The introduction of biologic drugs has considerably improved the outcome for patients with RA, but at the same time certain drugs, specifically the IL-6 inhibitors (i.e., tocilizumab), have been a source of controversy in terms of their effects on cardiovascular health, especially with regard to their effects on the lipid profile
[82][173]. A representative prospective study revealed that in patients undergoing tocilizumab therapy, serum concentrations of total cholesterol, LDL, HDL and triglycerides increased during the first 24 weeks of treatment
[83][174]. The results of several randomized clinical trials also showed increased LDL levels in tocilizumab-treated RA patients, of a magnitude greater than the increase seen in RA patients treated with conventional DMARDs
[84][85][175,176]. Nevertheless, recent studies have shown encouraging data regarding major adverse cardiovascular events with tocilizumab compared to other biologic DMARDs. Two studies conducted underscored a significant decrease in cardiovascular events with this drug
[86][87][177,178]. Zhang et al., revealed that tocilizumab reduced the risk of myocardial infarction significantly more than abatacept, another biologic DMARD
[86][177]. Kim et al. indicated better cardiovascular outcomes with tocilizumab when compared to TNFi
[87][178]. Furthermore, tocilizumab decreases inflammatory proteins such as serum amyloid A and may restore the anti-atherogenic function of HDL
[88][179]. Effects on HDL are observed directly in recent studies that found tocilizumab to increase HDL cholesterol efflux capacity in RA
[89][90][180,181]. Cholesterol efflux capacity is considered a strong negative ASCVD risk determinant
[91][182]. The atherogenic lipoprotein Lp(a) was also reduced by tocilizumab
[92][93][183,184].
3.2.5. JAK Kinase Inhibitors
JAK inhibitors, small molecules that target the JAK-STAT signaling pathway, are targeted synthetic DMARDs for the treatment of RA and other immune-mediated inflammatory diseases
[94][95][185,186]. Unlike the protein-based biologic DMARDs, the JAK inhibitors do not cause formation of anti-drug antibodies and can be taken orally
[96][187]. Unfortunately, the JAK inhibitors are associated with risk of venous thromboembolism and pulmonary embolism
[97][188]. The effect of these drugs on cardiovascular risk has not yet been determined as data is inconclusive. Charles-Schoeman et al. pooled data from multiple studies on the first generation JAK inhibitor tofacitinib showed low incidence of cardiac adverse events, comparable to that found with placebo
[98][189]. A further study by Charles-Shoeman with post hoc analysis, after 24 weeks of tofacitinib showed increased HDL levels which was associated with lower cardiovascular event risk
[99][190]. A long-term study over 9.5 years found incidence rates for major adverse cardiovascular event with tofacitinib of 0.4 with events per 100 patient-years, which is comparable to those seen with biologic agents
[100][191]. Upadacitinib, a newer and more selective JAK1 inhibitor, has shown comparable effects on cardiovascular risk to placebo and other JAK inhibitors. It raised both HDL and LDL while leaving the HDL-to-LDL ratio constant
[101][192].
Recent studies have demonstrated an increased risk of cardiovascular events in patients taking higher doses of JAK inhibitors. Th
is risk is enhanced for smokers. The overall e cardiac event risk from these drugs appears low, but more studies are in progress
[102][103][193,194].
3.2.6. HCQ: A Potential Double Agent
Despite its original intended purpose as an anti-parasitic agent, the therapeutic impact of HCQ extends beyond malaria to multiple autoimmune diseases in which it acts as an immunomodulator and its potential benefits continue to emerge
[25][104][105][106][118,195,196,197]. HCQ can improve the survival rates of patients with various autoimmune diseases including RA and systemic lupus erythematosus (SLE) via its immunosuppressive and anti-inflammatory activity
[107][108][109][198,199,200].
HCQ is a weak basic 4-aminoquinoline compound that differs from chloroquine by the placement of a single hydroxyl group
[106][107][197,198]. This subtle alteration decreases toxicity while conserving efficacy, rendering it safer and therefore preferable to chloroquine
[105][196]. The drug is administered orally, as a sulfate tablet, and appears to be well-tolerated, with efficient absorption, a large volume of distribution and bioavailability, as well as a prolonged half-life of about 40–50 days
[110][201]. Approximately 50% of HCQ remains plasma bound and is metabolized into three metabolites, desethyl-chloroquine, desethyl-hydroxychloroquine, and bis-desethyl-hydroxychloroquine, in the liver.
Although the exact mechanisms of action of this compound remain uncertain, it is postulated that immunosuppression results from its ability to block the stimulation of toll-like receptors, suppress T-cell proliferation, inhibit autophagy and reduce macrophage-mediated cytokine production and calcium signaling in B and T cells
[111][112][202,203]. Its atheroprotective attributes may be due to the reduction in circulating cytokines such as Il-1, IL-6 and TNF-α
[113][204].
In addition to its role as an anti-rheumatic drug, HCQ has anti-diabetic and cardioprotective capabilities. It improves glycemic control, positively impacts insulin sensitivity and metabolism, favorably influences the lipid profile and has anti-thrombotic and anticoagulant properties
[105][107][114][115][116][117][196,198,205,206,207,208]. In RA patients, HCQ improves microvascular endothelial function in RA
[118][209].
Additionally, HCQ is a favorable candidate for not only RA treatment but also the management of CVD in these patients as there are few contraindications and adverse effects. The most common side effects predominantly relate to the gastrointestinal issues, such as nausea, vomiting and diarrhea
[119][210]. Although rare, the possibility of developing retinal, neuromuscular, cardiac, and hematological impairments, including retinopathy, does exist
[120][211]. Despite its limited efficacy in the treatment of RA when used alone, HCQ’s utilization in combination therapies may have a significant impact on the cardiovascular risks associated with this rheumatic disease, thereby reducing the burden for both the individual and society
[121][212].