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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 5, September/October 2018
AFRICA
319
somewhat neglected component of tobacco usage with regard to
pro-inflammatory activity. Recently, however, nicotine has been
reported to possess endothelial disruptive, pro-inflammatory
activity,
42
while exposure of isolated human blood neutrophils
to nicotine
in vitro
has been reported to activate NETosis,
which was augmented by the combination of nicotine with
either TNF-
α
or APCA.
43
In this same study, administration
of nicotine to mice was found to accelerate collagen-induced
arthritis, which was accompanied by increased systemic levels
of myeloperoxidase-DNA complexes, an
in vivo
surrogate of
NETosis.
43
Moreover, chronic inhalation of nicotine by mice has
been found to cause pulmonary injury associated with increased
expression of pulmonary cytokines and proteases, mimicking the
features of chronic obstructive pulmonary disease.
44
Notwithstanding a high content of heavy metal toxicants,
cured tobacco also contains high levels of pro-inflammatory
microbial products, particularly bacterial endotoxins.
10,45
Endotoxins, which are potent activators of vascular endothelium,
neutrophils, monocytes/macrophages and platelets, as well as
other types of immune/inflammatory and structural cells, have
also been implicated in the pathogenesis of atherosclerosis.
46,47
In this context, users of smokeless tobacco products may be
particularly vulnerable to the pro-atherogenic effects of tobacco-
derived endotoxins, since these are inhaled or ingested without
modification by the combustion of tobacco. The impact of
tobacco use in the context of RA disease progression and
associated co-morbidity is often neglected by both patient and
clinician, even though globally, a high percentage of patients
with RA continue to smoke.
10,48
Effects of disease-modifying anti-rheumatic
drug and cytokine-targeted therapies on clini-
cal and systemic indices of CVD in patients
with RA
Methotrexate (MTX) is the pivotal traditional disease
modifying anti-rheumatic drug (DMARD) and has a proven
track record for the cost-effective management of RA. In
addition, MTX increases total cholesterol (TC), low-density
lipoprotein cholesterol (LDL-C), high-density lipoprotein
cholesterol (HDL-C) and triglyceride levels in RA, which might
be attributed to the decrease in inflammation.
24
MTX treatment
has been found to reduce mortality rate in RA patients by 70%
and showed a decrease of 21% in total cardiovascular risk,
including myocardial infarctions, congestive cardiac failure and
strokes.
49
This information confirms the belief that if systemic
inflammation in RA is reduced, the risk for CVD is also reduced.
It is therefore important to achieve remission or low disease
activity as soon as possible, not only to achieve better structural
and functional outcomes, but also to reduce the risk of CVD in
these patients.
49
As alluded to above, TNF-
α
is pivotally involved in the
pathogenesis of RA and is one of the main targets in the
treatment of the disease. Anti-TNF biologics are now standard
in the treatment of refractory RA. The main agents used in this
group are etanercept, adalimumab, infliximab and golimumab.
Treatment of RA with anti-TNF biologics may decrease CVD
risk by inhibiting endothelial dysfunction, and the progression of
atherosclerosis by decreasing the expression of pro-inflammatory
cytokines and endothelial adhesion molecules.
No changes in the levels of LDL-C or the ratio between
HDL-C and TC were found with long-term treatment of RA
patients with these immunotherapies. However, evidence derived
from clinical studies shows that TNF inhibitors can reduce
the risk for cardiovascular events between 30 and 70% in RA
patients.
Non-TNF biologics such as tocilizumab (TCZ), tofacitinib,
rituximab, abatacept and anakinra act on different arms of the
immune system and also demonstrate clinical efficacy in RA,
but little is known about the effects of these drugs on CVD
morbidity and mortality rates. In this context, evidence from a
limited number of clinical studies has indicated that lipid profiles
tend to alter when RA patients are treated with these drugs, but
results are inconclusive and more research is needed.
50
An important albeit unanswered question is ‘can the
remarkable advances in the management of RA be used to
manage patients with non-RA associated CVD?’ In this context,
an unmet need in the management of patients with CVD is
subclinical or ‘residual’ inflammatory risk, despite addressing
other cardiovascular risk factors, in the management of patients
with CVD. The identification of inflammatory mediators or
other biomarkers associated with cardiovascular risk has the
potential to stratify at-risk patients and develop novel therapies
for CVD in general.
51
In this context, it is noteworthy that studies
in cholesterol-fed rats have demonstrated anti-atherosclerotic
effects of MTX,
52,53
while several clinical trials are currently
exploring the role of anti-rheumatic drugs such as MTX and
IL-1 antagonists as novel therapies for non-RA CVD.
54,55
Conclusion
Cardiovascular co-morbidity has a significant impact on overall
prognosis in the management of patients with RA. It is important
to emphasise that classical risk factors for CVD are common in
RA patients and their treatment is as important as in the general
population. Controlling disease activity with aggressive and
early introduction of conventional DMARDs with escalation to
targeted or biologic therapies if required will enable control of
inflammation and lower the CVD burden.
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