ΡΕΥΜΑΤΙΚΕΣ ΝΟΣΟΙ

ΚΑΙ ΑΡΤΗΡΙΑΚΗ ΥΠΕΡΤΑΣΗ

Μ.Β.Παπαβασιλείου

Καρδιολόγος FESC

Διευθύντρια

Σισμανόγλειον ΓΝΑ

Clinical Hypertension Specialist ESH

ΔΗΛΩΣΗ ΣΥΜΦΕΡΟΝΤΩΝ

ΚΑΝΕΝΑ ΣΥΜΦΕΡΟΝ

Rheumatic disease is not a single

disorder

Rheumatic diseases encompass more

than 200 different diseases which

span from various types of arthritis to

osteoporosis and on to systemic

connective tissue diseases

Any organ system may be affected

EULAR

Rheumatology (Greek ρεύμα, rheuma, flowing current)

Basic Classification of the Rheumatic Diseases

A) Inflammatory Rheumatic Diseases

Diffuse connective tissue diseases• Rheumatoid arthritis (RA)

• Systemic lupus erythematosus(SLE)

• Systemic sclerosis (SS)

• Polymyositis (PM)-Dermatomyositis(DM)

• Sjőgren´s syndrome

• Vasculitides

Arthritis associated with spondylitis

(Spondylarthritis sero-negative)• Ankylosing Spondylitis (AS)

• Psoriatic Arthritis (PsA)

• Reactive Arthritis (ReA) (Reiter’s syndrome)

• Enteropatic arthritis –A.associated with inflammatory bowel Diseases

B. Degenerative Joint Disease (osteoarthritis)

C. Metabolic and Endocrine Diseases associated with rheumatic states(crystal induced arthropathy-gout, pseudogout)

D. Extraarticular disorders (low back pain, fibromyalgia)

E. Rheumatic syndrome associated with infectious agents

F. Bone and cartilage disorders (osteoporosis)

G. Others

Prevalence of autoimmune diseases:

The American Autoimmune Related Diseases Association, Inc

While the National Institutes of Health estimate that up to 23.5 million Americans suffer from autoimmune diseases,

AARDA puts the estimate at 50 million

Autoimmune disease is one of the top 10 leading causes of death in female children and women in all age

groups up to 64 years of age

Angylosing spondylitis f/m:1/4

Prevalence of rheumatic diseases

in central Greece BMC 2010

Osteoarthritis

The estimated prevalence of gout

across the world

Kuo, C.-F. et al.

Nat. Rev. Rheumatol. 2015

Prevalence of gout

in central Greece 4.71% f/m:0/8

BMC 2010

Image via ChildHealth-Explanation.com

Environmental toxins are a

major cause of autoimmune

disease

smoking

Atherothrombosis in the rheumatic diseases

Justin C. Mason, and Peter Libby Eur Heart J 2015;36:482-489

Pathogenesis of atherosclerosis in inflammatory rheumatic diseases

Justin C. Mason, and Peter Libby Eur Heart J 2015;36:482-489

Type I interferons

Immune dysregulation

and systemic

inflammation

Natural history of RA development

Holers VM Rheum Dis Clin North Am. 2014

Insights from Populations At-Risk for the Future

Development of Classified RA

Preclinical rheumatic disease

atherosclerosisCirculating disease-specific autoantibodies

Anti-citrullinated protein/peptide antibodies (ACPA)

inflammation is an important promoter of premature atherosclerosis in RA patients.

smoking

Systemic

Diseases of

Connective

Tissue

Schematic representation of the adventitious

"outside-in" paradigm in CVD

Daniel N. et al Hypertension. 2016

systemic inflammation

and endothelial

dysfunction

Reduction of NO production

in endothelial cells leads to

vasoconstriction, increased

production of ET-1 and

platelet activation

In RA, primary site of inflammation is synovial tissue, from which cytokines can be released into systemic circulation

Naveed Sattar et al. Circulation. 2003

How do

cytokines operate to

promote vascular

disease at the

molecular

level, and in which

tissues?

The answer likely

lies in the

pleiotropic functions

of cytokines,

because in addition

to their

role in regulating

immune responses,

cytokines mediate

numerous metabolic

effects

Relationship between changes in inflammatory and lipid parameters

Ernest Choy et al. Rheumatology 2014;53:2143-2154

HS-cTnT

ESR>60mm/h

Ang II in inflammation, immunity and RA

Chang Y, Wei W.

