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Artrite reumatoide come fattore
di rischio cardiovascolare
Marco Broggini
Delegato della Società Italiana di Reumatologia (SIR) per la Regione Lombardia
RA is associated with reduced life expectancy
Kaplan-Meier Survival Curves in a U.S. Population
Survival Probability
U.S. Females
U.S. Males
RA Females
RA Males
N = 886
SMR = 3.08
Years After Entry Into Study
SMR = standardized mortality ratio for patients with RA compared with non-RA controls.
Wolfe et al. Arthritis Rheum 1994; 37(4):481–94
Causes of death in RA:
CV mortality is increased in RA patients
1 - CV disease in RA has a higher case fatality than in the general
1 Goodson N et al. Ann Rheum Dis 2005; 64(11):1595–1601
2 - In a meta-analysis of 24 cohort studies, with 111,758 patients(2):
• 22,927 cardiovascular events were observed
• Mortality from CVD events was increased by 50% relative to nonRA control populations – SMR 1.50 (95% CI 1.39–1.61)
SMR: standardized mortality rates
2 Avina-Zubieta et al. Arthritis Rheum 2008; 59(12):1690–1697
CVD is the most prevalent extra-articular
and systemic manifestation in RA
Prevalence of ExRA and SysM by year
Hochberg MC et al. Current Medical Research and Opinion 2008; 24(2):469–480
The risk of myocardial infarction in RA patients is similar to
the risk in diabetes patients
CV events in RA patients, like in diabetes mellitus, have
a higher prevalence of silent ischemia and sudden death
Maradit-Kremers H et al. Arthr & Rheum 2005; 52(2):402–411
Lindhardsen J et al. Ann Rheum Dis 2011; 70:929–934
RA patients are at increased 10-year risk for CV
Estimated 10-year CV risk by age group
among RA patients and non-RA subjects
A retrospective populationbased cohort study with:
• 553 RA patients and 574
non-RA subjects free of
CVD at baseline
• Median follow-up time was
14.7 years for RA patients
and 16.1 years for non-RA
More than half of the newly diagnosed RA patients who were 50–59 years of age and all of
those >60 years of age had a >10% risk of CV disease within 10 years of their RA
Maradit-Kremers H et al. Arthr & Rheum 2008; 58(8):2268–2274
What are the classic CV risk factors?
• Advancing age
• Gender
• Family and personal history of CVD
– Elevated LDL-cholesterol
and/or low HDL-cholesterol
Sedentary lifestyle
Metabolic syndrome
Insulin resistance
Diabetes mellitus
These risk factors are separated
• Non-modifiable (age, gender,
family history)
• Modifiable (smoking, obesity,
hypertension, etc.)
Grundy SM et al. Circulation 1999, 100:1481-1492
Other risk factors that predispose to CVD
Ethnic characteristics
Psychosocial factors
Elevated triglycerides
Small LDL particles
Elevated homocysteine
Elevated lipoprotein(a)
Prothrombotic factors
(e.g., fibrinogen)
• Inflammatory markers
(e.g., C-reactive protein)
Grundy SM et al. Circulation 1999, 100:1481–1492
How can CV risk be assessed in routine
clinical practice?
Framingham Score
Reynolds Risk Score
However, the application of validated CV risk-scoring models to patients
with RA has been reported to underestimate their risk.
Grundy SM et al. Circulation 1999, 100:1481–1492
Conroy RM et al. Eur Heart J 2003; 24(11):987–1003
Available at
Dessein, PH et al. J. Rheumatology 2005 32:435–442
Mechanisms by which CV events can occur in RA
Firstly, the occurrence of CV classic
risk factors (such as diabetes mellitus,
dyslipidemia, and hypertension) might
be increased in patients with RA
Secondly, RA itself, particularly its chronic inflammatory
component, could be an independent CV risk factor, with a
greater burden of atherosclerosis and greater propensity
for atherothrombosis
Risk Factors
Events and
Other Factors
Finally, other factors (some
medications i.e. steroids,
immunologic factors i.e.
autoantibodies, genetic
factors) may have a negative
impact on CV risk
Del Rincon ID et al. Arthritis Rheum 2001; 44:2737–
2745 (modified)
Gonzalez A et al. Ann Rheum Dis 2008; 67:64–69
Dessein PH et al. J Rheumatol 2005, 32:435–442.
Cardiovascular diseases and their risk factors can be more
common in patients with RA than in matched controls
Age and sex-adjusted comorbidities of CV diseases
and risk factors among patients with RA and controls
† p < 0.01 for patients with RA vs controls
Data from an outcomes database between January 2001 and December 2002,
including 28,208 RA patients.
