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Inflammation and Cardiovascular Disease: 2017 Updates

Priscilla Hsue, MD FACC William Watt Kerr Professor of Medicine Division of Cardiology Zuckerberg San Francisco General University of California, San Francisco

Disclosures

§ Grant support from NIH § Grant support from Pfizer § Honoraria received from Gilead

Inflammation and CVD

• Inflammatory biomarkers are predictive of CV events
• Benefit of statins on CV events most pronounced among

individuals who lower LDL and inflammatory biomarkers

• Can targeted anti-inflammatory therapies reduce CV events

and prolong life (with effects on cancer)?

– CIRT – CANTOS

• Inflammation and heart failure (HFrEF and HFpEF)
• Special populations: DM, HIV, and RA
• Inflammation and atherosclerosis: pathophysiology

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Role of inflammation in atherothrombosis:

Hansson GK Circulation 2017 Hansson GK et al NEJM 2005

Inflammation in Atherosclerosis: From Pathophysiology to Practice

Libby P et al JACC 2009 Innate Immunity Adaptive Immunity

Residual inflammatory risk: what are options after statin treatment?

Ridker PM European Heart Journal 2016

• Dr. Phan to

discuss tomorrow!

PROVE-IT IMPROVE-IT

Residual Inflammatory Risk Residual Cholesterol Risk Both Neither hsCRP > 2 mg/L LDLC < 70 mg/dL hsCRP < 2 mg/L LDLC > 70 mg/dL hsCRP > 2 mg/L LDLC > 70 mg/dL hsCRP < 2 mg/L LDLC < 70 mg/dL

How Common is Residual Inflammatory Risk?

Ridker PM. Circulation Res 2017;120:617-9. 40mg Pravastatin vs 80mg Atorvastatin in 3745 ACS pts 40mg Simvastatin vs. 40mg simvastatin+ 10mg ezetimibe in 15179 ACS pts

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• Inflammatory biomarkers predict CV events

543 healthy men randomized to asa vs. placebo

Take home: Baseline hsCRP predicts risk of future MI and stroke in short/long term

1 2 3 4 1 2 3 4

Placebo Aspirin Relative Risk Myocardial Infarction Quartile of hsCRP

Ridker et al N Engl J Med 1997;336:973-9

16

Physicians Health Study: Benefit of aspirin is modified by underlying inflammation

The role of aspirin as an anti-inflammatory agent for protection against cardiovascular events

Benefit of aspirin is highest among pts with highest quartile of baseline hsCRP (Risk Reduction 55.7%, p=0.02) No benefit of aspirin among individuals with hsCRP in lowest quartile (Risk reduction 13.9%, p=0.77) Take home: benefit of aspirin directly related to hsCRP level

P=0.01 P=0.003 Quartile of IL-6 (range, pg/dL) Ridker et al Circulation 2000;101:1767-1772 P=0.3 1 4 ³2.28 Relative Risk of MI

• f future heart attack and stroke

P Trend = 0.001 1

£1.04 2 1.04-1.46 3 1.47-2.28

IL-6, a crucial inflammatory cytokine, is a strong predictor Nested case control in Physicians Health Study For each quartile increase in IL-6, there was as 38% increase in risk, P=0.001

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Coronary Heart Disease

3.0 2.5 2.0 1.5 1.0 4.0 8.0 0.5 1.0

hsCRP concentration (mg/L) Risk ratio (95% CI) All Vascular Deaths

3.0 2.5 2.0 1.5 1.0 2.0 4.0 8.0

Meta-analysis of 54 Prospective Cohort Studies Inflammation and risk of future cardiovascular events: 2010

Emerging Risk Factor Collaborators, Lancet January 2010

0.5 1.0 2.0

Emerging Risk Factor Collaborators, Lancet January 2010 The magnitude of independent risk associated with inflammation is at least as large, if not larger, than that of BP and cholesterol. However, in contrast to BP and cholesterol, no clinical trials have been completed to see if lowering inflammation can lower cardiac event rates.

