60 ndash
50 ndash
40 ndash
30 ndash
20 ndash
10 ndash
0 ndash
Febuxostat 80 mg
(n=262)
Febuxostat 120 mg (n=269)
Allopurinol 300 mg (n=268)
_ _
Patients with Normal Renal Function Patients with Impaired Renal Function
_
49 122253
170258
511
60258
010
126262 ᵃ ᵇ ᶜ
175269 ᵃ ᵇ
60268
bull Ten patients received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function
a = p lt 005 versus allopurinol in patients with impaired renal function b = p lt 0001 versus allopurinol in all patients c = p lt 0001 versus febuxostat 120 mg in all patients
Pro
po
rtio
n o
f p
atie
nts
()
Becker MA et al Arthritis Research amp Therapy 2010 12 R63
Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat APEX study Subjects (n =1072) with serum urate level
gt80 mgdL and gout and normal or impaired
RF (creat gt15 to lt20 mgdl)
Efficacy and Safety of Febuxostat for Urate Lowering in Gout Patients gt65 Years of Age
Jackson RL et al BMC Geriatrics 20121211
Per
cen
tag
e o
f S
ub
ject
s W
ith
SU
A lt
60
mg
d
L a p=0029 vs allopurinol
b plt0001 vs febuxosta 40 mg
c plt0001 vs allopurinol
d p=0004 vs allopurinol
a
bc bc
d
Elderly Subjects Often Have a Great Frequency of Comorbidities and Are Taking Multuple Drugs
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
13
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Jackson RL et al BMC Geriatrics 20121211
Pre
va
len
ce (
)
Febuxostat is an effective alternative to allopurinol which shows greater efficacy and minor adverse effects as urate lowering agent Starting doses are to be low and increased if necessary Strength of recommendation (95 CI) 82 (76 89)
Borghi C et al J Hypertens 2015331729ndash174
IMPORTANT QUESTIONS
What threshold should be adopted to define hyperuricemia
Is hyperuricemia an independent risk factor for cardiovascular disease
Can we improve cardiovascular and renal outcomes by lowering
sUA levels
When should urate-lowering therapy be started
Feig DI et al JAMA 200827300(8)924-32
Effect of Uric Acid Lowering on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension
Mean 24 hour blood pressure
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Pretreatment End of placebo phase
Pretreatment End of allopurinol phase
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sy
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Dia
sto
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
14
Comparison of randomized studies using xanthine oxidase inhibition in
heart failure
Tamariz L et al Circulation April 14 2015
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Reaction scheme for the XO-1113088mediated conversion of hypoxanthine to UA and suicide inhibitor allopurinol to the
dead1113088 end inhibitor oxypurinol
Tamta H et al Biochemistry 200671 Suppl 1S49-54
Allopurinol inhibits uric acid formation but produces ROS
Malik UZ et al Free Radic Biol Med 2011Jul 151(1)179-84
Allopurinol and Cardiovascular Outcomes in Adults With Hypertension
A total of 2032 allopurinol-exposed patients and 2032 matched nonexposed patients were
studied 10-year period
MacIsaac ML et al Hypertension 2016
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
05112016
15
Febuxostat RCT with CV outcome
Trial Drug 1deg objective Reference
BP control Febuxostat vs
Allopurinol
Clinic and ABPM NCT01701622
Coronary endothelial
dysfunction
Febuxostat vs
Placebo
Coronary flow NCT01763996
BP control Febuxostat vs
Placebo
ABPM NCT01496469
Exercise tolerance in
chronic angina
Febuxostat
vsPlacebo
Exercise test (ETT) NCT01549977
ClinicalTrialgov
Total health care resource costs according
to SUA levels
euro642 euro684 euro703 euro787
euro1515 euro1648euro1979
euro3096euro595euro625
euro704
euro724
euro0
euro1000
euro2000
euro3000
euro4000
euro5000
lt=6 gt6lt=7 gt7lt=8 gt8
Outpa entServices
Hospitaliza on
Pharmaceu cal
euro 2752 euro 2957 euro 3386 euro 4607
Mea
n a
nn
ual
to
tal c
ost
s (euro
)
Degli Esposti L et al NMCD 2016
Total hospitalization costs according
to SUA levels
euro1121 euro1167 euro1373euro1911
euro394 euro481euro606
euro1185
euro0
euro1000
euro2000
euro3000
euro4000
lt=6 gt6lt=7 gt7lt=8 gt8
Other HyperuricemiakidneydiseaseandCVD
Mea
n a
nn
ual
ho
spit
aliz
atio
ns
cost
s (euro
)
euro 1515 euro 1648 euro 1979 euro 3096
Degli Esposti L et al NMCD 2016
2014 EULAR recommendations on
the management of gout
Recommendation 11 (ULT)
All ULT should be started at a low dose and subsequently titrated upwards until the SUA target is reached SUA below 6 mgdl (360 micromolL) should be maintained lifelong
Median 9 min 8 max 9
Stack AG et al QJM 2013 106647 ndash 658
CV mortality
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