Han C et al. J Rheumatol 2006; 33;2167–2172
Classic CV risk factors are highly prevalent in RA
Patient characteristics in QUEST-RA study
• There was some variation between countries (less than 5% in Argentina and
France and greater than 10% in Finland, Germany, Poland, the UK, and the
• The overall prevalence for the whole cohort of lifetime myocardial infarction
was 3.2%, and the prevalence for stroke was 1.9%
• Overall prevalence of CV risk factors:
– Hypertension: 33%
– Hyperlipidemia: 14%
– Diabetes: 8%
– Ever-smoking: 43%
– Physical inactivity: 72%
– Obesity: 18%
Naranjo A et al. Arthritis Research & Therapy 2008; 10:R30
Obesity as a CV risk factor in RA
RA is associated with metabolic alterations that lead to reduction
in fat-free mass without any obvious change in total body weight.
Abnormal body composition phenotypes are overrepresented in RA
patients, especially in those within the ‘normal-weight’ BMI category(1)
The prevalence of overweight and obesity in RA, as assessed by the
general (WHO) BMI cutoff points, appears to be subject to geographical
variation, but appears to be similar to the general population(2)
Different from the general population, in patients with RA, low BMI
(<20 kg/m2) has been shown to be associated with a 3-fold increased
risk of CV death(3)
– Low BMI among people with RA may indicate uncontrolled active
systemic inflammation
Obesity is associated with the presence of other traditional CV risk
factors in patients with RA(4)
1 Giles JT et al. Arthritis Rheum 2008; 59:807–815.
2 Stavropoulos-Kalinoglou A et al. Rheumatology 2011; 50:450–462
3 Kremers HM et al. Arthritis Rheum 2004; 50;3450–3457
4 Stavropoulos-Kalinoglou A et al. Ann Rheum Dis 2009; 68:242–245.
Dyslipidemia in RA patients and CV risk
Hyperlipidemia (high total or low-density lipoprotein [LDL]-cholesterol)
appears to be less common in RA than in non-RA patients
– What is observed, though, is that patients with active untreated RA have
dyslipidemia with reduced total cholesterol (TC), LDL and high-density
lipoprotein cholesterol (HDL) levels, thereby increasing the atherogenic
index (i.e., the total cholesterol/HDL cholesterol ratio)(1–3)
Dyslipidemia in RA patients is associated with an increased CV risk
– TC was nearly significantly predictive for MI (HR 1.13 95% [CI 0.99 to 1.29],
p=0.07) and significantly predictive for future IS in RA (HR/SD 1.20 [95% CI 1.03
to 1.40], p=0.02)(1)
– A significant non-linear association for total cholesterol (TC) with risk
of CVD was found, with 3.3-fold increased risk for TC <4 mmol/l
(95% CI 1.5 to 7.2) and no increased risk of CVD for TC ≥4 mmol/l (p=0.57)(4)
In contrast, declines in inflammation may coincide with increases
in serum lipid values(5–8)
1 Semb AG et al. Ann Rheum Dis 2010; 69:1996–2001
2 Choy E et al. Ann Rheum Dis 2009; 68:460–469
3 Lazarevic MB et al. Semin Arthritis Rheum 1992; 22:172–178
4 Myasoedova E et al. Ann Rheum Dis 2011; 70:482–487
5 Steiner G et al. Semin Arthritis Rheum 2009; 38:372–381
6 Popa C et al. Ann Rheum Dis 2007; 66:1503–1507
7 Peters MJ et al. Ann Rheum Dis 2007; 66:958–961
8 Schimmel EK et al. Clin Exp Rheumatol 2009; 27:446–451
Physical inactivity in RA patients
Patients with RA would have a reduced level of physical activity
compared with the general population(1)
Patients with established RA as well as recent onset RA report
a reduced number of performed leisure activities(2–4)
A lower number of performed activities was found to be associated with
low education, higher age and more extensive disability (quantified
using the HAQ score)(3–4)
It is unknown the extent to which physical inactivity is associated
with an increased CV risk in RA patients
– There is extensive literature about this in the general population,
for example from the Framingham cohort(5)
1 Hootman JM et al. Arthritis Rheum 2003; 49:129–135
2 Eurenius E et al. Arthritis Rheum 2005; 53:48–55
3 Wikström I et al. Br J Occup Ther 2001; 64:87–92
4 Wikström I et al. Rheumatology (Oxford) 2006; 45:1162–1166
5 Franco OH et al. Arch Intern Med 2005; 165:2355–2360
Metabolic syndrome: increased prevalence associated with
RA in patients without clinical CV disease
* Non-RA percentages are presented raw and adjusted to age and sex distribution of RA subjects.
