2.2.2. RA activity and cardiovascular risk

Individual inflammatory parameters (erythrocyte sedimentation rate, ESR, and CRP), composite scores reflecting disease activity (such as disease activity score (DAS28) and clinical disease activity index (CDAI)), and disease severity (extra-articular disease) are commonly associated with cardiovascular complications in RA [1, 2, 22–28].

The link between systemic inflammation and cardiovascular outcomes persists even after adjusting according to classical risk factors (obesity, hypertension, hyperlipidemia) [1, 2, 20–22].

Thus, elevated CRP levels at the baseline and the duration of uncontrolled disease correlate with cardiovascular burden in RA [1, 2, 22–28], while very high disease activity over time or high disease activity at RA onset also contributes to the cardiovascular risk [22, 23]. Moreover, it seems that uncontrolled high disease activity promotes the highest risk of developing cardiovascular disease [1, 2, 21–28]. CRP also correlated with acute myocardial infarction, one of the central complications of early accelerated atherosclerosis in RA [1, 22, 23].

Clearly, low disease activity (DAS28 < 3.2) and remission (DAS28 < 2.6) are fundamental in preventing a 10-years risk of cardiovascular events (particularly fatal or nonfatal cases of cardiovascular disease) in RA [1, 22, 23, 29]. In fact, it seems that low stable disease activity is able to reduce the cardiovascular burden and is appropriate to attain a protective effect against cardiovascular disease in RA [1, 22, 23]. Similarly, clinical remission or the absence of inflammation may be associated with a reduced risk of cardiovascular disease in RA [1, 22, 23]; apparently, remission has no additional protective effect against cardiovascular risk profile compared with low disease activity [1, 2, 22, 23].

EULAR 2016 has recommended the use of a modified SCORE adapted for patients with RA, meaning SCORE multiplied by 1.5 irrespective of disease duration, seropositivity, or the

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According to EULAR recommendations [6], the assessment of RA patients should be adapted based on CV risk stratification and several individual factors such as change of specific antirheumatic medication [2, 6, 29, 30]. Thus, risk monitoring is warranted once every 5 years if the risk is low to moderate or more often if the patient has an intermediate and high risk or when adapting the therapeutic protocol [2, 6]. An interesting algorithm was recently adapted/ pro-

Cardiovascular risk stratification and further monitoring based on the risk class is essential in RA [1, 2, 6, 29, 30]. EULAR 2009 guidelines have proposed the assessment of the cardiovascular disease on an annual basis, except for patients classified as low risk or low disease activity

Updated EULAR 2016 guidelines released four new recommendations emphasizing the interval, scores, and protocol for cardiovascular disease screening [6]. Interestingly, cardiovascular risk assessment is no longer recommended annually but every 5 years or following a major change in the DMARD therapy (recommendation 2) [6]. Either local or national guidelines or SCORE are equally accepted for the calculation of CV risk (recommendation 3) [6]. Lipid profile comprising total cholesterol and its HDL fraction should be evaluated during stable

presence of systemic features [2, 6, 29, 30].

posed by Gualtierotti et al. (Figure 3) [2].

2.4. Recommendations for cardiovascular risk assessment in RA

Figure 3. Algorithm for cardiovascular risk assessment in RA (adapted from Gualtierotti [4]).

where the risk is typically monitored as 2–3 years [1–3, 6].

Thus, it becomes clear that the manipulation of inflammatory response and tight disease control [22, 23, 28] are able to prevent cardiovascular events in RA [3, 26].

#### 2.3. Cardiovascular risk assessment in RA

Different scores designed for the calculation of cardiovascular risk in general population (e.g., Framingham, SCORE, QRISK) underestimate the cardiovascular burden in patients with inflammatory rheumatic conditions, mainly RA [1, 2, 6, 29, 30]; thus, there is no standard or validated model for cardiovascular risk prediction in RA.

In EULAR 2009 has proposed to multiply by 1.5 points the SCORE risk for patients with RA if two out of three RA-related parameters are present: a disease duration more than 10 years, rheumatoid factor or ACPA positivity, and severe extra-articular manifestations [2, 6, 29, 30]. Despite good reliability, this score is not able to reclassify patients with RA in the adequate cardiovascular risk category [2, 6].

QRESEARCH Cardiovascular Risk Algorithm (QRISK) 2 is a prediction model including RA as a specific risk factor, multiplying with 1.4; it overestimates both nonfatal and fatal cardiovascular events [2, 6, 29, 30].

