Artrite reumatoide come fattore di rischio cardiovascolare

Marco Broggini Delegato della Società Italiana di Reumatologia (SIR) per la Regione Lombardia

SMR = standardized mortality ratio for patients with RA compared with non-RA controls.

U.S. Females

U.S. Males

RA Females

RA Males

1.0

0.9 0.8 0.7

0.6 0.5 0.4 0.3

0.2 0.1 0.0

0 5 10 15 20 25 Years After Entry Into Study

Surv

ival

Pro

babi

lity

N = 886 SMR = 3.08

Kaplan-Meier Survival Curves in a U.S. Population

RA is associated with reduced life expectancy

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 population(1) 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 non-

RA 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

Year

The risk of myocardial infarction in RA patients is similar to the risk in diabetes patients

Maradit-Kremers H et al. Arthr & Rheum 2005; 52(2):402–411

1

CV events in RA patients, like in diabetes mellitus, have a higher prevalence of silent ischemia and sudden death

Lindhardsen J et al. Ann Rheum Dis 2011; 70:929–934

RA patients are at increased 10-year risk for CV disease

A retrospective population-based 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 subjects

Estimated 10-year CV risk by age group among RA patients and non-RA subjects

Maradit-Kremers H et al. Arthr & Rheum 2008; 58(8):2268–2274

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 diagnosis

What are the classic CV risk factors? • Advancing age • Gender • Family and personal history of CVD

• Smoking • Obesity • Hypertension • Dyslipidemia

– Elevated LDL-cholesterol and/or low HDL-cholesterol

• Sedentary lifestyle • Metabolic syndrome • Insulin resistance • Diabetes mellitus

Grundy SM et al. Circulation 1999, 100:1481-1492

These risk factors are separated into:

• Non-modifiable (age, gender, family history)

• Modifiable (smoking, obesity, hypertension, etc.)

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?

Grundy SM et al. Circulation 1999, 100:1481–1492 Conroy RM et al. Eur Heart J 2003; 24(11):987–1003 Available at http://www.reynoldsriskscore.org Dessein, PH et al. J. Rheumatology 2005 32:435–442

Framingham Score SCORE

However, the application of validated CV risk-scoring models to patients with RA has been reported to underestimate their risk.

Reynolds Risk Score

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

Finally, other factors (some medications i.e. steroids, immunologic factors i.e. autoantibodies, genetic factors) may have a negative impact on CV risk

CVD Events and

Mortality RA Classic

Risk Factors Increased

Atherogenesis

Other Factors

Increased Atherothrombosis

Chronic Inflammation

Mechanisms by which CV events can occur in RA

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 QUEST-RA

• 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 USA)

• 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

Patient characteristics in QUEST-RA study

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

subjects

Del Rincón I et al. Arthr & Rheum 2003; 48(7):1833–1840 Ridker PM et al. NEJM 1997; 336(14):973–979

• 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)

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

Steroids • 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 dose-dependent

• 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

increase – Metabolic syndrome: No association – Hypertension: An association was observed – Early atherosclerosis: Conflicting results whether it can increase endothelial

dysfunction – 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 disease(3)

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 events

• By modifying postischaemic event repair by inflammatory cytokines

Dixon WG, Symmons DP. Ann Rheum Dis 2007; 66:1132–1136

QUEST-RA

• 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

Conclusions: • 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

Treatment Category RR (95% CI) P-value

Rofecoxib RA & NID 2.8. (1.9-4.2) <0.001

Valdecoxib RA & NID 2.3 (1.3-4.2) 0.012

Celecoxib RA & NID 1.3 (1.0-1.6) 0.106

Naproxen RA & NID 1.0 (0.7-1.5) 0.947

Acetaminophen RA & NID 0.9 (0.7-1.2) 0.688

Ibuprofen RA & NID 0.8 (0.5-1.2) 0.302

Diclofenac RA & NID 0.6 (0.3-1.4) 0.275

Etanercept RA 0.7 (0.5-0.9) 0.015

Infliximab RA 0.7 (0.6-1.0) 0.026

Adalimumab RA 0.7 (0.5-1.1) 0.089

MTX RA 1.0 (0.8-1.4) 0.756

Wolfe T et al. Arthritis Rheum 2007; 56 Suppl:S535. ACR 2007 #1340

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

Objective: • To assess long-term risks in

anti-TNF-treated patients for development of CVD events

Methods: • 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 cohort

• 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 stroke

Results:

• Overall, 2778 CVD events, 492 AMI, and 338 strokes occurred during follow-up

Conclusions: • 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

Jacobsson LT et al. Arthritis Rheum 2008; 58 Suppl:S900. ACR 2008 #1997

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 anti-atherogenic 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

Abatacept

•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 deceduti.

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

infusione, 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

AIM (Abatacept in Inadequate responders to MTX)

ATTAIN (Abatacept Trial in Treatment Anti-TNF INadequate responders)

ASSURE (Abatacept Study of Safety in Use with other RA therapies)

ATTEST (Abatacept or infliximab versus placebo, a Trial for Tolerability, Efficacy

and Safety in Treating RA) ARRIVE (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

Biological effect cytokine corresponding mechanism disease /

disorder reference

proadhesive activity IL-1β stimulation of adhesion promoting molecules (VCAM-1) atherosclerosis Kirii et al. 2003

atheromatous plaque destabilization IL-1α, IL-1β upregulation of matrix metalloproteinases atherosclerosis

Rajavashisth et al. 1999 Galis et al. 1995 Shah et al. 1995

modulation of cholesterol plasma level IL-1α, IL-1β SAA induction atherosclerosis

Kamari et al. 2007 Merhi-Soussi et al. 2005

stimulation of angiogenesis IL-1α, IL-1β VEGF induction atherosclerosis Salven et al. 2002,

Voronov et al. 2003

vessel wall inflammation IL-1α, IL-1β induction of inflammatory pathways through IL-1R I atherosclerosis Nicklin et al. 2000

induction of procoagulant activity IL-1β stimulation of tissue factor expression myocardial infarction Schwager and Jungi 1994

tissue damage, disease aggravation IL-1α mediation of sterile inflammation myocardial infarction Chen et al. 2007

enhancement of adverse remodeling IL-1β modulation of collagen deposition myocardial Infarction Bujak et al. 2000 Murtuza et al. 2004

myocardial dysfunction, disease aggravation

IL-1α, IL-1β iNOS induction myocarditis

Lim et al. 2002 Mikami et al. 1996 Nakano et al. 2001

development of the disease IL-1β IL-12-mediated activation of autoreactive CD4+ cells

autoimmune myocarditis

Eriksson et al. 2003

Ruolo della IL-1 nelle malattie CV

Vicenova, Physiology Research (2009); 58: 481-498