Cardiovascular risk in psoriasis:

Implications for your clinical

practice

Joel M Gelfand, MD, MSCE Medical Director, Clinical Studies Unit

Associate Professor of Dermatology and Epidemiology

Senior Scholar, Center for Clinical Epidemiology

and Biostatistics

Perelman School of Medicine

University of Pennsylvania

Disclosure statement

• I have been an investigator and/or consultant for

Amgen, Abbvie, Jansen, Merck (DSMB), Pfizer,

Lilly, Celgene, Coherus (DSMB), and Novartis

• This presentation is the sole work of Dr. Gelfand

Psoriasis: rapidly changing paradigms

Old Paradigm:

“Just a skin disease”

New paradigm:

“A systemic disease”

Mediating factors1

• Pathophysiology

Th1/17 inflammation (atherosclerosis, thrombosis, lipid metabolism)

Epidermal proliferation (↑uric acid, oxidative stress)

Angiogenesis (endothelial dysfunction)

• Treatment

Increase CV risk (e.g. cyclosporine, acitretin)?

Decrease CV risk (e.g. methotrexate)?

• Psychosocial impact

Depression, alcohol and smoking, lower socioeconomic status

Genes and loci

associated with

psoriasis,

diabetes and

CV diseases1

PSORS2/3/4

CDKAL1

ApoE4

TNFAIP32

Environmental

risk factors1

Smoking

Obesity

Psoriasis and co-morbidities paradigm

Azfar RS, Gelfand JM. Curr Opin Rheum 2008;20:416–422. CV: cardiovascular.

Well established comorbidities

of psoriasis • Heart Attack, Stroke, CV

death

• Metabolic syndrome (obesity,

insulin resistance, cholesterol

abnormalities, hypertension)

• Diabetes

• Psoriatic arthritis

• Mood Disorders (anxiety,

depression, suicide)

• Crohn’s Disease

• T cell lymphoma (rare)

Gelfand JM, et al. JAMA. 2006; 296:1735 Gelfand JM et al. JID 2006; 126:2194-201 Langan SM, et al. J Invest Derm. 2012; 132:556. Kurd SK Arch

Derm 2010;146:891-5 Armstrong AW, et al. J Hypertens. 2013; 31:433. Ma C, et al. Br J Dermatol. 2013; 168:486. Azfar RS, et al. Arch Dermatol. 2012;

148:995. Li W, et al. Am J Epidemiol. 2013; 175:402 Yeung H et al. JAMA Derm 2013;149:1173-9 Mehta NN, et al. Eur. Heart J. 2010; 31:1000 Najarian

DJ and Gottlieb AB JAAD 2003;48:805-21

Psoriasis and

CV Disease

publications

1978-2013

Emerging co-morbidities

• Sleep apnea

• Nonalcoholic steatohepatitis (NASH)

• Chronic obstructive pulmonary disease (COPD)

• Adverse infectious disease outcomes

• Chronic and end stage renal disease

• Peptic ulcer disease

Callis Duffin K et al JAAD 2009;60:604-8 Wakkee et al JAAD 2011; 65:1135-44 Van der Voort ET et al JAAD 2014;70: 517-24 Yeung H et

al. JAMA Derm 2013;149:1173-9 Yang YW et al Br J Derm 2011;165:1037-43

Risk of Cardiometabolic Disease in Patients

with More Severe Psoriasis

Clinical Significance: 1. Increased risk of MI, stroke,

cardiovascular death, diabetes

2. 5 years of life lost

3. 10 year risk of major CV event

attributable to psoriasis= 6%

4. Risk of cardiovascular disease in

patients with severe psoriasis similar to

risk conferred by diabetes

5. Patients treated for severe psoriasis are

30X more likely to experience MACE

(attributable to psoriasis) than to

develop a melanoma

1. Gelfand, J.M., et al. JAMA. 2006; 296:1735.

2. Gelfand, J.M., et al. J. Invest. Derm. 2009; 129:2411.

3. Mehta, N.N., et al. Eur. Heart J. 2010; 31:1000.

4. Mehta, N.N., et al. Am. J. Med. 2011; 124:775.e1-6.

5. Azfar R, et al.. Arch Derm 2012; 148:995-1000

Abuabara, K., et al. Br. J. Dermatol. 2010; 163(3):586

•Mortality Curve Mortality Curve

Outcome Adj. RR Mild Adj. RR Severe

MI1 1.05 1.5

Stroke2 1.06 1.4

CV Death3 Not done 1.6

MACE4 Not done 1.5

Diabetes5 1.11 1.5

Baseline prevalence of MI, cerebro and peripheral

vascular disease in iHOPE (N= 9000)

Yeung H et al. Psoriasis severity and the prevalence of major medical comorbidity. JAMA Derm 2013;149:1173-9

Odds R

atio

Comparison of cardiometabolic

outcomes: Psoriasis vs. RA

Ogdie A et al. Ann Rheum Dis. 2014 Jan;73(1):149-53.