Cardiovascular Safety of Anti-TNF and Non-TNF Biological Therapy in Patients with Rheumatoid Arthritis http://dx.doi.org/10.5772/intechopen.76684 93

Figure 3. Algorithm for cardiovascular risk assessment in RA (adapted from Gualtierotti [4]).

Tight control of inflammation in RA by non-biologic and/or biologic antirheumatic medication

Individual inflammatory parameters (erythrocyte sedimentation rate, ESR, and CRP), composite scores reflecting disease activity (such as disease activity score (DAS28) and clinical disease activity index (CDAI)), and disease severity (extra-articular disease) are commonly associated

The link between systemic inflammation and cardiovascular outcomes persists even after adjusting according to classical risk factors (obesity, hypertension, hyperlipidemia) [1, 2, 20–22]. Thus, elevated CRP levels at the baseline and the duration of uncontrolled disease correlate with cardiovascular burden in RA [1, 2, 22–28], while very high disease activity over time or high disease activity at RA onset also contributes to the cardiovascular risk [22, 23]. Moreover, it seems that uncontrolled high disease activity promotes the highest risk of developing cardiovascular disease [1, 2, 21–28]. CRP also correlated with acute myocardial infarction, one

Clearly, low disease activity (DAS28 < 3.2) and remission (DAS28 < 2.6) are fundamental in preventing a 10-years risk of cardiovascular events (particularly fatal or nonfatal cases of cardiovascular disease) in RA [1, 22, 23, 29]. In fact, it seems that low stable disease activity is able to reduce the cardiovascular burden and is appropriate to attain a protective effect against cardiovascular disease in RA [1, 22, 23]. Similarly, clinical remission or the absence of inflammation may be associated with a reduced risk of cardiovascular disease in RA [1, 22, 23]; apparently, remission has no additional protective effect against cardiovascular risk profile

Thus, it becomes clear that the manipulation of inflammatory response and tight disease

Different scores designed for the calculation of cardiovascular risk in general population (e.g., Framingham, SCORE, QRISK) underestimate the cardiovascular burden in patients with inflammatory rheumatic conditions, mainly RA [1, 2, 6, 29, 30]; thus, there is no standard or

In EULAR 2009 has proposed to multiply by 1.5 points the SCORE risk for patients with RA if two out of three RA-related parameters are present: a disease duration more than 10 years, rheumatoid factor or ACPA positivity, and severe extra-articular manifestations [2, 6, 29, 30]. Despite good reliability, this score is not able to reclassify patients with RA in the adequate

QRESEARCH Cardiovascular Risk Algorithm (QRISK) 2 is a prediction model including RA as a specific risk factor, multiplying with 1.4; it overestimates both nonfatal and fatal cardio-

of the central complications of early accelerated atherosclerosis in RA [1, 22, 23].

control [22, 23, 28] are able to prevent cardiovascular events in RA [3, 26].

usually accounts for the improved lipid level [1, 2, 6, 7].

with cardiovascular complications in RA [1, 2, 22–28].

compared with low disease activity [1, 2, 22, 23].

2.3. Cardiovascular risk assessment in RA

cardiovascular risk category [2, 6].

vascular events [2, 6, 29, 30].

validated model for cardiovascular risk prediction in RA.

2.2.2. RA activity and cardiovascular risk

92 Newest Updates in Rheumatology

EULAR 2016 has recommended the use of a modified SCORE adapted for patients with RA, meaning SCORE multiplied by 1.5 irrespective of disease duration, seropositivity, or the presence of systemic features [2, 6, 29, 30].

According to EULAR recommendations [6], the assessment of RA patients should be adapted based on CV risk stratification and several individual factors such as change of specific antirheumatic medication [2, 6, 29, 30]. Thus, risk monitoring is warranted once every 5 years if the risk is low to moderate or more often if the patient has an intermediate and high risk or when adapting the therapeutic protocol [2, 6]. An interesting algorithm was recently adapted/ proposed by Gualtierotti et al. (Figure 3) [2].

#### 2.4. Recommendations for cardiovascular risk assessment in RA

Cardiovascular risk stratification and further monitoring based on the risk class is essential in RA [1, 2, 6, 29, 30]. EULAR 2009 guidelines have proposed the assessment of the cardiovascular disease on an annual basis, except for patients classified as low risk or low disease activity where the risk is typically monitored as 2–3 years [1–3, 6].

