Presentation made during the 1st Inter-Hospital Rheumatology Fellows' Case Discussion on 9 June 2018 at the Speaker Feliciano Belmonte Auditorium, 7/F East Avenue Medical Center. Presentation highlights the needs to recognize gout as one of the rheumatic conditions that put patients at risk for developing CV disease.

1. Managing
Cardiovascular Risks in
Inflammatory Arthritis
Sidney Erwin T. Manahan, MD FPCP FPRA
Medical Specialist, Section of Rheumatology
East Avenue Medical Center

2. DISCLOSURES
• Honoraria, Ajanta Pharmaceuticals
• Honoraria and Educational Support, Pfizer
• Honoraria, MSD

3. EULAR Recommendations for
Cardiovascular Disease Risk Management
in Patients with Rheumatoid Arthritis and
Other Forms of Inflammatory Joint
Disorders: 2015/ 2016 Update
Agra R, Heslinga SC, Rollefstad S, Heslinga M, et al. Ann Rheum Dis 2017; 76: 17-28.
Rheumatoid
Arthritis
Psoriatic
Arthritis
Ankylosing
Spondylitis

4. What is the most prevalent
inflammatory joint disorder?
GOUT

5. Associations between Uric Acid & Disease
URIC ACID
Gout
Tophi
Nephrolithiasis
CV Disease
HPN
Kidney Disease
Crystals Soluble

6. Associations between Gout & Disease
GOUT
Cardiovascular Disease
• Coronary Artery Disease
• Vascular Events
• Peripheral Arterial Disease
Hypertension
Chronic Kidney Disease
Causality
Epiphenomenon

7. Risks of CV Diseases in Gout & HU
Study (Year) Gout Hyperuricemia
MRFIT (2006)
12,866 men over 6.5 years
MI Odds ratio 1.26
(95% CI 1.14 to 1.40)
MI Odds ratio 1.11
(95% CI 1.08 to 1.15)
Frammingham (1988)
5,209 subjects
Coronary HD RR 1.60
(95% CI 1.1 to 2.2)
HPFS (2007)
51,297 men over 12 years;
patients with no pre-existing
coronary artery disease
Total Mortality RR 1.28
(95% CI 1.15 to 1.41)
CV death RR 1.38
(95% CI 1.15 to 1.66)
Fatal CHD RR 1.55
(95% CI 1.24 to 1.93)
Renal Data System
(2008)
234,794 dialysis patients
Mortality HR 1.47
(95% CI 1.26 to 1.59)
Kuo et al (2010)
61,157 subjects
Total Mortality HR 1.46
(95% CI 1.12 to 1.91)
Total Mortality HR 1.07
(95% CI 0.94 to 1.22)
Singh JA. Ann Rheum Dis April 2015; 74 (4): 631-4.

8. Gout as an Independent Risk Factor
• Coronary Heart Disease
• Vascular Events
• Peripheral Arterial Disease
• Increased CV-related Deaths
• Higher in Women
• Higher in Young Patients
Andres M, Sivera F, Quintanilla FA, et al. Int J Clin Rheumatol 2015; 10 (5): 329-34.

9. Risks of CV Disease in HU
Study Odds Ratio (95% CI) Comments
Kim et al (2010)
402,997 general population
CAD 1.09
(1.03 to 1.16)
CAD Mortality 1.16
(1.01 to 1.30)
Higher risk of CAD mortality
in women
Wheeler et al (2005)
9,458 CAD vs 155,084 controls
CAD 1.13
(1.07 to 1.20)
Zhao et al (2013)
172,123 general population
CV Mortality 1.37
(1.19 to 1.57)
All Cause Mortality 1.24
(1.07 to 1.42)
Higher risk of CV mortality
in women; Higher risk of all
cause mortality in men
Braga et al (2015)
General population
CAD Incidence 1.21
(1.07 to 1.36)
CAD Mortality 1.21
(1.00 to 1.46)
Higher incidence and
mortality in women
Vasalle C, Mazzone A, Sabtino L, Carpegianni C. Diseases 2016; 4:12 doi:

10. Risks of CV Disease in HU
Study Odds Ratio (95% CI) Comments
Von Leuder et al (2015)
12,677 Complicated MI or HF pts
CV Mortality 1.47
(1.17 to 1.83)
All Cause Mortality 1.36
(1.11 to 1.67)
HF Hospitalization 1.28
(1.14 to 1.43)
Huang et al (2014)
General population vs CAD/ HF
HF Incidence 1.19
(1.17 to 1.21)
All Cause Mortality 1.04
(1.02 to 1.06)
Vasalle C, Mazzone A, Sabtino L, Carpegianni C. Diseases 2016; 4:12

11. Hyperuricemia as a Risk Factor
• CAD Incidence
• CV Mortality (Women)
• All Cause Mortality (Men)
• Heart Failure
• Higher in Women
Vasalle C, Mazzone A, Sabtino L, Carpegianni C. Diseases 2016; 4:12