** Lipid measures were not available in 21 RA and 324 non-RA subjects.
*** Glucose measures were not available in 35 RA and 284 non-RA subjects. HDL: high-density lipoprotein cholesterol.
Crowson CS et al. J Rheumatol 2011; 38:29–35
Role of inflammation in atherosclerosis associated with RA
Libby P. Am J Med 2008; 121:S21–S31
Full LE & Monaco C. Cardiovascular Therapeutics 2011; 29:231–242
Inflammatory Markers of RA and CV Risk: ESR and CRP
Myasoedova E et al. Ann Rheum Dis. 2011;70:482-487.
CRP as an inflammatory marker and the risk of CVD
Increased carotid artery IMT and the presence of carotid plaque are
associated with CRP in patients with RA patients as well as in healthy
• Carotid artery intima-media thickness (IMT) and carotid plaque were measured using high
resolution ultrasound in 204 RA patients, and 102 age- and sex-matched healthy persons
• The relationship of the carotid artery IMT and carotid plaque to inflammation markers was
examined, adjusting for age, sex, RA versus control status, and the cardiovascular (CV)
risk factors hypercholesterolemia, systolic blood pressure, diabetes mellitus, and body
mass index (BMI)
Del Rincón I et al. Arthr & Rheum 2003; 48(7):1833–1840
Ridker PM et al. NEJM 1997; 336(14):973–979
Congestive hearth failure (CHF) in RA
Data suggest that RA patients are at an increased risk of developing
congestive heart failure (CHF) when compared with non-RA patients
– The clinical presentation and the outcome of CHF differ significantly between
patients with and those without RA, being more subtle, myocardial function is
more likely preserved, while mortality is significantly higher
– These findings emphasize the importance of more vigilant screening of patients
with RA for early signs of heart failure
This risk is increased among RA patients who are rheumatoid factor
(RF) positive, or have extraarticular manifestations
Gonzalez-Gay M et al. Semin Arthritis Rheum. 2005; Oct;35(2):132–133
Nicola PJ et al. Arthritis Rheum 2005; 52:412–420
Gonzalez-Juanatey C et al. Semin Arthritis Rheum 2004; 33:231–238
Davis JM 3rd et al. Arthritis Rheum 2008; Sep;58(9):2603–2611
• Long-term use of high dose steroids have considerable effects on blood
pressure, insulin resistance, lipid profile, body weight and fat distribution, which
might significantly increase CV risk
• It has been demonstrated that the CV risk associated with steroids is dosedependent
• In RA, the usually prescribed doses are below 10 mg/day. In low doses, the effects
are summarized as follows:
– Lipids: No negative impact
– Fat distribution: Significant increase in abdominal fat
– Diabetes and insulin resistance: Conflicting results, but there was a trend to
– Metabolic syndrome: No association
– Hypertension: An association was observed
– Early atherosclerosis: Conflicting results whether it can increase endothelial
– CV events: With low doses, there are conflicting results, but with a trend toward
an increased CV risk
• One can argue that the anti-inflammatory effects of steroids could have
cardioprotective effects, but could not be confirmed given the unfavorable
benefit-risk ratio essentially because of its safety profile
Ruyssen-Witrand A et al. Joint Bone Spine 2011; 78(1):23–30
MTX use and CV mortality
• Methotrexate (MTX) may provide a substantial survival benefit,
largely by reducing CV mortality,as observed by Choi, et al(1)
• Discontinuation of or non-response to MTX treatment was associated
with a much higher mortality [SMR 5.56 (95% CI 3.29–7.83) and 4.11
(95% CI 2.56–5.66), respectively] while those who continued and
responded to MTX the SMR was 1.64 (95% confidence interval [95%
CI] 1.11–2.17)(2)
– No adjustment for baseline disease severity was done
• There is some evidence that MTX may promote atherosclerosis in
patients who have already shown signs of atherosclerotic vascular
1 Choi HK et al. Lancet 2002; 359:1173–1177
2 Krause D et al. Arthritis Rheum 2000; 43:14–21
3 Landewe RB et al. Lancet 2000; 355:1616–1617
Anti-TNF treatment may exert an influence
at any step or path of the atherosclerosis
TNF has an impact on atherosclerosis:
• By worsening classic risk factors by promoting dyslipidemia and insulin resistance
• By upregulating adhesion molecules, leading to fatty streak formation
• By leading to plaque rupture as it is involved in this inflammation pathway
• By promoting thrombophilia,
encouraging thrombotic
• By modifying postischaemic
event repair by inflammatory
Dixon WG, Symmons DP.
