Iperuricemia nell anziano: dal danno articolare al deterioramento cognitivo

Transcription

1 Iperuricemia nell anziano: dal danno articolare al deterioramento cognitivo Giovambattista Desideri Unità Operativa e SS di Geriatria Università degli Studi Dell Aquila

2 Prevalence per 1000 inhabitants Epidemiology of gout and hyperuricaemia (SUA >6 mg/dl) in Italy during the years Hyperuricemia Males 400 Hyperuricemia Female 350 Gout Males 300 Gout Females over 85 Trifirò G, et al. Ann Rheum Dis (2011).

3 Gout: The Fashionable Disease "the disease of kings "rich man's disease

4 Likelyhood ratio for various features in the diagnosis of gout - EULAR Ann Rheum Dis 2006;65:

5 Gout in the elderly: (a)tipical features 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. Tophi can supervene on Heberdenʼs and Bouchardʼs nodes.

6 Asymptomatic articular damage in hyperuricemia 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.

7 Hyperuricemia and gout: time for a new staging system? A proposed revised staging system for hyperuricaemia and gout, based on the American Heart Association heart failure staging system. Dalbeth N et al. Ann Rheum Dis 2014

8 Ann Rheum Dis 2016;0:1 14. Severe renal failure Treat as early as possible Education about the disease Individualised lifestyle advice Screening for comorbidifties and current medications Management of acute flare Presence of strong CYP3A4 P-glycoprotein inhibitors Avoid cochicine and NSAIDS Therapeutic options Depending on the severity, the number of affected joints and duration of attack Avoid colchicine Contra-indications to cochicine, NSAIDS and corticosteroids (oral and injectable) 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) Educate to self medicate Consider initiation of ULT (together with flare profilaxys) Resolution of flares Consider IL-1 blockers

9 Ann Rheum Dis 2016;0:1 14. If appropriate - stop diuretic - use losartan - use fenofibrate or statin Determine SUA target <5 mg/dl or <6 mg/dl Education about the disease Individualised lifestyle advice Screening for comorbidifties Management of Hyperuricemia in patients with gout Start prophylactic treatment Initiate ULT History of allergy to allopurinol start febuxostat or switch to a uricosuric Start Allopurinolo 100 mg/d Adapt the dosage to the renal function Slow titration up to the maximum allowed dosage Start febuxostat (or a uricosuric) Achieved target Yes No Achieved target Yes continue No Consider a combined therapy (XOI and uricosuric) No Achieved target Yes Continue Start pegloticase In severe chronic tophaceous gout

10 2016 Eular Recommendation for the Management of Hyperuricemia in Patients with Gout 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 patientyears 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. Richette P, et al. Ann Rheum Dis 2016;0:1 14. doi: /annrheumdis

11 Clinical Efficacy and Safety of Successful Longterm Urate Lowering with Febuxostat or Allopurinol in Subjects with Gout: EXCEL study proportion of subjects requiring gout flare treatment 0-<2 2-<4 4-<6 6-<8 8-<10 10-<12 12-<14 14-<16 16-<18 18-<20 20-<22 22-<24 24-<26 26-<28 28-<30 30-<32 32-<34 34-<36 36-<38 Becker MA, et al. J Rheumatol 2009; 36: Maintenance of SUA < 6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment Febuxostat 80 mg Febuxostat 120 mg Allopurinol Time (months)

12 20% treated 40% treated 60% treated

13 Total health care resource costs during 6 months from index date according to ULT SUA levels and Hx for kidney disease euros IRR (95% CIs) [Ref. 6 mg/dl] > 6 7 mg/dl > 7 8 mg/dl > 8 mg/dl 1.21 ( ) 1.24 ( ) 1.99 ( ) D20% 1.00 SUA levels and Hx for CVD IRR (95% CIs) [Ref. 6 mg/dl] > 6 7 mg/dl > 7 8 mg/dl > 8 mg/dl 1.10 ( ) 1.24 ( ) 1.75 ( ) 1.00 SUA levels and total mortality HR (95% CIs) [Ref. 6 mg/dl] > 6 7 mg/dl > 7 8 mg/dl > 8 mg/dl 0.98 ( ) 1.20 ( ) 2.12 ( ) 1.00 Degli Esposti L et al, NMCD 2016 Degli Esposti L et al, submitted

14 Hyperuricemia and Cardiorenal Metabolic Syndrome Chaudhary K et al Cardiorenal Med 2013;3:

15 Low uric acid levels in patients with Parkinson s disease: evidence from meta-analysis Parkinson Controls Shen L, Ji H-F. BMJ Open 2013