12. Potential Pathogenic Pathways
Singh JA. Ann Rheum Dis April 2015; 74 (4): 631-4.
Diet / Alcohol
Medications
Genetics
Kidney Disease
Co-morbidities
HPN, heart
failure, obesity,
CAD
HYPERURICEMIA GOUT CVD
Hypertension
Oxidized LDL
in plaques
Endothelial
Dysfunction
Systemic
Inflammation
Other pro-
atherogenic
factors
Duration, Severity, Other
determining factors

13. Urate Deposition leads to Inflammation
INSIDE THE JOINT
MSU deposits → Increased
synovial fluid WBC → persistent
low grade inflammation (even
prior to onset of arthritis)
SURROUNDING THE TOPHI
Inflammatory Cellular Infiltrate
surrounding tophi
Andres M, Sivera F, Quintanilla FA, et al. Int J Clin Rheumatol 2015; 10 (5): 329-34.
ACTIVATES INNATE IMMUNE
RESPONSE
Via NLR-P3 inflammasome
pathway ultimately inducing IL-1B
production

14. The Duality of Uric Acid
ANTI-OXIDANT
• Endothelial Protection
• Direct correlation with
total antioxidant capacity;
inverse correlation with
oxidative stress
PRO-OXIDANT
• Induces monocyte
apoptosis
• Increases inflammation
and cytokines
• Increases oxidative stress
Vasalle C, Mazzone A, Sabtino L, Carpegianni C.
Diseases 2016; 4:12

15. Interrelationships (HU, CRD, CVD)
CELL
PURINE
URIC ACID
XO
HYPERURICEMIA
SMC Proliferation
Vasoconstriction
RAS Activation
COX2 Activation
Tissue Hypoxia
Cell Death
Insulin Resistance
HYPERTENSION
ENDOTHELIAL DYSFUNCTION
& CARDIOVASCULAR DISEASE
RENAL DISEASE PROGRESSION

16. There is a 15% increase in CV
mortality for every 1 mg/dl
increase in uric acid levels.
Borghi C, Desideri G. Hypertension 2016; 67: 496-8.

17. Patients with asymptomatic
hyperuricemia with silent
MSU deposits suffered from
more severe coronary
atherosclerosis
Andres M, Quintanilla MA, Sivera F, et al.
Arthritis Rheumatol 2016; 68: 1531-9.

18. Cardiovascular risks of Gout Patients:
Rheumatology Clinics
Andres M, Bernal JA, Sivera F, et al. Ann Rheum Dis 2017; 76: 1263-8.
6.3
30.4
23.2
40.1
5.9
12.7 13.5
67.9
0
10
20
30
40
50
60
70
80
Low (SCORE
<1%)
Moderate
(SCORE 1-4%)
High (SCORE 5-
9%)
Very High
(SCORE >10%)
PercentageofPatientsSeen(N149)
Before cUS
After cUS

19. Metabolic Syndrome among Filipino Gout
Patients Seen at a Rheumatology Clinic
Conditions Frequency (%)
Hypertension 41 (65.1)
Metabolic Syndrome 30 (47.6)
Diabetes Mellitus 11 (17.5)
Chronic Kidney Disease 15 (23.3)
Heart Disease 2 (3.2)
Conditions Frequency (%)
Abdominal Obesity 25 (39.7)
Hypertension 23 (36.5)
Low HDL 20 (31.7)
Hypertriglyceridemia 19 (30.2)
Diabetes Mellitus 9 (14.3)
Dianongco ML, Magbitang AT, Salido EO. PJIM 2014; 52 (1): 1-4.

20. Cardiovascular Risks of Gout Patients
Primary Care Clinics
Gout (%) Non Gout (%) P-value
Co-morbids
Hypertension 38.8 21.6 <0..01
Diabetes mellitus 14.6 9.3 <0.01
Dyslipidemia 10.4 7.1 0.02
Individual CVDs
Angina pectoris 1.0 0.8 0.50
Myocardial Infarction 2.0 1.2 <0.01
Heart Failure 1.7 0.9 <0.01
Transient Ischemic Attack 0.8 0.7 0.78
Cerebrovascular Accident 1.6 1.0 0.06
Peripheral Arterial Disease 1.5 0.6 <0.01
Aortic Aneurysm 0.9 0.4 0.01
Janssens HJEM, Arts PGJ, Schalk BWM, Biermans MCJ. Joint Bone Spine 2016; xxx-xxxx

21. Reducing CV Risks
Does therapy for gout have an impact?

22. LoDoCo Trial on Secondary CV Prevention
Patient
532 patients who met the following criteria
(1) Angiographically proven CAD
(2) Stable disease for 6 months
(3) Compliant with therapy (ASA, Clopidogrel, Statins)
Intervention Colchicine 0.5 mg/d x 3 years
Comparator Standard Therapy
Methodology Prospective Randomized Observer Blinded Endpoint
Outcomes
Acute Coronary Syndrome
Out of Hospital Cardiac Arrest
Non-cardioembolic Stroke
Nidorf SM, Eikelboom JW, Budgeon CA, et al. J Am Coll Cardio 2013; 61 (4): 404-10.