Ann Rheum Dis 2007; 66:1132–1136
• MTX was associated with a 15% reduction in CV events,
18% reduction in MI and 11% reduction in stroke
• Anti-TNFs were associated with a 46% reduction in CV
events, 58% reduction in MI and 36% reduction in stroke
Naranjo A et al. Arthritis Research & Therapy 2008, 10:R30
The effect of RA treatment on the risk of MI: Increased
risk for some NSAIDs; decreased risk for anti-TNF therapy
• MI is increased in RA
• All COX-2 therapies increase the risk of MI in RA and non-RA patients, particularly in those with CVRF
• By contrast anti-TNF therapy decreases MI risk
Wolfe T et al. Arthritis Rheum 2007; 56
Suppl:S535. ACR 2007 #1340
RR (95% CI)
2.8. (1.9-4.2)
2.3 (1.3-4.2)
1.3 (1.0-1.6)
1.0 (0.7-1.5)
0.9 (0.7-1.2)
0.8 (0.5-1.2)
0.6 (0.3-1.4)
0.7 (0.5-0.9)
0.7 (0.6-1.0)
0.7 (0.5-1.1)
1.0 (0.8-1.4)
Anti-TNF therapy in RA and risk of acute MI (AMI), stroke and any cardiovascular
disease (CVD) events up to 7 years after treatment start – ARTIS
• To assess long-term risks in
anti-TNF-treated patients for
development of CVD events
• Subjects starting anti-TNF therapy
were from the Swedish Biologics
Register (ARTIS) (n=5299). For
each such subject, 4 matched
controls (n=21,084) were randomly
selected from the national RA
• Analyses were adjusted for disease
duration, co-morbidities (previous
hospitalization due to CVD,
diabetes, COPD), marital status,
hospital stays, and joint surgery at
entry to the study
• Outcomes: First hospitalisation
during follow-up with a main
diagnosis of any CVD, AMI or
Jacobsson LT et al. Arthritis Rheum 2008; 58 Suppl:S900.
ACR 2008 #1997
• Overall, 2778 CVD events, 492 AMI, and
338 strokes occurred during follow-up
• Anti-TNF therapy was not a risk factor for
CVD overall, although there were
indications of a lower occurrence of CVD,
AMI and stroke among women treated
with anti-TNF
• Response to anti-TNF therapy did not
emerge as a strong predictor of overall CVD
risk, although a non-significant tendency
towards a lower risk of stroke among
responders was noted
Meta-analysis with anti-TNF therapy
and CV events in RA : conclusion
• RA treatment with anti-TNF therapy is likely associated with
a reduced risk for all cardiovascular events, MI, and CVA
in observational cohorts
• There was heterogeneity among cohort studies and possible
publication bias
• RCTs demonstrated a trend toward decreased risk in CV events
Barnabe C et al. Arthritis Care & Research 2011; 63(4):522–529
Possible mechanisms by which anti-TNF therapy can
mediate and consequently lower CVD event rates
• No impact in classic risk factors (Hypertension, lipids,
glucose/insulin resistance, etc.)
• Coordinated reduction in other non-TNF cytokines, chemokines,
immune cells coordinating atherogenesis, atherothrombotic factors
• Improved physical function/fitness
• Associated with exposure to other medications that may be antiatherogenic or anti-atherothrombotic (Methotrexate)
• Associated with reduced exposure to other medications that may be
pro-atherogenic or pro-thrombotic (Glucocorticoids, certain NSAIDs)
EULAR recommendations on CV management (2011)
Peters MJL et al. Ann Rheum Dis 2010; 69:325–331
Role of Inflammation and Lipid Metabolism in Atherosclerosis
Libby P et al. Nature.2011;473:317-325
•Insulin resistance is increasingly recognized as an important cardiovascular
risk factor and is frequently seen in RA patients
•A relevant role is played by T cells in the initiation and perpetuation of adipose
tissue inflammation and consequently in the determinism of IR.
