Dr Sourabh MalviyaConsultant Rheumatologist

Medanta HospitalIndore

GOUT WITH CO-MORBIDTIES

Outline Background-Case

Number of Comorbidities

Pathophysiology

Gout with each comorbidities relation

Case – an example

Conclusion

Background Case A 28 YR Male, Admitted in CCU as acute

AWMI with LVF On Mechanical Ventilator With no comorbidities No addiction No Family History of

Cardiac illness Rheumatology consult for

joint pain & swelling in hands

Background Case Invetigations CBC- Hb 12gm./dl , TLC- 6500, PC – 4750000 LFT-WNL Creat 1.2 mg/dl UA- 10.3 mg/dl

Diagnosis – Chronic Tophaceous Gouty Arthritis

Acute AWMI with LVF

Uric Acid

Intelligence Alzheimer’s

Parkinson’s Disease

Gout Stone

MI

The Good The Bad

The Ugly

Tophi

CVA Dyslipidemia

Gout and comorbidities – Why to know?

Avg. 4 comorbidities in each gout pt during the course of disease

5% to 10% have 7 or more Prevalance increases with degree &

duration of hyperuricemia & gout These comorbidities and their treatment

may have an effect on the development of gout and on the choice of treatment

1.Stamp LK, Chapman PT., Rheumatology (Oxford). 2013 Jan;52(1):34-44.2.Michael H. Pillinger, et. Al.; Gout and Its Comorbidities: Bulletin of NYH Hospital of Joint Diseases 2010;68(3):199-203

Hypertensio

CVD

Renal impairment

Diabetes

Obesity

Hyperlipidaemia

Comorbidities of Gout & HyperuricemiaNHANES study 2007 – 08, 5,707 pts• 74% Hypertension• 71% CKD stage 2 or >• 53% obese• 26% DM• 14% MI• 11% CHF• 10% CVA

1.Zhu Y, Pandya BJ, Choi HK. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008. Am J Med. 2012 Jul;125(7):679-87.

Pathophysiology of Vascular Damage Due to Hyperuricemia

The Oxidant-Antioxidant Paradox Mechanisms of Uric Acid

1.Changyi Chen,Jian-Ming Lü , Qizhi Yao: Hyperuricemia-Related diseases and Xanthine Oxidoreductase (XOR) Inhibitors: An Overview ;1643-3750 , 2016; 22: 2501-2512

Schematic Diagram

Experimental models have shown that hyperuricemia-induced vascular dysfunction, inflammation and increased oxidative stress lead to insulin resistance, which later leads to impaired glucose tolerance and predisposes to the other components of the metabolic syndrome.

Comorbidities

Question Following co-morbidities can be seen with Gout- Best of

four1. Metabolic Syndrome, CVD & Stroke2. Metabolic Syndrome, CVD, Stroke & CKD3. Metabolic Syndrome, CVD, Stroke, CKD & Ocular

Abnormalities4. Metabolic Syndrome, CVD, Stroke, CKD, Ocular

Abnormalities & Malignancy

Hypertension Hypertension -74% with gout and 47% with hyperuricemia in

comparison to a population-estimated prevalence of 24% among normouricemic patients. NHANES 2007-08 survey

Hyperuricemia is seen in:• - 25% of patients with untreated hypertension

• - 50% of patients on diuretics

• - >75% of patients with malignant hypertension

Many medications used have effects on serum urate (SU) In the LIFE study, lowering of serum uric acid in the losartan grp

contributed to about 29% of the intervention effect on cardiovascular end points

Stamp LK, Chapman PT., Rheumatology (Oxford). 2013 Jan;52(1):34-44.Annemans L et al., Ann Rheum Dis 2008; 67:960-6.Chen SY et al., Clin Rheumatol 2007;26:1453-7.Johnson R et al., Hypertension 2003;41:1183-90.

Does ULT has effect on blood pressure?

ULT may contribute to a reduction in blood pressure.

In a study of 48 hyperuricaemic patients-allopurinol 300 mg/day for 3 months resulted in a significant reduction in blood pressure

In another study of 30 adolescents (aged 11-17 years) with essential hypertension, allopurinol 200 mg b.i.d. for 4 weeks resulted in a significant reduction in blood pressure

But Cochrane review concluded that evidence is still insufficient to recommend ULT

Kanbay M et al., Int Urol Nephrol 2007;39: 1227-33Feig D et al., JAMA 2010;300:924-32.Gois PH, Souza ER. Online). 2013; 1:CD008652.

Peripheral arterial disease Manifestation of atherosclerosis Higher SU levels were significantly associated with PAD,

independently from traditional cardiovascular risk factors (3987 participants in NHANES 1999–2009)

Shankar A, Klein BE, Nieto FJ, et al. Association between serum uric acid level and peripheral arterial disease. Atherosclerosis. 2008; 196:749–55. [PubMed: 17275005]

Cardiovascular disease

CVD risk increases by 60% in Gout Uric acid level - independent predictor of all-cause death, (hazard ratio of

1.26)• Men with UA levels in the upper 1/3 were 1.7 – fold more likely to

die from any cause• Increase of uric acid > 4 mg/ml ,a “red flag” to the increase risk of CVD

& especially in those already at risk for CVD

1.Krishnan E et al., Arthritis Rheum 2006;54:2688-96.; Krishnan E et al., Arch Intern Med 2008;168:1104-10.; Choi H, Curhan G., Circulation 2007; 116:894-900.; Edwards N.,CurrOpin Rheum 2009;21:132-7.; Kim S et al. Arthritis Care Res 2009;61:885-92.; Baker J et al., Angiology 2007;58:450-7.2.oachimescu AG, Brennan DM, Hoar BM, et al.: Serum uric acid an independent predictor of all-cause mortality in patients at high risk of cardiovascular disease: a preventive cardiologyinformation system (PreCIS) database cohort study. Arthritis Rheum 2008, 58:623–630.

