3.2. Glucocorticoids enhance the cardiovascular risk in RA

3.1. Non-biologic DMARDs: methotrexate and non-methotrexate drugs (e.g., sulfasalazine,

Table 2. Cardiovascular profile of anti-rheumatic drugs: non-biologic and biologic DMARDs, corticosteroids, NSAIDs.

Drug Positive effects Negative effects Overall influence

Arterial hypertension May be responsible of cardiomyopathy although rarely

dyslipidemia, insulin resistance, hypertension All NSAIDs increase CV risk (prothrombotic effect)

Contraindicated in severe heart failure (class III/IV NYHA)

Abnormal lipids Complex effect

Methotrexate Improved RA activity High homocysteinemia Protective

Reduced inflammation May increase CV events, BMI,

on CV safety

Complex effect Protective

Protective

Complex effect Complex effect

Complex effect

Recent meta-analysis as well as real-life data showed that traditional synthetic DMARDs are able to reduce the cardiovascular risk in RA. However, the precise cardioprotective mechanism

Undoubtedly, methotrexate and non-methotrexate agents efficiently control inflammation and disease activity, alter the lipid spectrum and concentration, and are able to reduce the arterial

Furthermore, methotrexate, the drug of choice as first-line treatment, is associated with a consistent reduction in mortality (70%), a decline in the rate of total cardiovascular events (around 28%), and up to 18% lower risk of myocardial infarction in patients with RA [31]. Unlike the anti-TNF agents, methotrexate is not related to a significant decrease in strokes and major adverse cardiac events; nevertheless, it seems that the risk of heart failure is also

The interesting hypothesis of inflammatory origin of cardiovascular disease prompted the ongoing randomized Cardiovascular Inflammation Reduction Trial (CIRT) aiming to investigate whether low-dose methotrexate is able to decrease rates of heart attacks, strokes, and cardiovascular death among stable coronary artery disease patients with type 2 diabetes and/ or metabolic syndrome, conditions associated with an enhanced pro-inflammatory response [3]. Although the study was designed to perceive a 25% cardiovascular risk decline within the

antimalarials, leflunomide) improve cardiovascular outcomes in RA

stiffness, improving cardiovascular risk in different RA scenarios [1–32].

of classic immunosupressants remains still under debate.

Improved RA activity, improved lipid profile, reduced risk of diabetes

TNF inhibitors Improved RA activity, reduced insulin

Improved RA activity Safe in heart failure Safe in heart failure Safe in heart failure

resistance

96 Newest Updates in Rheumatology

decreased [1, 2, 31, 32].

Other csDMARDs Leflunomide Antimalarials

Non-TNF inhibitors Tocilizumab Rituximab Abatacept Tofacitinib

Corticosteroids

NSAIDs

The association between corticosteroids and the rate of total as well as individual cardiovascular events was systematically evaluated in patients with inflammatory rheumatic disorders, principally in RA and systemic lupus. It is widely accepted that corticosteroids are able to shape the cardiovascular risk by two competitive pathways [1, 2, 6, 31, 34]:


Their cardiotoxicity as well as cardiovascular mortality is dose-dependent (actual and previous cumulative dose) [1, 2, 6]. Sustained administration of corticosteroids classically accounts not only for an increased risk of myocardial infarction, stroke, and congestive heart failure but also for all major adverse cardiac events in RA patients as suggested by different studies and metaanalyses [1, 2, 6, 31, 34].

The well-known trend in RA is to maintain the lowest dose of corticosteroids for the shortest period of time and tapering as soon as remission or low disease activity (recommendation 10, EULAR 2016) [6]; the benefits of further administration should be deliberated and reconsidered once the disease outcomes have been achieved [6].

Although NSAIDs no longer represent the mainstay of RA therapeutic protocol, both nonselective and COX2-selective medications are still used, even if intermittently, during RA flares and in short-time administration [1, 2, 22, 23, 31, 35]. NSAID safety profile should be emphasized, as their effect on cardiovascular outcomes in RA is challenging. Both nonselective NSAIDs and coxibs increase the cardiovascular risk in general population; however, not all of them exert the same deleterious cardiovascular effect, especially talking about patients with RA [2, 6, 31, 35].