Risk Ratio (95%CI)

0.5 1.0 1.2 1.4 1.8

Risk Ratio (95%CI) per 1-SD higher usual values

Adjusted for age, gender, smoking, diabetes, BMI, triglycerides, alcohol, lipid levels, and hsCRP

hsCRP Systolic BP T

• tal cholesterol

Non-HDLC 1.37 (1.27-1.48) 1.35 (1.25-1.45) 1.16 (1.06-1.28) 1.28 (1.16-1.40) Meta-analysis of 54 Prospective Cohort Studies

www.reynoldsriskscore.org

Age Smoking SBP TC HDLC hsCRP Family History HbA1c Reynolds Risk Score hsCRP (mg/L) is not CRP (mg/dL) Cardiovascular Inflammation Reduction Trial (CIRT) Translation to clinical practice Ridker PM JAMA 2007 Ridker PM Circulation 2008

• Individuals benefit the most from statins who reduce LDL and

reduce inflammatory markers

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Statin treatment, hsCRP, and CV events

CARE: Secondary prevention using 40mg pravastatin Median hsCRP was 21.6% lower in those on pravastatin at 5 years

Ridker P at al Circulation 1998 Ridker P et al Circulation 1999

0.00 0.02 0.04 0.06 0.08 0.10 0.0 0.5 1.0 1.5 2.0 2.5

Follow-Up (Y ears) LDL > 70 mg/dL, hsCRP > 2 mg/L LDL > 70 mg/dL, hsCRP < 2 mg/L LDL < 70 mg/dL, hsCRP > 2 mg/L LDL < 70 mg/dL, hsCRP < 2 mg/L

Ridker et al NEJM 2005;352:20-28.

PROVE IT-TIMI 22: 80mg atorvastatin vs. 40mg pravastatin after ACS

Lower is better not only for LDL but also inflammation

Ridker P European Heart Journal 2016 Rosuvastatin 20 mg (N=8901)

4-week run-in

No Prior CVD or DM

Men >50, Women >60

LDL <130 mg/dL hsCRP >2 mg/L Placebo (N=8901) Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany , Israel, Mexico, Netherlands, Norway , Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay , United States, Venezuela Mean LDLC 104 mg/dL, Mean HDLC 50 mg/dL, hsCRP 4 mg/L

JUPITER

Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP

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JUPITER

Ridker P et al NEJM 2008 (MI, CVA, UA/Revascularization, CV Death

• 44%

251/8901 142/8901

HR 0.56, 95%CI 0.46-0.69 P<0.00001 NNT = 25 Libby P et al JACC 2009

Benefit of JUPITER in all subgroups, most among those with low LDL and low hsCRP

5 4 3 2 1

hsCRP RP de decrease se 37 pe percent at 12 mo months hsCRP (mg/L)

20 140 120 100 80 60 40

LDL (mg/dL)

24 36 48

Months

12

LDL DL decr crease 50 per ercent at 12 mo months hs

Is the large benefit

• bserved in the

JUPITER Trial due to lipid lowering, to inflammation inhibition,

• r to a combination of

these two processes?

Cardiovascular Inflammation Reduction Trial (CIRT) JUPITER: Are statins anti-inflammatory?

• Studies of anti-inflammatory agents used in RA

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Atherothrombosis in rheumatic diseases

Mason JC et al Eur Heart Journal 2015 Cardiovascular Inflammation Reduction Trial (CIRT)

Why Low Dose Methotrexate (LDM)?

• II. Observational evidence strongly suggests a reduction in vascular events

Cohort Group HR* (95 % CI) Endpoint Exposure Wichita RA 0.4 (0.2 - 0.8) Total Mortality LDM Choi 2002 0.3 (0.2 - 0.7) CV Mortality LDM 0.4 (0.3 – 0.8) CV Mortality LDM < 15 mg/wk Netherlands RA 0.3 (0.1 – 0.7) CVD LDM only van Helm 2006 0.2 (0.1 – 0.5) CVD LDM + SSZ 0.2 (0.1 – 1.2) CVD LDM + HCQ 0.2 (0.1 – 0.5) CVD LDM + SSZ + HCQ Miami VA PsA 0.7 (0.6 – 0.9) CVD LDM Pradanovich 2005 0.5 (0.3 – 0.8) CVD LDM < 15 mg/wk RA 0.8 (0.7 – 1.0) CVD LDM 0.6 (0.5 – 0.8) CVD LDM < 15 mg/wk CORRONA RA 0.6 (0.3 – 1.2) CVD LDM Solomon 2008 0.4 (0.2 – 0.8) CVD TNF-inhibitor QUEST-RA RA 0.85 (0.8 – 0.9) CVD LDM Narango 2008 0.82 (0.7 – 0.9) MI LDM 0.89 (0.8 - 1.0) Stroke LDM UK Norfolk RA, PsA 0.6 (0.4 – 1.0) Total Mortality LDM 2008 0.5 (0.3 – 1.1) CV Mortality LDM

• To directly test the inflammatory

hypothesis of atherothrombosis. To evaluate in a randomized, double-blind, placebo-controlled trial whether LDM given at a target dose of 15 to 20 mg po weekly will reduce rates of myocardial infarction, stroke, or cardiovascular death among patients with stable coronary artery disease and either type 2 diabetes or metabolic syndrome.