•Upregulation of proinflammatory adipocytokines and a downregulation of
leptin and adiponectin with a consequent decreasing of insulin-induced
glucose transport
•Immunotherapy targeted on T cells could be able to improve insulin resistance
indirectly, via reduced activation of adipose tissue infiltrating T cells
Ursini F et al. Clinical Rheumatol 2012
Effetti cardiaci del trattamento con abatacept
• Studi preclinici in vivo indicano che non c’è relazione diretta o indiretta tra
abatacept ed il sistema cardiovascolare
• Sulla base del peso molecolare di circa 100 kD, abatacept non dovrebbe
avere accesso ai canali ionici
• Non dovrebbe alterare le correnti ioniche o la selettività del canale come si
può verificare con molecole di farmaci di piccole dimensioni
Abatacept (BMS-188667) FDA 2005
Effetti cardiaci del trattamento con abatacept
• ASSURE (Abatacept Study of Safety in Use with other RA thErapies)
• Studio di fase III, multicentrico, randomizzato, in doppio cieco, controllato
verso placebo della durata di 1 anno
• Sono stati raccolti ed analizzati i dati sulla sicurezza di abatacept in
pazienti con AR ed affetti anche da altre patologie
• 1441 pazienti con AR trattati con più di un farmaco tradizionale e/o
biologico appartenente alla classe dei DMARDs approvati per la terapia
della AR per un periodo di almeno tre mesi
Effetti cardiaci del trattamento con abatacept
• Durante la fase di trattamento in doppio cieco, 5 pazienti nel gruppo
abatacept totale (0,5%) e 4 pazienti nel gruppo placebo totale (0,8%) sono
Cause di decesso nel gruppo abatacept:
 cardiopatia ipertensiva 2 giorni dopo la prima infusione,
 aterosclerosi coronarica e cardiopatia ischemica acuta 13 giorni dopo la 12a
 aterosclerosi centrale e aterosclerosi coronarica con stenosi focale
significativamente avanzata 7 giorni dopo la 13a infusione
 arresto cardiaco 29 giorni dopo la 12a infusione
 Causa di morte sconosciuta in paziente non sottoposto ad autopsia
Cause di decesso nel gruppo placebo
 CHF 55 giorni dopo la 7a infusione
 Arresto cardiopolmonare 37 giorni dopo la 14 a infusione
 arresto cardiaco 28 giorni dopo la 14a infusione
Effetti cardiaci del trattamento con abatacept
• Il numero di pazienti con scompenso cardiaco era troppo
basso (1-2%) per poter permettere di trarre conclusioni,
anche se la frequenza complessiva di SAEs e l'interruzione
per eventi avversi AEs sono state comparabili tra il gruppo
abatacept ed il gruppo placebo
Weinblatt M,et al . Arthritis Rheum 2006
Effetti cardiaci del trattamento con abatacept
(Abatacept in Inadequate responders to MTX)
(Abatacept Trial in Treatment Anti-TNF INadequate responders)
(Abatacept Study of Safety in Use with other RA therapies)
(Abatacept or infliximab versus placebo, a Trial for Tolerability, Efficacy
and Safety in Treating RA)
(Abatacept Researched in Rheumatoid arthritis patients with an
Inadequate anti-TNF response to Validate Effectiveness).
L’ esposizione cumulativa ha incluso 4149 pazienti
Hocheberg et al Ann Rheum. Dis 2010
Il tasso di incidenza di disturbi cardiaci non aumentava con una
crescente esposizione ad abatacept , così come non aumentava il
tasso di incidenza annuale dei disturbi cardiaci seri
Ruolo della IL-1 nelle malattie CV
Biological effect
proadhesive activity
corresponding mechanism
disease /
stimulation of adhesion promoting molecules
Kirii et al. 2003
atheromatous plaque destabilization
IL-1α, IL1β
upregulation of matrix metalloproteinases
Rajavashisth et al.
Galis et al. 1995
Shah et al. 1995
modulation of cholesterol plasma level
IL-1α, IL1β
SAA induction
Kamari et al. 2007
Merhi-Soussi et al.
stimulation of angiogenesis
IL-1α, IL1β
VEGF induction
Salven et al. 2002,
Voronov et al. 2003
vessel wall inflammation
IL-1α, IL1β
induction of inflammatory pathways through IL-1R I
Nicklin et al. 2000
induction of procoagulant activity
stimulation of tissue factor expression
myocardial infarction
Schwager and Jungi
tissue damage, disease aggravation
mediation of sterile inflammation
myocardial infarction
Chen et al. 2007
enhancement of adverse remodeling
modulation of collagen deposition
myocardial Infarction
Bujak et al. 2000
Murtuza et al. 2004
iNOS induction
Lim et al. 2002
Mikami et al. 1996
Nakano et al. 2001
myocardial dysfunction, disease
development of the disease
IL-1α, IL1β
Vicenova, Physiology
activation of
Eriksson et al. 2003
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