It is widely recognized that long-term NSAIDs increased the risk of all cardiovascular events and stroke in general population, particularly if cardiovascular disease is documented (congestive heart failure, ischemic heart disease, peripheral arterial disease, or cerebrovascular disease) [2, 6, 31]; only few studies have addressed the cardiovascular outcomes of COX2 selective and traditional NSAIDs specifically in RA [1, 2, 6, 31, 35].

In fact, the magnitude of coronary event risk reduction was reported irrespective of the baseline risk stratification (by gender, age, cardiovascular risk factors, disease duration), drug exposure, as well as the risk window [2, 31, 36, 37]. Additionally, the ability to achieve optimal control of RA activity instead of simply improved disease control or TNF-i per se theoretically

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Still considered the "black box" of TNF biologic class, the link between TNF blockade and moderate to severe congestive heart failure (class III/class IV NYHA) remains controversial [1, 2, 31, 36]. Clearly, heart failure in general population is associated with high TNF-α, with consistent correlation between serum levels and clinical significance and severity of cardiac failure [1, 31, 36]. However, TNF inhibitors are able to improve ventricular dysfunction in

Overall, TNF inhibitors significantly damper the cardiovascular comorbidity in RA, especially

Data about tocilizumab, a humanized monoclonal antibody acting against the IL-6 receptor (membrane-bound and soluble), and its cardiovascular toxicity are widely accessible from different clinical trials, including ADACTA, TOWARD, MEASURE, and ENTRACTE [38–41]. Although modest increases of LDL- and HDL-cholesterol as well as triglycerides were noticed in RA patients treated with tocilizumab in randomized controlled trials, only ENTRACTE was specifically designed to evaluate the cardiovascular safety and to compare net cardiovascular risk-benefit ratio of anti-IL-6 therapy with biologics with another mechanism of action, such as

As a potent inhibitor of IL-6 signaling, tocilizumab is associated with excellent clinical efficacy essentially related to patent decline in systemic inflammatory biomarkers; in addition, tocilizumab-associated altered lipid profile, mainly increased LDL-cholesterol, is broadly recognized and potentially connected with atherogenesis and atherothrombosis in patients with

Moderate elevations of LDL-cholesterol, HDL-cholesterol, and triglycerides were faced in RA patients under tocilizumab in phase II and phase III trials, but the atherogenic implications of

A summary of trials reflecting the cardiovascular safety profile of tocilizumab in RA comprises

ADACTA, a randomized clinical trial to evaluate tocilizumab monotherapy vs. adalimumab monotherapy for the treatment of RA, suggested that tocilizumab meaningfully decreases systemic inflammation as supported by low ESR and CRP levels and disease activity (DAS28, CDAI). Changes are obviously more evident as compared to adalimumab, a totally humanized monoclonal anti-TNF antibody; however, tocilizumab induces higher LDL-cholesterol levels

stabilizes the pattern of ischemic heart disease in RA [1–3, 31, 36, 37].

experimental models of cardiac failure [1, 2, 6, 31, 36, 37].

in patients declared responders to such therapies.

etanercept, in active seropositive RA [1, 2, 38–41].

these changes are still unsettled [1, 2, 38–41].

more than adalimumab do [39].

RA [1, 2, 3, 39–42].

the following:

3.4. Non-TNF DMARDs: tocilizumab

## 3.3. Biologic DMARD: TNF inhibitors decrease the cardiovascular risk in RA

TNF-α, a pivot pro-inflammatory cytokine involved in both systemic and local (synovial microenvironment) persistent inflammations in RA, may also alter lipid metabolism, insulin resistance, and endorse endothelial dysfunction [1, 2, 6, 31, 36, 37]. Moreover, chronic inflammation and atherosclerosis share common pathways, tailoring the basis of amplified cardiovascular risk in inflammatory rheumatic conditions [1, 2].

On the other hand, TNF inhibitors provide multifaceted influences on cardiovascular safety in patients with RA comprising [1, 2, 6, 31, 37]:


Thus, it seems that TNF inhibitors are efficient in reducing cardiovascular comorbidities in RA, comprising not only all cardiovascular events but also some specific stroke, myocardial infarction, and even MACE [1–3, 31, 36, 37].