Clin Exp Immunol. 2015

The roles of Ang II on innate and adaptive immunity.

Ang II via AT1R signalling in immune cells contributes to the inflammatory

responses and activation of the immune system.

CRP is able to

up-regulate the

expression

of AT1 receptors

thus activating the

RAS

Comorbidities

Traditional and nontraditional risk factors

for CVD in RA

Amaya-Amaya J, et al Biomed Res Int. 2014;2014

Prevalence of evaluated comorbidities in the 3920 patients with RA

Maxime Dougados et al. Ann Rheum Dis 2014;73:62-68

COMORA: international, cross-sectional study

List of diseases, which are considered in 39 different

multimorbidity indices

Claudia Diederichs et al. J Gerontol A Biol Sci Med Sci 2011-311

Meta-analysis

in older people

Annemans, et al. Ann Rheum Dis 2008;67:960-966.

UK population German population

Comorbid conditions in two European

populations of patients with gout

ORs of individual studies and of pooled data for the association between

MetS and RAThe Risk of MetS in Patients with RA: A Meta-Analysis of Observational Studies

Jianming Zhang et al PLoS One. 2013;8(10):e78151.

S A Karvounaris, et al. Ann Rheum Dis. 2007

Correlation of DAS28 with the number of MetS

components present

N=200 RA

400 C

M Age 63y

Mediterranean

patients

Key soluble biomarkers that are associated with different stages of the atherosclerotic pathway in the MetS and RA

Lukasz Kozera et al. Rheumatology 2011;50:1944-1954

SAA: serum amyloid A;

PAI-1: plasminogen activator inhibitor-1.

Distribution of BMI categories among an Italian cohort

of adult autoimmune disease patients

Gremese,E et al Front Immunol. 2014

Cytokine-related link between obesity and chronic inflammation

Obesity is associated with increased levels of leptin, PAI-1, IL-6 and TNF-α

Anna Russolillo et al. Rheumatology 2013;52:62-67

Leptin and homocysteine distribution according to HTN

status and adjusted probability of HTN

Manavathongchai S, et al Rheumatol. 2013

Physical inactivity is most common among adults who have

both heart disease and arthritis

Physical inactivity among adults age ≥18 years, by arthritis and heart disease status

Data Source: Behavioral Risk Factor Surveillance System, United States, 2005 and 2007; as printed in:

Bolen J, Murphy L, Greenlund K, , Helmick CG, Hootman J, Brady TJ, Langmaid G, Keenan N. Arthritis as

a potential barrier to physical activity among adults with heart disease — United States, 2005 and

2007. MMWR 2009;58(7):165-169.

Venn diagram showing the number of overlapping

genes between psoriasis and its comorbidities

Sundarrajan S, et al PLOS ONE 2016

ATHEROSCLEROSIS

Atherosclerosis and chronic inflammatory disease

Katharina Andrea Schuett et al

Front Immunol. 2015;6:591.

descending

aorta severe inflammatory RA

Pasceri V Circulation 1999

Elaine Husni Cleaveland clinic 2010

Proportion of patients with carotid plaque according to ESR AUC category and the number of conventional CV risk

Churl Hyun Im et al. Rheumatology 2015;54:808-815

AUC: area under the curve

RA patients

Multivariable regression analysis with identified

covariables associated with cIMT

van Breukelen—van der Stoep DF, et al PLOS ONE 2015

PWV is high in SLE patients and correlates with SBP

Sacre K, et al PLOS ONE 2014

Increased Arterial Stiffness in SLE Patients at Low Risk for CVD:

A Cross-Sectional Controlled Study

Assessment of aortic stiffness B: 2D guided M-mode images of the mid descending

thoracic aorta in a 39 year old SLE patient with aortic

stiffness based on minimal change in aortic diameters

during systole and diastole

Roldan PC, et al Rheumatology (Sunnyvale). 2014

CVD

conventional risk

factors

Meta-analysis of the influence of diverse chronic

inflammatory conditions on multiple CV (stroke, CAD) and type 2 DM outcomes

Alex Dregan et al. Circulation. 2014;130:837-844

CV events prior to or early after diagnosis of SLEin the systemic lupus international collaborating clinics cohort

Multivariable logistic regression for the outcome of early MI

M B Urowitz et al. Lupus Sci Med 2016;3:e000143

The excess risk of CVD in RA seems to be comparable to the risk of CVD

conferred by DM2, suggesting that RA is also a CHD equivalent.

