4. Conclusions

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

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

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.

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

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

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 car-

cholesterol levels in up to one-fourth of cases [38].

100 Newest Updates in Rheumatology

influence on lipid modifications [38].

placebo in active disease [40, 41].

toward a less pro-inflammatory phenotype [40, 41].

patients with active RA remains of considerable interest [40, 41].

diovascular and non-cardiovascular safety of both drugs [1–3].

Systemic autoimmune rheumatic conditions, specifically RA, are widely associated with excessive cardiovascular morbidity, with a magnitude similar to that related to traditional cardiovascular risk factors, particularly diabetes.

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

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 warranted so as to improve cardiovascular outcomes in RA.