Ogdie A et al. Ann Rheum Dis. 2014 Oct 28. pii: annrheumdis-2014-205675.

Dubreuil M et al Rheumatology 2014 Feb;53(2):346-52.

Metabolic problems start early:

Emerging pediatric data • Prevalence metabolic syndrome in

pediatric psoriasis =30% vs control 7.4%

(P<0.05)1

• Odds ratio of obesity in pediatric psoriasis2

– Overall: 4.3

– Mild: 3.6

– Severe: 4.9

1. Au SC et al Association between pediatric psoriasis and the metabolic syndrome JAAD 2012;66:1012-3

2. Paller AS et al. Association of pediatric psoriasis severity with excess and central adiposity: an international

cross-sectional study. JAMA Dermatol. 2013 Feb;149(2):166-76.

Psoriasis and cardiometabolic

disease: Mechanistic insights Metabolic and CV gene

expression > cycle and

inflammatory disease

categories in lesional vs non

lesional psoriasis biopsies

KC-Tie2 psoriasis skin

specific inflammation mouse

model demonstrates

development of aortic

inflammation and thrombosis

Wang Y, Gao H, Loyd CM, Fu W, Diaconu D, Liu S, Cooper KD, McCormick TS, Simon DI, Ward NL Chronic skin-specific inflammation promotes vascular inflammation and thrombosis J

Invest Dermatol. 2012 Aug;132(8):2067-75.

Suárez-Fariñas M, Li K, Fuentes-Duculan J, Hayden K, Brodmerkel C, Krueger JG. Expanding the psoriasis disease profile: interrogation of the skin and serum of patients with moderate-to-

severe psoriasis. J Invest Dermatol. 2012 Nov;132(11):2552-64.

Psoriasis is more than skin deep: results

from advanced FDG-PET/CT Imaging

• Psoriasis is associated with

increased vascular

inflammation independent of

traditional risk factors and

equivalent to 10 years of

aging

• Subclinical inflammation in

liver and joints

FDG-PET/CT: A reliable, dynamic and responsive

surrogate marker of cardiovascular risk

• FDG-PET measurement of

vascular inflammation is:

1. A marker of CD68+ macrophage

metabolic activity

2. Reliable

3. Predictive of future CV events

4. Responsive to CV risk factor

modification

• Psoriasis patients demonstrate

vascular inflammation equivalent

to 1 decade of aging > than

controls

Rudd et al. J Am Coll Cardiol. 2007 Aug 28;50(9):892-6 Tahara et al. J Am Coll Cardiol. 2006 Nov 7;48(9):1825-31. Rudd et al. Circulation. 2002 Jun 11;105(23):2708-11. Alavi et al. Clin Nucl Med. 2001 Apr;26(4):314-9 Lee et al. J Nucl Med. 2008 Aug;49(8):1277-82 Rominger et al. J Nucl Med. 2009 Oct;50(10):1611-20. Arauz et al. Clin Neurol Neurosurg. 2007 Jun;109(5):409-12. Mehta NN et al. Arch Derm 2011;147:1031-9.

Friedewald VE, et al. Am J Cardiol. 2008 Dec 15; 102(12):1631-43.

Kimball AB, et al. J Am Acad Dermatol. 2008 Jun;58(6):1031-42.

New Clinical Care Recommendations: Educate

and Screen for CV risk factors

Clinical Implications: Elevated

Cardiovascular risk in severe psoriasis

Standard Screening Recommendations

• Hypertension – Every 2 year if BP <120/80 mm Hg

– Every year if BP 120 to 139/80 to 89 mm Hg.

• Diabetes (Fasting plasma glucose, HbA1c, or OGTT) – Adults ≥ 45

– Adults BMI ≥25kg/m2 who have one or more additional RFs

– Repeat every 3 years

• Cardiovascular risk assessment: – Traditional risk factors every 4-6 years in patients 20-79

– Estimate 10 year risk in those 40 -79

US Preventative Services Task Force (HTN) 2007

American Diabetes Association Guidelines 2014 (Diabetes Care 2014;37:S5-S13)

ACC/AHA 2013 Guideline on the assessment of CV risk

CV risk factors are under screened and

under managed in psoriasis patients

• CDC US population data

indicates poor screening rates

for hypertension

– Severe psoriasis dermatology:

