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]. Data are summarized in Table 2.


methotrexate group, failure to achieve this magnitude of risk reduction will not degrade the

Cardiovascular Safety of Anti-TNF and Non-TNF Biological Therapy in Patients with Rheumatoid Arthritis

http://dx.doi.org/10.5772/intechopen.76684

97

Data about other synthetic DMARDs are not consistent. Leflunomide has indirect positive effects on cardiovascular outcome through reducing disease activity, while its role in promoting hypertension is a potential limitation, particularly if high blood pressure is documented [1, 2]. Antimalarials, specifically hydroxychloroquine, are able to modulate lipid profile and to reduce the risk of diabetes, although rare cases of cardiomyopathy have been described [1, 2, 31, 33]. Finally, sulfasalazine seems to exert also protective effects, while further studies are

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

• The risk for future cardiovascular disease is increased due to not only metabolic effects, e.g., abnormal lipid metabolism, impaired glucose tolerance, insulin resistance, relative

• The cardiovascular risk is attenuated through rapid and salutary anti-inflammatory and

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 meta-

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 reconsi-

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

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

weight gain, or true obesity, but also glucocorticoid-induced hypertension.

immune inflammatory background of cardiovascular pathology [3].

3.2. Glucocorticoids enhance the cardiovascular risk in RA

anti-proliferative effects of corticosteroids.

dered once the disease outcomes have been achieved [6].

analyses [1, 2, 6, 31, 34].

RA [2, 6, 31, 35].

shape the cardiovascular risk by two competitive pathways [1, 2, 6, 31, 34]:

required to clearly define its role [2].

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

#### 3.1. Non-biologic DMARDs: methotrexate and non-methotrexate drugs (e.g., sulfasalazine, antimalarials, leflunomide) improve cardiovascular outcomes in RA

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 of classic immunosupressants remains still under debate.

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

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 decreased [1, 2, 31, 32].

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 methotrexate group, failure to achieve this magnitude of risk reduction will not degrade the immune inflammatory background of cardiovascular pathology [3].

Data about other synthetic DMARDs are not consistent. Leflunomide has indirect positive effects on cardiovascular outcome through reducing disease activity, while its role in promoting hypertension is a potential limitation, particularly if high blood pressure is documented [1, 2]. Antimalarials, specifically hydroxychloroquine, are able to modulate lipid profile and to reduce the risk of diabetes, although rare cases of cardiomyopathy have been described [1, 2, 31, 33]. Finally, sulfasalazine seems to exert also protective effects, while further studies are required to clearly define its role [2].