What Studies say association between SU, cardiovascular disease, and cardiovascular death ?

CHF• Gout pts 80% progressively

increases risk of CHF• Increased XO activity in damaged myocardial tissue • Increase urate precursors and radical oxygen species• Cardiac hypertrophy• Myocardial fibrosis• Left ventricular remodeling and contractility impairment

Krishnan E. Gout and the risk for incident heart failure and systolic dysfunction. BMJ Open. 2012 Feb 15;2(1):e000282.Kanbay M et al., Int Urol Nephrol 2007;39: 1227-33.; Norman A et al., Lancet 2010;375: 2161-7.; Rentoukas E et al., Int J Cardiol 2010; 145:257-8.

• ULT may be beneficial• Oxypurinol 405 patients

reported a trend toward improved outcomes

• Allopurinol - significant reduction in CHF re-admissions or death (RR 0.69; 95% CI 0.60, 0.79) and reduced all-cause mortality (RR 0.74; 95% CI 0.61, 0.90)

Uric Acid is a Risk Factor for Myocardial Infarction & Stroke• 4385 participants in Rotterdam, 1990-1993 were > 55 yr, free

from CVA & CHD• Average f/u was 8.4 yrs• Relationship betwn SUA & risk of CVD is linear• High SUA levels assoc with risk of MI & CVA• Age & sex adjusted hazard ratios for highest vs lowest

quintile of UA were• 1.68 CVD• 1.87 MI• 1.57 CVA

• SUA is a strong risk factor for MI & stroke

1.Bos MJ et al. Stroke. 2006;37:1503-1507.2.Weir CJ, Muir SW, Walters MR, Lees KR: Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke. Stroke 2003, 34:1951–1956.3. Wong KY, MacWalter RS, Fraser HW, et al.: Urate predicts subsequent cardiac death in stroke survivors. Eur Heart J 2002, 23:788–793.

Hyperuricemia and Stroke

High normal SU (SU >5.75 mg/dL for men; >4.8 mg/dL for women) concentrations were associated with a significantly increase in white matter hyperintense signals compared to participants with low to moderate SU levels

Weir CJ, Muir SW, Walters MR, Lees KR: Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke. Stroke 2003, 34:1951–1956.54. Wong KY, MacWalter RS, Fraser HW, et al.: Urate predicts subsequent cardiac death in stroke survivors. Eur Heart J 2002, 23:788–793.

Renal impairment & Urate Nephropathy Renal impairment is associated with hyperuricaemia, which also

contributes to renal impairment Under-excretion of urate is a common cause of hyperuricaemia Increase -reactive oxygen species leads to activation of the renin

angiotensin system (RAS) -- > vasoconstriction of the afferent arteriolar system and glomerular hypertrophy

Arteriolopathy Direct effect of urate in tubular cells Transition of renal tubular cells leading to renal fibrosis

Stamp L, Dalbeth N., Semin Arthritis Rheum. 2016 Jul 28. pii: S0049-0172(16)30147-0

Effect of urate lowering on renal function

In patients with CKD, allopurinol has been shown to slow the

progression of renal disease

A post-hoc analysis of the FOCUS study demonstrated that

febuxostat was associated with an improvement in renal function

Siu YP et al., Am J Kidney Dis 2006;47:51-9.; Goicoechea M et al., Clin J Am Soc Nephrol 2010;5:1388-93.; Stamp L, Dalbeth N., Semin ArthritisRheum. 2016 Jul 28. pii: S0049-0172(16)30147-0; Whelton A et al.,J Clin Rheumatol 2011;17: 7-13.

Insulin resistance and metabolic syndrome

Insulin Resistance,and Obesity- Metabolic Syndrome ( MS)

MS commonly seen – UA 10 mg/dL or above than less than 6.0 mg/dL (70.7% and 18.9% respectively).

MS - 62.8% and 25.4% with and without gout UA levels is independently correlated with IR shown in a Korean study of

> 50000

Hyperuricemia were more likely to develop IR and pre-diabetes, HR 1.36 (95% CI 1.23–1.51) and 1.25 (95% CI 1.04–1.52), respectively (A recent 15-year follow-up study on 5,012 US non-diabetic adults)

Insulin resistance increases by 35% in gout patients

1.Yoo HG, Lee SI, Chae HJ, et al. Prevalence of insulin resistance and metabolic syndrome in patients with gouty arthritis.Rheumatol Int. 2009 Dec 20; Epub ahead of print.2. Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol. 2007 Aug;293(2):C584-96

Diabetes and Gout Men with gout are at risk of developing type 2 diabetes compared

with men without gout (RR for incident type 2 diabetes 1.34 (95% CI 1.09, 1.64)

Gout - 35% to 65% increase in risk for future incidence of Type II diabetes

Prevalence in pts with gout ( 25.7% ) and 7.8% without gout

Those with established diabetes or significantly increased HbA1c may

be at lower risk due to uricosuric effect of glycosuria

Choi H et al., Rheumatology 2008;47:1567-70.

EYE

Take Home messages Gout is bigger risk factor for co-morbidities

Evaluation and management of co-morbidities should be done in a pt

of Gout

Treat-to-target approach

Keep UA around 4-5 mg/dl in co-morbid condition in pts with gout

When choosing gout therapies, consider individual patient’s

comorbidities and potential drug interactions.

Surgical -Strike De-monetization