4%

– Non psoriasis/non

dermatology: 61%

• Danish psoriasis patients on

biologics were less likely to

receive pharmacotherapy for

established CV risk factors

P for trend = 0.02

51.6

53.9

50.6

56.5

59.5

44

48

52

56

60

NoPsoriasis

PsoriasisOverall

Mild(<2%)

Moderate(3-10%)

Severe(>10%)

Pre

vale

nce o

f U

ncontr

olle

d

Hypert

ensio

n (

%)

Takeshita, J et al. JAMA Dermatology 2014, 2014 Oct 15. doi:

10.1001/jamadermatol.2014.2094

Alamadari HS et al J Drugs Dermatol 2013;12:e14-9

Ahlehoff O Plos One 2012;7:e36342

1970: Silent Killer 2004: Secret Killer 2015: Visible Killer?

Should psoriasis be aggressively treated

to lower the risk of CV disease?

Q: Should psoriasis be aggressively treated

to lower the risk of CV disease?

A: We don’t know

• Observational data suggest methotrexate

and TNF inhibitors are lower the risk of

CV events

• Data do not yet exist to demonstrate a

protective effect of phototherapy,

apremilast, and ustekinumab on CV

events

Micha R et al. Am J Cardiol 2011;108:1362–1370.

Barnabe C et al. Arthritis Care Res (Hoboken) 2011;63:522–529

Prodanovich S et al. J Am Acad Dermatol 2005;52:262–267.

Wu JJ et al. Arch Dermatol 2012;148:1244–1250.

Ahlehoff O et al. J Int Med 2013;273:197–204..

Randomized Placebo Controlled Trials evaluating

impact of anti-inflammatory treatment on CV risk

• Vascular Inflammation in Psoriasis Trial (VIP) and

VIP-Ustekinumab – Does treatment with adalimumab or phototherapy lower vascular

inflammation and improve lipid metabolism in patients with moderate to

severe psoriasis? (NCT01553058)

– Does treatment with ustekinumab lower vascular inflammation and

improve lipid metabolism in patients with moderate to severe psoriasis

(NCT02187172)

• Cardiovascular Inflammation Reduction Trial

(CIRT) – Does methotrexate lower the risk of major vascular events in patients

with a history of MI and diabetes or metabolic syndrome?

(NCT01594333)

Screening Period Up to 180 days for treatment washout

Double-blind, placebo-controlled period

12 Weeks

96 Patients

FDG

PET

/CT

• FDG-PET scan • CV biomarkers

0 12 52 weeks

Key inclusion criteria:

BSA of ≥ 10%; PASI of ≥ 12% Diagnosis of Psoriasis > 6 months Candidate for systemic and phototherapy

n=32 Adalimumab

n=32 UVB

n=32 Placebo

Vascular Inflammation in Psoriasis (VIP & VIP-E)

FDG

PET

/CT

40 Weeks Adalimumab

52 Weeks Adalimumab FDG

PET

/CT

• FDG-PET scan • CV biomarkers

• FDG-PET scan • CV biomarkers • Randomization

Assessments every 4 weeks Assessments every 10 weeks

Open label period 40-52 Weeks

N=21 Placebo

N=21 Ustekinumab

Weeks 12 0 52 64

52 Weeks Ustekinumab

Screening

Period

Double-Blind Placebo-

Controlled Period Open Label Treatment Period

FD

G P

ET

-CT

FD

G P

ET

-CT

40 Weeks Ustekinumab

42 Subjects

FD

G P

ET

-CT

FD

G P

ET-C

T

• FDG-PET scan

• CV biomarkers

• Randomization

• FDG-PET scan

• CV biomarkers

• FDG-PET scan

• CV biomarkers

VIP-U Trial Schematic Ustekinumab vs Placebo

“. . . For the secret of the

care of the patient is in

caring for the patient.” – Francis W. Peabody October

21 1925

Psoriasis: Look beyond the skin

To refer patients for the VIP trials:

215-662-SKIN or SkinVIP@upenn.edu

Acknowledgements

Collaborators

D. Margolis, B. Strom,

A. Troxel, N. Mehta,

A. Van Voorhees

Post Docs

A. Neimann, R. Azfar, S. Langan,

A. Ogdie, J. Takeshita Z. Chiesa

Pre Docs

D. Shin, S. Kurd, N. Smith, E.

Dommasch, K Abuabara, S.

Wang N. Seminara, J. Wan, H.

Yeung, J. Chung

Coordinators

S VanderBeek, D. Leahy, R. Attor

• Funding through NIAMS

F32, K23, K24, RC1 and

NHLBI R01HL089744 and R01HL111293

• National Psoriasis

Foundation

• Dermatology Foundation

• American Skin Association

• Psoriasis Research

Association in memory of

Herman Beerman