Updated EULAR 2016 guidelines released four new recommendations emphasizing the interval, scores, and protocol for cardiovascular disease screening [6]. Interestingly, cardiovascular risk assessment is no longer recommended annually but every 5 years or following a major change in the DMARD therapy (recommendation 2) [6]. Either local or national guidelines or SCORE are equally accepted for the calculation of CV risk (recommendation 3) [6]. Lipid profile comprising total cholesterol and its HDL fraction should be evaluated during stable disease or remission (recommendation 4) [6]. Finally, surrogate biomarkers for subclinical atherosclerosis such as plaques on Doppler carotid ultrasound are recommended for the extensive screening of the cardiovascular disease in RA patients [6].

Updated EULAR 2015/2016 guidelines for cardiovascular comorbidity in RA are listed below [6]: 1. Lowering the cardiovascular risk in RA largely relies on both early diagnosis and tight

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2. The cardiovascular risk reassessment is advised at least every 5 years or when major

3. EULAR endorses the application of risk assessment scores according to the general population such as systematic coronary risk evaluation (SCORE) or national guidelines for CVD

4. A systematic evaluation of lipid profile including non-fasting total cholesterol and lowand high-density lipoprotein fractions is mandatory to further mitigate the cardiovascular risk; however, measurements should be achieved during stable RA or in remission disease.

5. A correct estimate of the increased risk of cardiovascular events in RA encompasses for a

6. Surrogates of subclinical atherosclerosis and cardiovascular disease such as artery plaques identified by carotid ultrasound screening are useful to perceive the increased cardiovas-

7. Several protective measures, e.g., healthy diet, exercise on a daily basis, and smoking cessation, should underline the general approach of RA patients with raised cardiovascular risk.

8. New trends in treating hypertension and dyslipidemia with specific medication including antihypertensives and statins are widely recommended in patients with RA with such

9. Since both traditional nonselective NSAIDs and coxibs have an increased risk of developing cardiovascular toxicity in RA, these drugs are carefully proposed in such patients, especially in those with prior history of or at increased risk to develop further cardiovascular events (congestive heart failure, ischemic heart disease, peripheral arterial or cere-

10. If mandatory, long-term corticosteroids are managed to minimize the total dosage, with

3. Cardiovascular safety of non-biologic and biologic anti-rheumatic drugs

Evidence-based medicine provides key insights into the consequences of various classes of antirheumatic drugs on cardiovascular risk in RA, suggesting that TNF inhibitors (TNF-i) and methotrexate decrease the risk of such events, while corticosteroids and IL-6 receptor inhibition via tocilizumab exert a multifaceted intervention on cardiovascular outcomes [1, 2, 26, 31].

tapering as soon as remission or low disease activity is reached.

control of disease activity as well as the disease flares.

changes in DMARD therapy are specified.

modified risk score multiplied by 1.5.

risk evaluation.

cular risk in RA.

comorbidities.

brovascular disease).

Data are summarized in Table 2.

Recommendations for the management of CV risk in RA take into account three essential points [1, 2, 6, 14]: (i) control of disease activity meaning early diagnosis and dynamic choice of the antirheumatic drug starting with non-biologic DMARDs followed by biologic DMARDs, with or without glucocorticosteroids until reaching the therapeutic target (remission or low disease activity), (ii) non-pharmacological management of risk factors including smoking cessation, adequate level of physical activity, as well as healthy diet, (iii) pharmacological management of risk factors comprising statins for lipid abnormalities, antihypertensives, antidiabetics, etc.

Optimized disease control within the so-called treat-to-target (T2T) strategy consistently improves the cardiovascular risk in RA, as remission and low disease activity become realistic goals [1, 2, 4, 6, 7]. Recent advances in the pathobiology of the disease and the link between inflammation, RA disease activity, and cardiovascular issues have highlighted the following [1, 2, 6, 7]: (i) disease duration is not an independent cardiovascular risk factor; (ii) disease activity, the number, and duration of flares significantly alter the CV risk; (iii) reducing inflammation obviously improves the CV outcomes; and (iv) long-term DMARD therapy results in lowering the CV risk.

Not only chronic persistent systemic as well as local inflammation and RA disease activity endorse excessive cardiovascular burden in RA but also traditional CV risk factors, e.g., body mass index, lipids, gender, tobacco smoking, and hypertension [1–3, 6].