16 Alexander the great, Darwin, Harvey, Newton, Sydenham,. This association cannot be mere co-incidence.

17 Study of Serum Uric Acid and its Correlation with Intelligence Quotient and Other Parameters in Normal Healthy Adults 100 medical students in the age group of 17 to 20 years Patil U et al. International Journal of Recent Trends in Science And Technology 2013

18 Lessons from comparative physiology: could uric acid represent a physiologic alarm signal gone awry in western society? 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 intelligence.) 1. Uric acid can increase locomotor activity in rats 2 caffeine Uric acid increases with emotional or physical stress 3 1 Orowan E. Nature 1955;175: Barrea CM et al. Pharmacol Biochem Behav1989;33: Rahe RH et al. Psychosom Med 1974;36: Johnson RJ et al. J Comp Physiol B (1):

19 SUA and cognitive function and dementia 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 mmol/l. Euser SM et al. Brain 2009: 132;

20 Gout, Hyperuricemia, and the Risk of Cardiovascular Disease: Cause and Effect? Shah A, et al. Curr Rheumatol Rep (2010) 12:

21 Odi et amo. quare id faciam fortasse requiris

22 SUA, oxidative stress and cardiovascular disease: a comprehensive hypothesis Borghi C, Desideri GB, Hypertension 2016 XO-overactivity (genetic, induced) XO- overfeeding (food, fructose, purines) Oxidative stress Cellular entry of Uric Acid Serum Uric Acid Gout Intracellular Uric Acid HTN, CKD CV disease i.c. oxidative stress ( enos) mitochondrial dysfunction RAAS activation High TG,MS,TOD

23 Hyperuricemia and Stroke Incidence: A Systematic Review and Meta-Analysis Kym SY et al. Arthritis & Rheumatism Vol. 61, No. 7, July 15, 2009, pp

24 Serum Uric Acid Levels and Cerebral Small Vessels Disease: relationship with lacunar infarcts ALL LIs Silent LIs Size of LIs F. Crosta i (submitted)

25 Serum uric acid and brain ischemia in normal elderly adults Schretlen DJ et al. Neurology 2007;69:

26 Cerebral Ischemia Mediates the Effect of Serum Uric Acid on Cognitive Function Mean age, 59.9±18.9 mg/dl Serum UA, 4.5±1.4 mg/dl 108 community-dwelling adults aged 20 to 96 years WM PS IF VeM WM PS IF VeM Vannorsdall TD, et al. Stroke. 2008;39:

27 Serum Uric Acid and Cognitive Function in 96 Community-Dwelling Older Adults Nu mber (%) in lowest quartile lo w-moderate UA high UA Odd Ratio (95% CI) Cognitive domain (n=71) (n=25) 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) *p<0.001 **p<0.01 ***p<0.05 Schretlen DJ, et al. Neurophychology, 2007, Vol. 21, No. 1,

28

29 Uric Acid and Dementia in Community-Dwelling Older Persons: The InChianti Study elderly subjects (age 74.38±7.58 years) 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 ( ) 3.06 ( ) 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 ( ) 3.63 ( ) 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 ( ) 3.32 ( ) 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) ( ) ( ) Ruggiero C, et al. Dement Geriatr Cogn Disord 2009;27:

30 Serum Uric Acid Levels in Patients with Alzheimer s Disease Compared to Healthy Controls: A Meta-Analysis Chen X et al. Plos One 2014

31 Could uric acid directly promote neuronal dysfunction and/or damage?

32 Ependymal cells of the mouse brain express urate transporter 1 (URAT1) Novak, V. & Hajjar, I. Nat. Rev. Cardiol. 7, (2010);

33 Association between plasma uric acid and blood-brain barrier integrity in AD Bowmna GL et al. J Alzheimers Dis January ; 19(4):

34 Differentiated SHSY5Y neuroblastoma were used to reproduce an in vitro model of early and late AD Early AD: oligomeric Aß 1-42 Late AD: fibrillary Aß b tubulin III GAP-43 NF 200

35 Desderi G et al. J. Cell. Physiol. 9999: 1 10, 2016.

36 Ambivalenza biologica dell acido urico

37 Why having gout can mean you'll end up with heart disease..? How one illness can be linked to another Which came first?

38 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 Ulrik M. Mogensen, 2016 McMurray JJV NEJM 2016

39 Conclusioni: le certezze La malattia da deposito di urato (gotta) è molto frequente nell anziano e molto spesso viene misconosciuta La terapia deve mirare a mantenere stabilimente l uricemia al di sotto dei 6 mg/dl Conclusioni: le prospettive Il mantenimento dell uricemia ad di sotto dei 6 mg/dl potrebbe tradursi in importanti benefici sulle patologie cardiovascolari, cerebrali e renali