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Iperuricemia nell’anziano: dal danno articolare al deterioramento cognitivo
Giovambattista DesideriUnità Operativa e SS di Geriatria
Università degli Studi Dell’Aquila
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
Pre
val
ence
per
100
0 in
hab
itan
ts
Gout: The Fashionable Disease
"the disease of kings”
"rich man's disease”
Ann Rheum Dis 2006;65:1301–1311
Likelyhood ratio for various features in the diagnosis of gout - EULAR
Gout in the elderly: (a)tipical features
Tophi can supervene on Heberdenʼs and
Bouchardʼs nodes.
Gout is one of the most painful type of arthritis, but 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
The presence of tophi in the hands and the upper extremities can be mistaken for rheumatoid nodules.
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 “double contour sign.”
Asymptomatic articular damage in hyperuricemia
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.
Presence of
strong CYP3A4
P-glycoprotein
inhibitors
Treat as early as possible
Severe renal
failure
Avoid colchicine
Contra-indications to
cochicine, NSAIDS and
corticosteroids (oral and
injectable)
Education about the disease
Individualised lifestyle advice
Screening for comorbidifties
and current medications
Therapeutic options
Depending on the severity, the
number of affected joints and
duration of attack
Colchicine
(1 mg followed 1
hour later by 0.5 mg)
NSAID
(classic or coxibs +
PPI if appropriate)
Prednisolone
(30-35 mg/d for 5
days)
IA
Injection of
corticosterod
Combination therapy
(for istance colchicine
+NSAID or corticosteroids)
Resolution of flaresEducate to self medicate
Consider initiation of ULT
(together with flare profilaxys)
Avoid cochicine
and
NSAIDS
Consider IL-1 blockers
Management of
acute flare
Ann Rheum Dis 2016;0:1–14.
<5 mg/dL
Management of
Hyperuricemia in
patients with goutAnn Rheum Dis 2016;0:1–14.
<6 mg/dL
Education about the disease
Individualised lifestyle advice
Screening for comorbidifties
If appropriate
- stop diuretic
- use losartan
- use fenofibrate
or statin
Initiate ULT
Start Allopurinolo 100 mg/d
Adapt the dosage to the renal function
Slow titration up to the maximum
allowed dosage
Start pegloticase
In severe chronic
tophaceous gout
Determine SUA target
or
Consider a combined therapy(XOI and uricosuric)
Start
febuxostat (or a uricosuric)
No Achieved target Yes
No Achieved target Yes continue
start
febuxostat
or switch to a
uricosuric
Start prophylactic treatment
Achieved target
No
Yes
Continue
History of allergy to allopurinol
2016 Eular Recommendation for the Management of Hyperuricemia in Patients with Gout
Richette P, et al. Ann Rheum Dis 2016;0:1–14. doi:10.1136/annrheumdis-2016-209707
The greatest concern with the use of allopurinol in patients with renal failure is the
development of serious cutaneous adverse reactions (SCARs), which includes drug
rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS) and
toxic epidermal necrosis. Allopurinol was found to be the most common drug associated
with SJS or toxic epidermal necrolysis in Europe
Allopurinol-induced SCARs are rare, the incidence rate being about 0.7/1000 patient-
years in allopurinol initiators in the USA,but the mortality rate is high (25%–30%
Renal failure has been associated with an increased risk of SCARs and poor
outcome. Decreased renal function results in decreased clearance and higher serum
levels of oxypurinol, which could induce a cytotoxic T-cell respons and trigger
hypersensitivity reactions in SCARs.
Febuxostat has been found more effective in patients with CKD than allopurinol
given at doses adjusted to creatinine clearance and therefore can be used in these
patients.
Data do not support any cross-reactivity between the two drugs.
Clinical Efficacy and Safety of Successful Longterm Urate Lowering with Febuxostat or Allopurinol in Subjects with Gout: EXCEL study
Becker MA, et al. J Rheumatol 2009; 36:1273-1282.