Cause‐Specific Mortality in Male US

Veterans With RA

England BR, et al Arthritis Care Res (Hoboken). 2016

Risk of CV mortality in patients with RA:

A meta‐analysis of observational studies

Aviña-Zubieta JA, et al Arthritis Rheum. 2008

N=111758

50% increased risk of

CVD death in patients with RA

HYPERTENSION

Hypertension pathways in RA

V. F. Panoulas et al. Rheumatology 2008;47:1286-1298

Immune

activation caused

by vascular

oxidation

promotes fibrosis

and HTN

Wu J, Saleh MA, et al

J Clin Invest. 2016

CV risks among rheumatic diseases.Prevalence of CV risk factors in RA, gout, OA, CTD,

PMR and CPS

Inger L. Meek et al. Rheumatology 2013;52:210-216

ORs in comparison with the general population.

chronic localized or generalized pain syndromes (CPSs

prevalence of HTN is estimated to 52–73%

Chronic Disease Risk Factors are Common

among Adults with Arthritis

Data source: National Health Interview Survey, 2007; as printed in: Murphy L, Bolen J, Helmick CG, Brady

TJ. Comorbidities Are Very Common Among People With Arthritis. Poster 43. 20th National Conference on

Chronic Disease Prevention and Control, CDC February 2009.

17/2/2017

Prevalence of HTN, hypercholesterolemia and AMI in the CIRD cohort

(Exp) and in the unexposed matched cohort (Unexp)chronic inflammatory rheumatic diseases (CIRD)

Castañeda S et al

Arthritis Rheum. 2015

N=2234 Exp

N=677 Unexp

CARMA ProjectHTN

HTN

Prevalence of BP levels under the studied conditions.

in the overall RA cohort as well as in the general population

of the ATTICA study

Protogerou AD, et al

Arthritis Res Ther. 2013

N=242

RA patients

Relative risk of MI in hypertensive RA patients versus those without

HTN using random effect model

Baghdadi LR, et al. PLOS ONE 2015

The Impact of Traditional CV Risk Factors on CV Outcomes in Patients with RA:

A Systematic Review and Meta-Analysis

Frequency of RA in strata defined by the quartiles of total

daily sodium intake and smoking exposure

Salgado E, et al

Medicine (Baltimore). 2015

Control of CV risk factors: proportion of patients in whom therapeutic

goals were met for treatment of HTN, dyslipidemia and diabetes

Chung CP, et al Semin Arthritis Rheum. 2012

N=197 RA

N=274 controls

Clusters of Disease in VA• National VHA data used to identify cohort aged 55 to 64

years in 2000 (N=741,847)

• ICD-9 codes used to identify presence of 11 chronic

conditions and mutually exclusive clusters created

Condition N (%) 5-Year

Mortality %

Hypertension + Diabetes 47,568 (6.4) 6.3

IHD + Hypertension 28,154 (3.8) 6.3

Hypertension + Osteoarthritis 23,692 (3.2) 2.9

IHD + Hypertension + Diabetes 19,161 (2.6) 11.1

Hypertension + COPD 11,883 (1.6) 12.2

Hypertension + Diabetes + Osteoarthritis 9,136 (1.2) 5.3

Feig DI, et al.

N Engl J Med 2008

Uric acid mediated hypertension

Grayson PC, et al. Arthritis Care Res (Hoboken) 2011;63(1):102-10.

Hyperuricaemia is related to incident HTN

Hyperuricaemia is associated with an increased risk for incident

HTN, independent of traditional HTN risk factors

Decreased Increased

Risk of hypertension

0 1 3

Chen JH, et al. Arthritis Rheum 2009;61(2):225-232.

HRs of hyperuricaemia on CV mortality

and all-cause mortality

(1)

(2)

CV mortality

all-cause mortality

Gout and CVD

Prevalence of CV risk factors in rheumatic and gout patients

and a sample of the general population

Adapted from: Meek IL, et al. Rheumatology 2013;52(1):210-6.

0

10

20

30

40

50

60

70

100

Hypertension Overweight Obesity Current

smoking

Pati

en

ts (

%)

66%

56%

72%

28%

17%26%

21%

62%

General population (n=4523)

Rheumatic outpatients (n=1233)*

*

*

*

* p<0.05

83%*

80

90

94%*

*48%

26%

Gout patients (n=129)

ADENURIC® is a trademark of Teijin Limited, Tokyo, Japan.