• Cardiovascular Inflammation Reduction Trial (CIRT)

Overall Design and Primary Aim N = 7,000 NHLBI-Sponsored 350- 400 US and Canadian Sites

Stable CAD (past history of MI or multi-vessel CAD on angiogram) On Statin, ACE/ARB, BB, ASA Persistent Evidence of Inflammation Diabetes or Metabolic Syndrome LDM 15-20 mg po

• nce weekly

+ daily folate LDM placebo po

• nce weekly

+ daily folate Nonfatal MI, Nonfatal Stroke, Cardiovascular Death

Colchicine as an anti-inflammatory agent in CAD

Plaque stabilization in ACS

Low Dose Colchicine for 2o Prevention Stable CAD, Reduced CV events Pre-Colchicine Post-Colchicine Vaidya K JACC CV Imaging 2017 Nidorf SM et al JACC 2013

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• Moving upstream in the inflammatory pathway: IL-1β

Targeting inflammation: Moving upstream

Ridker P Circulation Research 2016

IL-1β inhibition using canakinumab

• Canakinumab is a human monoclonal IL-1β

antibody indicated for treatment inflammatory disorders such as CAPS and Muckle-Wells syndrome

– Dosing is quarterly subcutaneous injection

• Binds IL-1β and blocks interaction of cytokine

with type I and II receptors

• Produces a rapid and sustained inhibition of

inflammation with only modest effects on lipids

Ridker P et al Lancet August 27, 2017

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Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation

• f hsCRP (> 2 mg/L)

Randomized Canakinumab 150 mg SC q 3 months Randomized Placebo SC q 3 months Primary CV Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Randomized Canakinumab 300 mg SC q 3 months* Key Secondary CV Endpoint: MACE + Unstable Angina Requiring Unplanned Revascularization (MACE+) Randomized Canakinumab 50 mg SC q 3 months

Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

N = 10,061 39 Countries April 2011 - June 2017 1490 Primary Events

Ridker ESC 2017

Critical Non-Cardiovascular Safety Endpoints: Cancer and Cancer Mortality, Infection and Infection Mortality

Canakinumab SC q 3 months Characteristic Placebo (N=3347) 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) Age (years) 61.1 61.1 61.2 61.1 Female (%) 25.9 24.9 25.2 26.8 Current smoker (%) 22.9 24.5 23.4 23.7 Diabetes (%) 39.9 39.4 41.8 39.2 Lipid lowering therapy (%) 93.7 94.0 92.7 93.5 Renin-angiotensin inhibitors (%) 79.8 79.3 79.8 79.6 Prior Revascularization (%) 79.6 80.9 82.2 80.7 LDL cholesterol (mg/dL) 82.8 81.2 82.4 83.5 HDL cholesterol (mg/dL) 44.5 43.7 43.7 44.0 Triglycerides (mg/dL) 139 139 139 138 hsCRP (mg/L) 4.1 4.1 4.2 4.1 CANTOS - Baseline Clinical Characteristics

Ridker ESC 2017 Percent Change from Baseline (median) hsCRP LDLC HDLC TG Placebo Canakinumab 50 Canakinumab 150 Canakinumab 300 Months

CANTOS: Dose-Dependent Effects on Inflammatory Biomarkers and Lipids (48 Months) Placebo SC q 3 mth Canakinumab 50mg SC q 3 mth Canakinumab 150mg SC q 3 mth Canakinumab 300mg SC q 3 mth

Ridker PM et al. N Engl J Med. 2017;377:1119-31

Canakinumab SC q 3 months Placebo (N=3347) 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) P-trend Primary Endpoint IR (per 100 person years) HR 95%CI P 4.5 1.0 (referent) (referent) Secondary Endpoint IR (per 100 person years) HR 95%CI P 5.1 1.00 (referent) (referent) CANTOS: Primary Clinical Outcome Effects on MACE and MACE +