Febuxostat 80 mg
Febuxostat 120 mg
0-<
2
2-<
4
4-<
6
6-<
8
8-<
10
pro
po
rtio
no
f s
ub
jec
tsre
qu
irin
gg
ou
t
flare
treatm
en
t
Time (months)
0
10
20
30
40
50
Allopurinol
10
-<1
2
12
-<1
4
14
-<1
6
16
-<1
8
18
-<2
0
20
-<2
2
22
-<2
4
24
-<2
6
26
-<2
8
28
-<3
0
30
-<3
2
32
-<3
4
34
-<3
6
36
-<3
8
38
-40
Maintenance of SUA < 6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of
subjects requiring gout flare treatment
≈40%
treated≈20%
treated
≈60%
treated
Total health care resource costs during 6 months from index date according to ULT
Degli Esposti L et al, submitted
euros
D20%
1.00
1.99 (1.77-2.24)
1.24 (1.08-1.41)
1.21 (1.09-1.35)
IRR (95% CIs)[Ref. ≤ 6 mg/dl]
> 6 ≤ 7 mg/dl
> 7 ≤ 8 mg/dl
> 8 mg/dl
1.75 (1.65-1.85)
1.24 (1.18-1.32)
1.10 (1.05-1.15)
IRR (95% CIs)[Ref. ≤ 6 mg/dl]
> 6 ≤ 7 mg/dl
> 7 ≤ 8 mg/dl
> 8 mg/dl
1.00
[Ref. ≤ 6 mg/dl]
> 6 ≤ 7 mg/dl
> 7 ≤ 8 mg/dl
> 8 mg/dl
1.00
2.12 (1.98-2.27)
1.20 (1.11-1.29)
0.98 (0.92-1.04)
HR (95% CIs)
SUA levels and Hx for kidney disease
SUA levels and Hx for CVD
SUA levels and total mortality
Degli Esposti L et al, NMCD 2016
Chaudhary K et al Cardiorenal Med 2013;3:208–220
Hyperuricemia and Cardiorenal Metabolic Syndrome
Low uric acid levels in patients with Parkinson’s disease: evidence from meta-analysis
Shen L, Ji H-F. BMJ Open 2013
Parkinson Controls
Alexander the great, Darwin, Harvey, Newton, Sydenham, ….
This association cannot be mere co-incidence….
Study of Serum Uric Acid and its Correlation withIntelligence 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): 67–76.
Uric acid having similar structure to that of caffeine and theobromine acts as a cerebralstimulant and thought to be responsible for betterdevelopment of brain and more intelligence.)1.
Uric acid can increase locomotor activityin rats2
Uric acid increases with emotional or physical stress3
1 Orowan E. Nature 1955;175:683–684.
2 Barrea CM et al. Pharmacol Biochem Behav1989;33:367–369.
3 Rahe RH et al. Psychosom Med 1974;36:258–268.
caffeine
SUA and cognitive function and dementia
Euser SM et al. Brain 2009: 132; 377–382
The mean age of the total sample of 4618 participants
was 69.4 years, 61% were female and the mean
serum level of uric acid was 322.3 mmol/l.
Shah A, et al. Curr Rheumatol Rep (2010) 12:118–124
Gout, Hyperuricemia, and the Risk of Cardiovascular Disease: Cause and Effect?
Odi et amo….