Aggressive T2T approach in daily clinical practice for patients with RA proved successful in negatively impacted systemic and synovial inflammation, impair cytokine release, and promote quantitative and qualitative lipid changes, significantly decreasing the cardiovascular disease in such patients [1, 2, 6, 7]. Conversely, anti-inflammatory drugs (e.g., not only NSAIDs and COX-2 inhibitors but also steroids) are commonly associated with high cardiovascular safety issues [1, 2, 6].

Regardless of substantial progresses in RA treatment, patients develop and die considerably earlier than the general population mainly related to cardiovascular comorbidities, generally in connection with accelerated atherosclerosis and cardio-metabolic complication [1, 2, 13, 18, 21].

#### 2.5. 2016 EULAR recommendation for CV management

Since broad cardio-metabolic evaluation and optimal strategies for cardiovascular risk reduction are still poorly integrated in routine practice in autoimmune conditions [13, 18, 21], EULAR has recently updated guidelines for cardiovascular disease risk assessment and management in systemic inflammatory conditions including RA, psoriatic arthritis, and ankylosing spondylitis [6]. An extended EULAR task force has reconsidered the old guidelines and released new overarching principles and recommendations in accordance to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) statement suggesting an appropriate algorithm for cardiovascular risk management in these patients [6].

Updated EULAR 2015/2016 guidelines for cardiovascular comorbidity in RA are listed below [6]:

disease or remission (recommendation 4) [6]. Finally, surrogate biomarkers for subclinical atherosclerosis such as plaques on Doppler carotid ultrasound are recommended for the

Recommendations for the management of CV risk in RA take into account three essential points [1, 2, 6, 14]: (i) control of disease activity meaning early diagnosis and dynamic choice of the antirheumatic drug starting with non-biologic DMARDs followed by biologic DMARDs, with or without glucocorticosteroids until reaching the therapeutic target (remission or low disease activity), (ii) non-pharmacological management of risk factors including smoking cessation, adequate level of physical activity, as well as healthy diet, (iii) pharmacological management of risk factors comprising statins for lipid abnormalities, antihypertensives, antidiabetics, etc.

Optimized disease control within the so-called treat-to-target (T2T) strategy consistently improves the cardiovascular risk in RA, as remission and low disease activity become realistic goals [1, 2, 4, 6, 7]. Recent advances in the pathobiology of the disease and the link between inflammation, RA disease activity, and cardiovascular issues have highlighted the following [1, 2, 6, 7]: (i) disease duration is not an independent cardiovascular risk factor; (ii) disease activity, the number, and duration of flares significantly alter the CV risk; (iii) reducing inflammation obviously improves the CV outcomes; and (iv) long-term DMARD

Not only chronic persistent systemic as well as local inflammation and RA disease activity endorse excessive cardiovascular burden in RA but also traditional CV risk factors, e.g., body

Aggressive T2T approach in daily clinical practice for patients with RA proved successful in negatively impacted systemic and synovial inflammation, impair cytokine release, and promote quantitative and qualitative lipid changes, significantly decreasing the cardiovascular disease in such patients [1, 2, 6, 7]. Conversely, anti-inflammatory drugs (e.g., not only NSAIDs and COX-2 inhibitors but also steroids) are commonly associated with high cardio-

Regardless of substantial progresses in RA treatment, patients develop and die considerably earlier than the general population mainly related to cardiovascular comorbidities, generally in connection with accelerated atherosclerosis and cardio-metabolic complication [1, 2, 13, 18, 21].

Since broad cardio-metabolic evaluation and optimal strategies for cardiovascular risk reduction are still poorly integrated in routine practice in autoimmune conditions [13, 18, 21], EULAR has recently updated guidelines for cardiovascular disease risk assessment and management in systemic inflammatory conditions including RA, psoriatic arthritis, and ankylosing spondylitis [6]. An extended EULAR task force has reconsidered the old guidelines and released new overarching principles and recommendations in accordance to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) statement suggesting an

appropriate algorithm for cardiovascular risk management in these patients [6].

mass index, lipids, gender, tobacco smoking, and hypertension [1–3, 6].

2.5. 2016 EULAR recommendation for CV management

extensive screening of the cardiovascular disease in RA patients [6].

therapy results in lowering the CV risk.

94 Newest Updates in Rheumatology

vascular safety issues [1, 2, 6].