Ridker ESC 2017

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Canakinumab SC q 3 months Placebo (N=3347) 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) P-trend Primary Endpoint IR (per 100 person years) HR 95%CI P 4.5 1.0 (referent) (referent) 4.1 0.93 0.80-1.07 0.30 3.9 0.85 0.74-0.98 0.021* 3.9 0.86 0.75-0.99 0.031 0.020 Secondary Endpoint IR (per 100 person years) HR 95%CI P 5.1 1.00 (referent) (referent) 4.6 0.90 0.78-1.03 0.11 4.3 0.83 0.73-0.95 0.005* 4.3 0.83 0.72-0.94 0.004 0.003 *Statistically significant, adjusted for multiplicity, in accordance with the pre-specified closed-testing procedures CANTOS: Primary Clinical Outcome Effects on MACE and MACE +

Ridker ESC 2017

Placebo SC q 3 months Canakinumab 150/300 mg SC q 3 months

HR 0.85 95%CI 0.76-0.96 P = 0.007

Ridker PM et al. N Engl J Med. 2017;377:1119-31

Cumulative Incidence (%) Follow-up Y ears

CANTOS: Primary Cardiovascular Endpoints

HR 0.83 95%CI 0.74-0.92 P = 0.0006

MACE MACE - Plus

2 3

Follow-up Y ears

35 - 40% reductions in hsCRP and IL-6 No change in LDLC

1 4 5

Cumulative Incidence (%)

1 2 3 F o l lo w - u p Y e a rs 4 5

0.0 0.0 5 0.1 0.1 5 0.2 0.2 5 e Inc ide nc ive Cu mul at

C o n f i r m e d M A C E + U rg e n t R e v a s c b y M e d i a n 3 M o n t h h s C R P P l a c e b o > = 1 . 8 m g / L < 1 . 8 m g / L Placebo Canakinumab (on treatment hsCRP < median) Canakinumab (on treatment hsCRP > median) HR (95%CI) P 1.0 (referent) (referent) 0.95 (0.84-1.08) 0.47 0.73 (0.63-0.83) 0.0001

Cumulative Incidence (%)

HR 0.73 95%CI 0.63-0.83 P=0.0001

for those with reductions in hsCRP > median at 3-months (1.8 mg/L)

CANTOS: Greater Risk Reduction Among Those With Greater hsCRP Reduction (MACE+) Canakinumab SC q 3 months Endpoint Placebo (N=3347) 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) P-trend Primary 1.00 0.93 0.85 0.86 0.020 Secondary 1.00 0.90 0.83 0.83 0.002 Myocardial Infarction 1.00 0.94 0.76 0.84 0.028 Urgent Revascularization 1.00 0.70 0.64 0.58 0.005 Any Coronary Revascularization 1.00 0.72 0.68 0.70 <0.001 Stroke 1.00 1.01 0.98 0.80 0.17 Cardiac Arrest 1.00 0.72 0.63 0.46 0.035 CV Death 1.00 0.89 0.90 0.94 0.62 All Cause Mortality 1.00 0.94 0.92 0.94 0.39 CANTOS: Consistency of HRs Across All Cardiovascular Endpoints

Ridker ESC 2017

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0.5 1.0 Canakinumab Superior Canakinumab Inferior 0.5 Canakinumab Superior Canakinumab Inferior 1.0 Group Women Men Age < 60 yrs Age > 60 yrs Diabetes No diabetes Non Smoker Smoker BMI < 30 kg/m2 BMI > 30 kg/m2 LDLC < 80 mg/dL LDLC > 80 mg/dL hsCRP < 4 mg/L hsCRP > 4 mg/L HDLC > 45 mg/dL HDLC < 45 mg/dL TG < 150 mg/dL TG > 150 mg/dL Overall

MACE MACE + CANTOS: Consistency of Effect Across All Patient Groups

Ridker ESC 2017

Canakinumab SC q 3 months Adverse Event Placebo

(N=3347)

50 mg

(N=2170)

150 mg

(N=2284)

300 mg

(N=2263)

P-trend Any SAE 12.0 11.4 11.7 12.3 0.43 Leukopenia 0.24 0.30 0.37 0.52 0.002 Any infection 2.86 3.03 3.13 3.25 0.12 Fatal infection 0.18 0.31 0.28 0.34 0.09/0.02* Injection site reaction 0.23 0.27 0.28 0.30 0.49 Any Malignancy 1.88 1.85 1.69 1.72 0.31 Fatal Malignancy 0.64 0.55 0.50 0.31 0.0007 Arthritis 3.32 2.15 2.17 2.47 0.002 Osteoarthritis 1.67 1.21 1.12 1.30 0.04 Gout 0.80 0.43 0.35 0.37 0.0001 ALT > 3x normal 1.4 1.9 1.9 2.0 0.19 Bilirubin > 2x normal 0.8 1.0 0.7 0.7 0.34 CANTOS: Additional Outcomes (per 100 person years of exposure) * P-value for combined canakinumab doses vs placebo

