Current Pharmaceutical Design, 2012, 18, 1543-1555 1543

Adverse Cardiovascular Effects of Antirheumatic Drugs: Implications for Clinical

Practice and Research

Armen Yuri Gasparyan1,*, Lilit Ayvazyan2, Giuseppe Cocco3, and George D. Kitas1,4

1
Department of Rheumatology, Clinical Research Unit, Dudley Group NHS Foundation Trust (A Teaching Trust of University of Bir-
mingham, UK), Russell's Hall Hospital, Dudley, West Midlands, United Kingdom; 2Department of Medical Chemistry, Yerevan State
Medical University, Yerevan, Armenia; 3Medical Practice, Cardiology and Rheumatology Office, Rheinfelden, Switzerland; 4Arthritis
Research UK Epidemiology Unit, University of Manchester, Manchester, United Kingdom

Abstract: Clinical manifestations of most rheumatic diseases have changed over the past few decades, largely due to advances in thera-
pies targeting autoimmune and (auto)inflammatory pathways. Improvements in the management of rheumatic diseases have also now
brought to the fore the issue of comorbidities. It has become evident that the burden of cardiovascular morbidity and mortality is in-
creased in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and the spondyloarthropathies, amongst other conditions. As a
result, efforts have switched toward investigating the effects of conventional antirheumatic and new biologic agents on inflammation-
induced atherothrombosis. Evidence is accumulating suggesting a beneficial cardiovascular profile of some antirheumatic drugs, such as
methotrexate and hydroxychloroquine, but it also indicates the possibility of a variety of adverse events developing in the short- and
long-term. The aim of this review is to highlight cardiovascular adverse effects of the drugs widely used in the treatment of rheumatic
diseases. The literature search was performed through PubMed, the Cochrane Library, Scopus, and Web of Science databases using the
following terms: “antirheumatic drugs”, “inflammation”, “rheumatic diseases”, “cardiovascular diseases”, “adverse events”, “toxicity”,
“drug design”, and “drug interactions”. Adverse events ranging from infusion-related hypertension and myocardial ischemia, to restric-
tive cardiomyopathy and congestive heart failure have been reported in large trials and case series on most antirheumatic drugs. Clini-
cians should be alert of the wide variety of cardiovascular adverse effects of individual antirheumatic drugs, and should carefully monitor
blood pressure and markers of inflammation, thrombosis, myocardial ischemia, electrolytes, and lipid disturbances while administering
these drugs. Future prospective studies should specifically investigate the cardiovascular safety of most antirheumatic drugs as part of
mono- or combination therapy in relation to different dosage regimens, duration of therapy, age, and gender.
Keywords: Antirheumatic agents, monoclonal antibodies, rheumatic diseases, cardiovascular diseases, inflammation, risk factors, adverse
events.

INTRODUCTION morbidity and mortality in inflammatory rheumatic diseases [5-7].

Clinical manifestations and complications of rheumatic diseases
have changed over the past few decades, owing to the advances in
diagnostics and discovery of numerous drugs with targeted action
on autoimmune and inflammatory factors implicated in the patho-
physiology of these diseases. Subsequently, quality of life, func-
tional activity and long-term outcomes in patients with most in-
flammatory rheumatic diseases have greatly improved. In fact, con-
ventional disease-modifying antirheumatic drug (DMARD) therapy
has substantially decreased the prevalence of destructive rheuma-
toid arthritis (RA) and inflammatory amyloidosis [1]. Further im-
provements in the course of RA are expected with the advent of
biological agents suppressing synovial and systemic inflammation
poorly controlled by DMARDs [2]. Another relevant example is the
successful case of colchicine therapy in familial Mediterranean
fever (FMF), a common autoinflammatory disorder in the Mediter-
ranean region, which was frequently associated with renal amyloi-
dosis and premature death due to the end-stage renal failure before
introducing colchicine for prevention of flares in FMF [3, 4].
The changes in the landscape of antirheumatic therapies and
improvements in the management of rheumatic diseases with asso-
ciated aging of the patient populations have raised the issue of co-
morbidities. In particular, it has been shown that accelerated athero-
sclerosis, sharing pathophysiological features with classic inflam-
matory rheumatic diseases, such as RA and systemic lupus erythe-
matosus (SLE), leads to an increased burden of cardiovascular
*Address correspondence to this author at the Dudley Group NHS Trust,
Russell’s Hall Hospital, North Block, Clinical Research Unit, Dudley, West
Midlands, DY1 2HQ, United Kingdom; Tel: +44-1384-244842; Fax: +44-
1384-244808; E-mails: a.gasparyan@gmail.com;
armen.gasparyan@dgh.nhs.uk
To tackle the issue of cardiovascular comorbidities, a great deal of
effort has been invested towards investigating the effects of conven-
tional antirheumatic and new biologic agents on inflammation-
induced atherothrombosis [8]. Preliminary evidence has accumu-
lated suggesting a beneficial effect of the pharmacological suppres-
sion of inflammation on atherosclerotic cardiovascular comorbidity
[9, 10] and distinguishing methotrexate as a relatively safe antir-
heumatic drug and a promising antiatherosclerotic agent [11, 12]. In
a large, prospectively followed cohort of 41,885 patients with RA,
methotrexate monotherapy and even tumor necrosis factor alpha
antagonists (which are contraindicated in advanced heart failure),
substantially reduced risk of hospitalization for congestive heart
failure (Rate Ratio [RR] 0.8, 95% Confidence Interval [CI] 0.6-1.0
and 0.5, 95%CI 0.2-0.9, respectively) [13]. The list of antirheumatic
drugs with pleiotropic effects on atherogenesis in rheumatic dis-
eases is rapidly expanding [14], pending confirmation of their im-
pact on cardiovascular events in large, specifically designed trials.
In the mean time, data are accumulating on toxicity and diverse,
including cardiovascular, adverse effects of antirheumatic drugs
[15-18], which are not always reported in research studies and
sometimes are overlooked in clinical practice due to insufficient
awareness of their specific signs. A variety of causes are believed to
underlie these adverse effects, with polypharmacy, overdosage, and
unjustifiably long pharmacotherapy most commonly reported [19-
21].
The aim of this review is to highlight cardiovascular adverse
effects of drugs widely used in the treatment of rheumatic diseases.
SEARCH STRATEGY
We performed a literature search through PubMed, the Coch-
rane Library, Scopus, and Web of Science databases for English-
language sources using the following terms: “antirheumatic drugs”,

