ΡΕΥΜΑΤΙΚΕΣ ΝΟΣΟΙ ΚΑΙ ΑΡΤΗΡΙΑΚΗ...
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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).
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