Ridker ESC 2017

1 2 3 4 5 Follow-up Years 0.000 0.005 0.010 0.015 0.020 0.025 0.030 Cumulative Incidence

Lung Cancer

Placebo 50mg 150mg 300mg

Placebo Canakinumab 50 mg Canakinumab 150 mg Canakinumab 300 mg HR (95%CI) P 1.0 (referent) (referent) 0.77 (0.49-1.20) 0.25 0.61 (0.39-0.97) 0.034 0.33 (0.18-0.59) 0.00008

P-trend across groups = 0.0003 Cumulative Incidence (%) 0.0 1.0 2.0 3.0

CANTOS: Additional Non-Cardiovascular Clinical Benefits Incident Lung Cancer

Canakinumab 300 mg 67% reduction in incident lung cancer P =0.00008

Ridker ESC 2017

1 2 3 4 5 Follow-up Years 0.000 0.005 0.010 0.015 0.020 0.025 0.030 Cumulative Incidence

Fatal Lung Cancer

Placebo 50mg 150mg 300mg

Placebo Canakinumab 50 mg Canakinumab 150 mg Canakinumab 300 mg HR (95%CI) P 1.0 (referent) (referent) 0.71 (0.40-1.26) 0.24 0.64 (0.36-1.14) 0.13 0.23 (0.10-0.54) 0.0002

P-trend across groups = 0.0002 Cumulative Incidence (%) 0.0 1.0 2.0 3.0

CANTOS: Additional Non-Cardiovascular Clinical Benefits Fatal Lung Cancer

Canakinumab 300 mg 77% reduction in fatal lung cancer P =0.0002

Ridker ESC 2017

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1 2 3 4 5 Follow-up Years 0.000 0.005 0.010 0.015 0.020 0.025 0.030 Cumulative Incidence

All Fatal Cancer

Placebo 50mg 150mg 300mg

Placebo Canakinumab 50 mg Canakinumab 150 mg Canakinumab 300 mg HR (95%CI) P 1.0 (referent) (referent) 0.86 (0.59-1.24) 0.42 0.78 (0.54-1.13) 0.19 0.49 (0.31-0.75) 0.0009

P-trend across groups = 0.0007 Cumulative Incidence (%) 0.0 1.0 2.0 3.0

CANTOS: Additional Non-Cardiovascular Clinical Benefits Cancer Mortality

Canakinumab 300 mg 51% reduction in death from any cancer P =0.0009

Ridker Lancet 2017

• Why does lowering inflammation impact cancer?

Grivennikov, Greten, Karin. Cell 2010;140:883-99.

Immunity, Inflammation, and Cancer

Sub-clinical chronic inflammation increases cancer risk (hsCRP is also a risk factor for certain cancers, in particular lung cancer) Inflammation in the tumor micro-environment impacts upon tumor initiation, progression, invasiveness, and metastatic progression

Ridker ESC 2017

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Charles A. Dinarello. Cancer Metastasis Rev 2010;29:317-329. Ron Apte, et al; Cancer Metastasis Rev. 2006;25:387-408. Anne Lewis, et al; J Transl Med. 2006;4:48.

Chronic Inflammation, Tumor Progression, and IL-1 Inhibition

Ridker ESC 2017

Lancet November 13 2017

Cumulative incidence of CV events in placebo group and in CKB groups Based on 3 month on treatment hsCRP above or below 2mg/L

• Inflammation and heart failure

Van Tassell BW Circulation 2013

IL-1 Pathway and inflammation also implicated in heart failure

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hsCRP and low EF are predictive of survival

Clin Cardiol. 2010;33(11):708-714 Am Heart J. 2004;147(5):931-938 hsCRP and LVEF<50% were independent predictors of adverse

• utcomes: HR 2.6 and 3.7

Elevated hsCRP at discharge associated with worse prognosis in setting of acute HF Van Tassell B et al Circ Heart Failure 2017 Redfield MM. N Engl J Med 2016; 375:1868