KIDNEY

Renal manifestations of systemic diseases commonly

seen by rheumatologists

Anders and Vielhauer Arthritis Research & Therapy 2011

(15-50%)

30-50% of patients will have clinical manifestations of renal

disease at the time of diagnosis: deposition of circulating immune complexes

Tubular abnormalities (60-80%)

(100%)

?

Aetna Database – Cohort-wide Incidence Rates(Events per 1,000 Patient-years, Unadjusted)

139

1 0.3

85

3

38

8

0

20

40

60

80

100

120

140

160

Even

ts/1

,000 P

Y

N=40594 RA: leflunomide, methotrexate

or another DMARD, including biologic

DMARDs

RA prevalence 0.63%

74% women

Age:51–64 y

81% on monotherapy

or 2 drug

combinations

Mechanisms through which drugs used in RA affect BP

V. F. Panoulas et al. Rheumatology 2008;47:1286-1298

PG: prostaglandin

Lef: leflunomide

Anti-rheumatic drugs and CV risk

Justin C. Mason, and Peter Libby Eur Heart J 2015

(5.0 mm Hg )

Predictive factors for HTN in CIRD subjects

Singwe-Ngandeu M et al Open Journal of Rheumatology and Autoimmune Diseases 2016

Chronic inflammatory rheumatic diseases (CIRD

Nonsteroidal anti-inflammatory drugs antagonized the antihypertensive

effect of b-blockers (BP elevation, 6.2 mm Hg) more than did vasodilators and diuretics

RAAS-b 20mmHg

CaCBs

Mortality

Emmert Roberts et al. Ann Rheum Dis 2016;75:552-559

Paracetamol: not as safe as we thought?

A systematic literature review of observational studies

Current Pharmaceutical Design

2012;18(11):1502-11

Therapeutic Advances Musculoskeletal Disease

Predicted probability of rapid IMT progression, according to the ESR,

stratified by: (A) use of methotrexate; (B) use of anti-TNF agents

del Rincón I, et al Ann Rheum Dis. 2015

erythrocyte sedimentation rate (ESR),

Typical PET/CT images before and after anti-TNF-α therapy.

Kaisa M. Mäki-Petäjä et al.

Circulation. 2012;126:2473-2480

Following anti-TNF-

α therapy, there

was a significant

reduction in mean

aortic TBRmax

The proportion of hot slices

was reduced (from 49.5±28.9

to 33.3±27.1%, P=0.03)

ETAN: etanercept (soluble TNF-a receptor inhibitor)

INFLIX : infliximal (TNF-a inhibitor)

Risks of CKD among RA patients treated with medications

Chiu HY, et al PLOS ONE 2015

Managing Hypertensive Patients With

Gout Who Take Thiazide

Joel Handler The Journal of Clinical Hypertension 2010

Effect of Allopurinol on Blood Pressure: A Systematic Review and Meta‐Analysis

Forest plot showing the effect of allopurinol on SBP

Agarwal V et al The Journal of Clinical Hypertension 2012

Effect of Allopurinol on Blood Pressure: A Systematic Review and Meta‐Analysis

Forest plot showing the effect of allopurinol on DBP

Agarwal V et al The Journal of Clinical Hypertension 2012

Forest plots illustrating the effect of different allopurinol cohorts on outcome

Rachael L. MacIsaac et al. Hypertension. 2016;67:535-540

>65 y

with HTN

N=2032 allopurinol-exposed

2032 matched nonexposed

rates of stroke

and cardiac events

Guidelines

RisksBenefits

Benefits of early DMARDs outweigh their risks

Yes DMARDs are safe when monitored regularly

E

A

R

L

Y

For all patients with RA

as evidence on the increased

CVD risk in patients

who are in the early stages of

RA, patients with a recent RA

diagnosis and patients without

extra-articular manifestations

EULAR recommendations for CVD risk management in patients with RA

and other forms of inflammatory joint disorders: 2015/2016 update

EULAR 2016

EULAR recommendations 2016

for gout: diagnosis

Zhang W, et al. Ann Rheum Dis 2006;65(10):1301-1311.

10

Risk factors and associated co-morbidity can be assessed

during the diagnosis of gout, including features of the metabolic

syndrome (obesity, hyperglycaemia, hyperlipidaemia, hypertension).

The Big Bang