quare id faciam fortasse requiris…
SUA, oxidative stress and cardiovascular disease:
a comprehensive hypothesis
XO-overactivity (genetic, induced)
XO-”overfeeding” (food, fructose, purines)
HTN, CKD
CV disease
Serum Uric Acid
Cellular entry of
Uric Acid
Intracellular Uric
Acid
i.c. oxidative stress ( eNOS)
mitochondrial dysfunction
RAAS activation
Oxidative stress
High TG,MS,TOD
Gout
Borghi C, Desideri GB, Hypertension 2016
Hyperuricemia and Stroke Incidence: A Systematic
Review and Meta-Analysis
Kym SY et al. Arthritis & Rheumatism Vol. 61, No. 7, July 15, 2009, pp 885–892
Serum Uric Acid Levels and Cerebral Small Vessels Disease: relationship with lacunar infarcts
F. Crosta i (submitted)
ALL LIs
Silent LIs Size of LIs
Schretlen DJ et al. Neurology 2007;69:1418–1423
Serum uric acid and brain ischemia in normal elderly adults
Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive FunctionMean age, 59.9±18.9 mg/dL
Serum UA, 4.5±1.4 mg/dL
Vannorsdall TD, et al. Stroke. 2008;39:3418-3420
WM PS IF VeM WM PS IF VeM
108 community-dwelling adults aged 20 to 96 years
Serum Uric Acid and Cognitive Function in 96 Community-Dwelling Older Adults
General verbal 16(23) 8(32)
General visuospatial 15(21) 9(36)
Processing speed * 11(16) 13(52)
Working memory ** 13(18) 11(44)
Verbal memory *** 14(20) 10(40)
Visual memory 18(25) 4(16)
Verbal fluency 18(25) 6(24)
Nu mber (%) in lowest quartile
low-moderate UA high UA
Cognitive domain (n=71) (n=25)
Odd Ratio (95% CI)
*p<0.001 **p<0.01 ***p<0.05 Schretlen DJ, et al. Neurophychology, 2007, Vol. 21, No. 1, 136–140
Ruggiero C, et al. Dement Geriatr Cogn Disord 2009;27:382–389
Uric Acid and Dementia in Community-Dwelling
Older Persons: The InChianti Study
Adjusted for UA tertile OR p
age, sex, BMI,
education
1) 3.82±0.53 mg/dL
2) 5.05±0.27 mg/dL
3) 6.72±1.24 mg/dL
1 (reference)
2.34 (0.87–6.24)
3.06 (1.10–8.52)
-
0.0895
0.0323
+ alchohol, energy intake, smoking,
chol, plasma vit. E
1) 3.82±0.53 mg/dL
2) 5.05±0.27 mg/dL
3) 6.72±1.24 mg/dL
1 (reference)
2.73 (0.96–7.75)
3.63 (1.22–10.77)
-
0.0585
0.0199
+ renal function, hypertension,
CVD, CBVD
1) 3.82±0.53 mg/dL
2) 5.05±0.27 mg/dL
3) 6.72±1.24 mg/dL
1 (reference)
2.62 (0.91–7.52)
3.32 (1.06–10.42)
-
0.1465
0.0262
+ MMSE basal score 1) 3.82±0.53 mg/dL
2) 5.05±0.27 mg/dL
3) 6.72±1.24 mg/dL
1 (reference)
11.02 (1.69–72.00)
18.89 (2.04–174.67)
-
0.0122
0.0096
1.016 elderly subjects (age 74.38±7.58 years)
Chen X et al. Plos One 2014
Serum Uric Acid Levels in Patients with Alzheimer’s Disease Compared to Healthy Controls:
A Meta-Analysis
Could uric acid directly promote neuronal dysfunction and/or damage?
Novak, V. & Hajjar, I. Nat. Rev. Cardiol. 7, 686–698 (2010);
Ependymal cells of the mouse brain express urate transporter 1 (URAT1)
Bowmna GL et al. J Alzheimers Dis. 2010 January ; 19(4): 1331–1336
Association between plasma uric acid and blood-brain
barrier integrity in AD
Differentiated SHSY5Y neuroblastoma were used to reproduce an in vitro model of early and late AD
b tubulin III
GAP-43 NF 200
Early AD: oligomeric Aß 1-42
Late AD: fibrillary Aß
Desderi G et al. J. Cell. Physiol. 9999: 1–10, 2016.
Ambivalenza
biologica
dell’acido urico
Why having gout can mean you'll end up with heart
disease..? How one illness can be linked to another
Which came first?http://www.dailymail.co.uk
Why having gout can mean you'll end up with heart
disease..? How one illness can be linked to another
Zinman D et al. NEJM 2015
Ulr
ik M
. M
og
en
se
n, 2
01
6M
cM
urr
ay
JJV
NE
JM
2016
La malattia da deposito di urato (gotta) è moltofrequente nell’anziano e molto spesso viene misconosciuta
La terapia deve mirare a mantenere stabilimentel’uricemia al di sotto dei 6 mg/dL
Conclusioni: le certezze
Il mantenimento dell’uricemia ad di sotto dei 6 mg/dLpotrebbe tradursi in importanti benefici sulle patologiecardiovascolari, cerebrali e renali
Conclusioni: le prospettive