A meta-analysis of several observational studies and registries in RA patients treated with TNF inhibitors performed by Roubille et al. showed a significant reduction in the risk of all cardiovascular events (up to 30%), myocardial infarctions, strokes, and major adverse cardiac events with biologics vs. non-biologic DMARDs [1–3, 31, 36, 37]. However, no significant effect on heart failure was detected [2, 31]. Interestingly, the risk of future cardiovascular consequences under anti-TNF medication is twice lower that the risk with non-biologic non-methotrexate drugs [1–3, 31, 36, 37].

Besides, Ljung et al. recently published their study investigating the effects of response to anti-TNF agents on short-term (1- and 2-year follow-up) risk of acute coronary syndrome in individuals with active RA and no previous ischemic or congestive heart disease before starting TNF-i as the first biologic agent [37].

RA patients classified as good (but not moderate) EULAR responders (improvement of more than 1.2 points in disease activity score) to anti-TNF therapy showed a 50% risk reduction of acute myocardial infarction or unstable angina pectoris or acute myocardial infarction as the underlying cause of death in short-term follow-up, similarly to the risk of acute coronary events in general population [1, 2, 6, 31, 36, 37].

In fact, the magnitude of coronary event risk reduction was reported irrespective of the baseline risk stratification (by gender, age, cardiovascular risk factors, disease duration), drug exposure, as well as the risk window [2, 31, 36, 37]. Additionally, the ability to achieve optimal control of RA activity instead of simply improved disease control or TNF-i per se theoretically stabilizes the pattern of ischemic heart disease in RA [1–3, 31, 36, 37].

Still considered the "black box" of TNF biologic class, the link between TNF blockade and moderate to severe congestive heart failure (class III/class IV NYHA) remains controversial [1, 2, 31, 36]. Clearly, heart failure in general population is associated with high TNF-α, with consistent correlation between serum levels and clinical significance and severity of cardiac failure [1, 31, 36]. However, TNF inhibitors are able to improve ventricular dysfunction in experimental models of cardiac failure [1, 2, 6, 31, 36, 37].

Overall, TNF inhibitors significantly damper the cardiovascular comorbidity in RA, especially in patients declared responders to such therapies.

#### 3.4. Non-TNF DMARDs: tocilizumab

disease) [2, 6, 31]; only few studies have addressed the cardiovascular outcomes of COX2-

TNF-α, a pivot pro-inflammatory cytokine involved in both systemic and local (synovial microenvironment) persistent inflammations in RA, may also alter lipid metabolism, insulin resistance, and endorse endothelial dysfunction [1, 2, 6, 31, 36, 37]. Moreover, chronic inflammation and atherosclerosis share common pathways, tailoring the basis of amplified cardio-

On the other hand, TNF inhibitors provide multifaceted influences on cardiovascular safety in

• Rapid and effective control of chronic inflammation signaling with significant decrease in inflammatory parameters (serum CRP levels and ESR), RA activity, and delay articular

• Changes in lipid pattern with increase in HDL-cholesterol fraction, total cholesterol, triglycerides with or without influence on LDL-cholesterol fraction, and with no major impact on the atherogenic index (TC/HDL); in fact, the trend of rising serum lipids under anti-TNF therapy typically reflects the stabilization through the lipid levels before the RA onset • Improvement of endothelial dysfunction and insulin sensitivity as well as the anti-

Thus, it seems that TNF inhibitors are efficient in reducing cardiovascular comorbidities in RA, comprising not only all cardiovascular events but also some specific stroke, myocardial infarc-

A meta-analysis of several observational studies and registries in RA patients treated with TNF inhibitors performed by Roubille et al. showed a significant reduction in the risk of all cardiovascular events (up to 30%), myocardial infarctions, strokes, and major adverse cardiac events with biologics vs. non-biologic DMARDs [1–3, 31, 36, 37]. However, no significant effect on heart failure was detected [2, 31]. Interestingly, the risk of future cardiovascular consequences under anti-TNF medication is twice lower that the risk with non-biologic non-methotrexate

Besides, Ljung et al. recently published their study investigating the effects of response to anti-TNF agents on short-term (1- and 2-year follow-up) risk of acute coronary syndrome in individuals with active RA and no previous ischemic or congestive heart disease before

RA patients classified as good (but not moderate) EULAR responders (improvement of more than 1.2 points in disease activity score) to anti-TNF therapy showed a 50% risk reduction of acute myocardial infarction or unstable angina pectoris or acute myocardial infarction as the underlying cause of death in short-term follow-up, similarly to the risk of acute coronary

selective and traditional NSAIDs specifically in RA [1, 2, 6, 31, 35].

vascular risk in inflammatory rheumatic conditions [1, 2].

patients with RA comprising [1, 2, 6, 31, 37]:

damage articular

98 Newest Updates in Rheumatology

oxidative response of HDL

tion, and even MACE [1–3, 31, 36, 37].

starting TNF-i as the first biologic agent [37].

events in general population [1, 2, 6, 31, 36, 37].

drugs [1–3, 31, 36, 37].