Inflammation also plays a role in HFpEF

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Koller L et al. Eur Heart J 2014;16:758

Myocardial relaxation and inflammation in HFpEF

Take home: C reactive protein, the preferred inflammatory CV biomarker, predicts cardiovascular mortality in patients with HFpEF

IL-1

Baseline 14 days 28 days Crossover Anakinra Placebo

Screening Tests

Anakinra Placebo

• 1. Chart review
• 2. CRP
• 3. Labs
• 1. CPX
• 2. CRP
• 3. Labs
• 1. CPX
• 2. CRP
• 3. Labs
• 1. CPX
• 2. CRP
• 3. Labs

Inclusion Criteria Symptoms and signs of congestive heart failure LVEF>50% and LVEDVi<97 ml/m2 Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness as shown by one of the following:

• LVEDP>16 mmHg at invasive measurement
• E/E’>15 at Tissue Doppler Echocardiography
• E/E’ 8-15 if one of the following conditions are present: LVH,LAE, atrial

fibrillation, E/A<0.5+DT>280ms

• BNP>200 pg/ml (not due to a concomitant disease such as pulmonary

arterial hypertension, pulmonary embolism, acute renal failure, or other) CRP> 2.0 mg/L Abbreviations: BNP=brain natriuretic peptide; CRP=C-reactive protein; LAE=left atrial enlargement; LVEDP=left ventricular end-diastolic pressure; LVEDVi= left ventricular end- diastolic volume index; LVEF=left ventricular ejection fraction; LVH=left ventricular hypertrophy

Am J Cardiol 2014 Take home: L-1 Blockade with anakinra reduced inflammatory markers and improved aerobic exercise capacity

• Inflammation and CVD: DM, HIV and RA

1 2 3

Quartile of IL-6

Pradhan et al JAMA 2001; 286:327-34

10 8 6 4 2 12 16 14 4 10 8 6 4 2 12 14 16 1 2 3

Quartile of hsCRP

4

Relative Risk IL-6 Relative Risk hsCRP

Fully adjusted BMI-adjusted Crude Women’s Health Study: Inflammation is also associated with an increased risk of developing diabetes

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Effects of IL-1β inhibition on inflammatory markers and fibrinogen (n=556 pts with DM and high CVD risk)

Ridker P et al Circulation 2012

HIV as a model of chronic inflammation

• HIV-infected individuals have excess rates/risk of CVD including

heightened arterial inflammation.

• Chronic inflammation persists in the setting of treated HIV

infection and is strongly predictive of CV risk and clinical events

• Strategies to lower inflammation in HIV have had mixed results

(either with ART or other interventions).

Freiberg M JAMA IM 2013, Subramanian S JAMA 2012; Hsue P JAHA 2012 Lancet 2013

Multiple factors cause persistent inflammation during ART

Deeks, Lewin, Havir; Lancet 2013

Low Dose Methotrexate and HIV

• Randomized double blinded placebo controlled study in treated

and suppressed HIV-infected individuals with CVD or 1 CV risk factor (N=176)

• Occurring simultaneously as the trial in uninfected pts with CVD
• Primary endpoints are safety, impact on inflammatory

markers/immune activation, and endothelial function with FDG- PET/CT in a subset

• Fully enrolled with followup completed, results to be presented at

CROI 2018

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IL-1β inhibition with canakinumab in HIV

• In this pilot study (n=10), a single dose of

canakinumab was well-tolerated in treated HIV- infected individuals

• Canakinumab significantly reduced inflammatory

markers (IL-6, hsCRP, and sCD163)

• A single dose of canakinumab did not impact T cell

activation or monocyte phenotypes (with exception

• f CCR5+ monocytes)
• Monocyte function was reduced which is consistent

with inflammatory marker findings

• Canakinumab significantly reduced arterial

inflammation and bone marrow activity

TARGET Study: Impact of Anti-Inflammatory TX in RA

Inflammation and CVD: 2017 Update Acknowledgements:

• ZSFG/UCSF: Peter Ganz, MD
• Nora Goldschlager, MD
• Steven Deeks, MD
• Jonathan Graf, MD
• Brigham and Women’s Hospital: Paul Ridker, MD
• Brigham and Women’s Hospital: Peter Libby, MD
• Virginia Common Wealth University: Benjamin Van Tassell, PharmD Antonio Abbate,

MD/PhD

Feel free to contact me with questions: Priscilla.hsue@ucsf.edu