23. LoDoCo Trial Results
Outcome Control (n 250) Treatment (n 282) HR (95% CI)
Primary Outcome 40 (16) 15 (5.3) 0.33 (0.18 to 0.59)
Acute Coronary Syn 34 (13.6) 13 (4.6) 0.33 (0.18 to 0.63)
OOH Cardiac Arrest 2 (0.8) 1 (0.35) 0.47 (0.04 to 5.15)
NCE Stroke 4 (1.6) 1 (0.35) 0.23 (0.03 to 2.03)
Components of ACS
Stent related 4 (1.6) 4 (1.4) NS
Non-stent related 30 (12) 9 (3.2) 0.26 (0.12 to 0.55)
NSR AMI 14 (5.6) 4 (1.6) 0.25 (0.08 to 0.76)
NSR Unstable Angina 16 (12) 5 (2.4) 0.27 (0.10 to 0.75)
Nidorf SM, Eikelboom JW, Budgeon CA, et al. J Am Coll Cardio 2013; 61 (4): 404-10.

24. Large population based trials failed to
show a clear CV risk reduction with urate
lowering therapy.

25. Xanthine Oxidase Inhibitor
Patient 24, 108 propensity score matched pairs in US insurance claims
Intervention Allopurinol, Febuxostat
Outcome
Composite non-fatal CV outcome consisting of:
(1) Myocardial infarction
(2) Coronary revascularization
(3) Stroke
(4) Heart failure
Results
Non initiators CVD risk 21.4 (95% CI 19.8 – 23.2) / 1000 p-y
Initiators CVD risk 24.1 (95% CI 22.6 – 26.0) / 1000 p-y
Hazard ratio 1.16 (95% CI 0.99 – 1.34)
Conclusion
XOI initiation was not associated with an increase or decrease in
composite CVD risk
Kim SC, Scheneeweiss S, Choudhry N, et al. Am J Med 2015; 123:653.e7-653.e16.

26. EULAR Recommendations for
Cardiovascular Disease Risk Management
in Patients with Rheumatoid Arthritis and
Other Forms of Inflammatory Joint
Disorders: 2015/ 2016 Update
Agra R, Heslinga SC, Rollefstad S, Heslinga M, et al. Ann Rheum Dis 2017; 76: 17-28.
Rheumatoid
Arthritis
Psoriatic
Arthritis
Ankylosing
Spondylitis
Gout (?)

27. EULAR 2016 Update: Overarching Principles
1. Clinicians should be aware of the higher risk for CVD in
patients with IJD
2. Rheumatologists are responsible for CVD risk
management of patients with IJD
3. NSAID and steroid use should be in accordance with
treatment-specific recommendations
Agra R, Heslinga SC, Rollefstad S, Heslinga M, et al. Ann Rheum Dis 2017; 76: 17-28.

28. EULAR 2016 Update: Recommendations
RA, PsA and AS Gout
Disease activity should be controlled optimally to
lower CVD risks
SUA should be lowered to
target
Risk assessment should be regularly and after
major changes in anti-rheumatic therapy
• Low to moderate risk – Every 5 years
• High to very high risk – More frequent
Follow national guidelines
(start screening at 35 y/o)
CVD risks assessment should be according to
national guidelines
Follow national guidelines
Lipids should be measured when disease activity is
stable or in remission
Follow national guidelines
Use the 1.5 multiplication factor when using CVD
risk prediction models in patients with RA
Agra R, Heslinga SC, Rollefstad S, Heslinga M, et al. Ann Rheum Dis 2017; 76: 17-28.

29. EULAR 2016 Update: Recommendations
RA, PsA and AS Gout
Carotid ultrasound may be considered for
asymptomatic atherosclerotic plaques
Potential Role in risk
assessment for gout
Emphasize health diet, regular exercise and
smoking cessation
Anti-HPN and statins should be used as in the
general population
NSAID use should be with caution among patients
with documented CVD or in presence of CVD risk
factors
Steroid dose should be kept to a minimum and
taper should be attempted during remission or low
disease activity. Reasons to continue GC should be
regularly checked
Agra R, Heslinga SC, Rollefstad S, Heslinga M, et al. Ann Rheum Dis 2017; 76: 17-28.

30. CV Risk Management for IJDs
• HbA1c / Fasting Blood Sugar
• Lipid profile
• Regular BP monitoring
• Check Smoking Status
• Counsel and address risk factors present
• Consider Risk Assessment Tools (recognize their limitations)
Singh JA. Ann Rheum Dis April 2015; 74 (4): 631-4.

31. In Summary
• There is an association between gout and hyperuricemia with
cardiovascular diseases
• Patients with gout are at increased risk with cardiovascular diseases
• Guidelines on managing CV risks among inflammatory arthritis can
also be applied to patients with gout