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

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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