3.3. Biologic DMARD: TNF inhibitors decrease the cardiovascular risk in RA

Data about tocilizumab, a humanized monoclonal antibody acting against the IL-6 receptor (membrane-bound and soluble), and its cardiovascular toxicity are widely accessible from different clinical trials, including ADACTA, TOWARD, MEASURE, and ENTRACTE [38–41].

Although modest increases of LDL- and HDL-cholesterol as well as triglycerides were noticed in RA patients treated with tocilizumab in randomized controlled trials, only ENTRACTE was specifically designed to evaluate the cardiovascular safety and to compare net cardiovascular risk-benefit ratio of anti-IL-6 therapy with biologics with another mechanism of action, such as etanercept, in active seropositive RA [1, 2, 38–41].

As a potent inhibitor of IL-6 signaling, tocilizumab is associated with excellent clinical efficacy essentially related to patent decline in systemic inflammatory biomarkers; in addition, tocilizumab-associated altered lipid profile, mainly increased LDL-cholesterol, is broadly recognized and potentially connected with atherogenesis and atherothrombosis in patients with RA [1, 2, 3, 39–42].

Moderate elevations of LDL-cholesterol, HDL-cholesterol, and triglycerides were faced in RA patients under tocilizumab in phase II and phase III trials, but the atherogenic implications of these changes are still unsettled [1, 2, 38–41].

A summary of trials reflecting the cardiovascular safety profile of tocilizumab in RA comprises the following:

ADACTA, a randomized clinical trial to evaluate tocilizumab monotherapy vs. adalimumab monotherapy for the treatment of RA, suggested that tocilizumab meaningfully decreases systemic inflammation as supported by low ESR and CRP levels and disease activity (DAS28, CDAI). Changes are obviously more evident as compared to adalimumab, a totally humanized monoclonal anti-TNF antibody; however, tocilizumab induces higher LDL-cholesterol levels more than adalimumab do [39].

TOWARD trial, evaluating tocilizumab in combination with traditional DMARD therapy, revealed the role of IL-6 blockade not only in reducing articular and systemic inflammation but also in improving insulin resistance, along with its capacity to promote increased total cholesterol levels in up to one-fourth of cases [38].

ENTRACTE has demonstrated a relative increase in the incidence of cardiovascular events among severe active RA patients with a background of cardiovascular risk factors receiving tocilizumab, specifically the hazard of MACE. Additionally, the average level of LDLcholesterol was consistently higher under tocilizumab as compared with etanercept. Nevertheless, the cardiovascular issues with tocilizumab vs. etanercept should be deliberated/ interpreted in the context of its clinical efficacy and general, non-cardiovascular, safety profile.

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3.5. Other non-biologic and targeted DMARDs: rituximab, abatacept, and tofacitinib

biomarkers. Also, rituximab has no influence on arterial stiffness [1–3, 6, 7, 42].

alter the arterial tonus [1–3, 6, 7].

vascular risk factors, particularly diabetes.

cardiovascular burden in various RA settings.

warranted so as to improve cardiovascular outcomes in RA.

4. Conclusions

Conflict of interest

No conflict of interest declared.

• Abatacept, by blocking the T and B costimulation, commonly acts on lipid pattern resulting in high total cholesterol and its fractions (HDL-cholesterol and LDL-cholesterol), without a significant decrease in the atherogenic index; however, abatacept is known to

• Tofacitinib, a JAK inhibitor already approved for the management of RA, promotes similar changes in lipid profile as tocilizumab do, meaning an increase of both HDL-cholesterol and

Systemic autoimmune rheumatic conditions, specifically RA, are widely associated with excessive cardiovascular morbidity, with a magnitude similar to that related to traditional cardio-

A multifaceted dynamic interplay between chronic systemic inflammation, RA-specific issues, early accelerated atherosclerosis, and classic cardiovascular risk factors typically highlights the

The optimal strategy to identify patients at increased risk to develop cardiovascular disease as well as the correct assignment of different risk categories is mandatory in routine practice in every RA case. Furthermore, the selection of suitable medication (non-biological, TNF inhibitor, or non-TNF biological antirheumatic drug) according to cardiovascular toxicity is

LDL-cholesterol, with a minimal impact on atherogenic index [1–3, 6, 7, 43].

• Rituximab, a B-cell depletory agent, typically indicated as a second-line biologic therapy after failure of at least one anti-TNF agent, showed no significant differences as compared to placebo in terms of cardiovascular events. There is no cardiovascular safety concern related to rituximab; furthermore, it seems that rituximab is able to improve lipid metabolism, alter HDL-cholesterol to a low atherogenic profile, as well decrease prothrombotic

Tocilizumab may induce particular changes in lipid pattern, with potential relevance for cardiovascular safety. Persistent increase in mean fasting plasma lipids, within the normal range, is commonly reported with tocilizumab, together with a consistent decrease in serum CRP, suggesting that abnormal lipid levels may, in part, be related to significant decline in inflammation [38].

An increase in total cholesterol was observed in one out of five RA included in the study, while high LDL and altered HDL status from a pro-inflammatory to a significantly low inflammatory status (12 and 15%, respectively) increases of 30% in the total cholesterol:HDL-cholesterol ratio (12% cases) and more frequent in the LDL-cholesterol:HDL-cholesterol ratio (20%) were also reported. Finally, increases in the mean apolipoprotein A-I and apolipoprotein B, within the normal range, without changes in the ApoB:ApoA-I ratio were also commonly described. Only a limited number of patients initiated statin therapy during the study, with positive influence on lipid modifications [38].

MEASURE trial of tocilizumab effects on surrogates of vascular risk in RA was powered to demonstrate the modulation of lipid and lipoprotein particle (LDL, HDL, VLDL) levels and composition (HDL-associated serum amyloid A), alongside other surrogates of vascular risk (markers of coagulation, thrombosis, and vascular function) with IL-6 receptor inhibition vs. placebo in active disease [40, 41].

McInnes et al. [41] not only reported a dramatic decrease in inflammation in such patients but also demonstrated quantitative and qualitative changes in lipid metabolism profile. Overall, tocilizumab prompted the increase in total cholesterol, LDL-cholesterol, and triglycerides by week 12 of administration, while no significant influence on proatherogenic small LDL particle concentration, oxidized (ox)LDL, or HDL-cholesterol levels, in addition to ApoB:ApoA-1 ratio. Furthermore, tocilizumab-based IL-6 signal blockade altered the HDL particle composition toward a less pro-inflammatory phenotype [40, 41].

Besides, HDL-associated serum amyloid A, secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen, and D-dimers presented a sizeable decrease, while the antioxidant enzyme associated with HDL, paraoxonase, and level significantly increased under tocilizumab. Since a prothrombotic status heightened risk for cardiovascular events independently of established risk factors in general population, the reduction of thrombotic potential with tocilizumab in patients with active RA remains of considerable interest [40, 41].

However, the clear benefit of such modifications for cardiovascular risk is still debatable.

ENTRACTE, a randomized clinical trial aiming to evaluate cardiovascular events with either i. v. tocilizumab monthly or etanercept s.c weekly, was designed as a non-inferiority study comparing cardiovascular safety of tocilizumab vs. the TNF receptor, etanercept, in RA. Primary endpoint focused on major cardiovascular adverse events (MACE) (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke), while secondary endpoints were cardiovascular and non-cardiovascular safety of both drugs [1–3].

ENTRACTE has demonstrated a relative increase in the incidence of cardiovascular events among severe active RA patients with a background of cardiovascular risk factors receiving tocilizumab, specifically the hazard of MACE. Additionally, the average level of LDLcholesterol was consistently higher under tocilizumab as compared with etanercept. Nevertheless, the cardiovascular issues with tocilizumab vs. etanercept should be deliberated/ interpreted in the context of its clinical efficacy and general, non-cardiovascular, safety profile.

#### 3.5. Other non-biologic and targeted DMARDs: rituximab, abatacept, and tofacitinib