1873-4286/12 $58.00+.00 © 2012 Bentham Science Publishers

1544 Current Pharmaceutical Design, 2012, Vol. 18, No. 11
“inflammation”, “rheumatic diseases”, “cardiovascular diseases”,
“adverse events”, “toxicity”, “drug design”, and “drug interac-
tions”. Preference was given to the sources published in the past 5
years. Information on the currently used antirheumatic drugs and
their cardiovascular adverse effects was also obtained from the
open-access sources of the US Food and Drug Administration
Agency (FDA) [22].
BIOLOGIC AGENTS
Tumor Necrosis Factor (TNF)-
blockers
Elucidation of the critical role of TNF-
in the development and
progression of RA and other diseases has substantially altered
treatment strategies in current rheumatology practice [23, 24]. It has
been shown that TNF-
, a potent immunoregulatory and proin-
flammatory cytokine produced in large quantities by monocytes,
macrophages, and T-lymphocytes, activates nuclear factor kappaB
and other transcription factors of adhesion molecules, proteolytic
enzymes and other cytokines, and stimulates chemotaxis of neutro-
phils, thereby facilitating inflammation in the synovium and in
other tissues [25-27]. Remarkably, the agents targeting the TNF-

cascade are now recommended for administration even in early RA
and in conditions with low severity of inflammatory arthritis [28].
Anti-TNF-
agents neutralize soluble and/or membrane-bound
TNF, acting as monoclonal antibodies (human-mouse chimeric
antibody infliximab and fully humanized antibodies adalimumab,
golimumab, and certolizumab-pegol) or soluble receptor (fully
humanized TNF receptor-IgG1 fusion protein etanercept) [29].
Over the past decade, five anti-TNF-
agents have been approved
in the US and Europe for the treatment of RA: infliximab, etaner-
cept, adalimumab, certolizumab-pegol, and golimumab [30]. Some
of these drugs have also been successfully applied in the treatment
of psoriasis and psoriatic arthritis [31], ankylosing spondylitis [32],
juvenile idiopathic arthritis [33], inflammatory bowel disease [34,
35], non-infectious ocular inflammation, pyoderma gangrenosum,
Behçet disease (BD), and other vasculitides [36-38].
Based on the outcomes of numerous experimental and clinical
studies, TNF-
is viewed as a cytokine playing a crucial role in
rheumatic disease-associated endothelial dysfunction and acceler-
ated atherosclerosis [39, 40], justifying the use of anti-TNF-

agents for both suppressing activity of rheumatic diseases and de-
creasing cardiovascular burden. Most notably, evidence derived
from observational cohort studies and randomized controlled trials
has accumulated indicating benefits of anti-TNF-
therapies in
terms of reducing the incidence of MI, heart failure and cerebrovas-
cular events in RA [41-43].
However, despite the optimism over the cardioprotective effects
of anti-TNF-
agents, there have also been reports necessitating a
cautious approach to anti-TNF-
therapy in patients with estab-
lished cardiovascular disease and mild heart failure (New York
Heart Association [NYHA] I and II functional classes) and contra-
indicating the therapy in those with NYHA III and IV classes [44,
45]. Large prospective studies are warranted to distinguish determi-
nants of heart failure in RA cohorts exposed to different anti-TNF-

agents. This is particularly important in view of the data from the
large cohort study on 2,757 patients with RA treated with inflixi-
mab, etanercept, or adalimumab indicating that the incidence of
heart failure over a 3-year follow-up substantially increases in those
with high disease activity, concomitant glucocorticoid or cyclooxy-
genase (COX)-2 inhibitor therapy, while anti-TNF therapy itself
contributes to the risk non-significantly (adjusted Hazard Ratio
[HR] 1.66, 95%CI 0.67-4.1, P=0.28) [46].
Factors affecting cardiovascular safety of different anti-TNF-

agents vary. A prime factor, in this regard, is the route of the drug
administration, with acute infusion-related reactions constituting
rare but sometimes life-threatening events (eg, anaphylactic reac-
tions due to intravenously administered infliximab) [47]. A study
Gasparyan et al.
on 113 patients with RA treated with infliximab reported on hy-
potension, hypertension, and tachycardia in 3% of cases; these ef-
fects resolved within several hours following cessation of the infu-
sion [48]. Sporadic cases of acute coronary syndromes during in-
fliximab infusion have also been reported, warning that chest pain
and dyspnea during the infusion should be carefully evaluated to
rule out ischemic origin, even in the young patients [49, 50]. Addi-
tionally, case series of life-threatening tachy- and bradyarrhythmias
and complete heart block developing during or immediately after
infliximab infusion have been published, requiring ECG monitoring
and vigilance in patients with preexistent arrhythmias [51, 52].
Moreover, an earlier study on 150 patients with NYHA class III and
IV heart failure revealed that high doses of infliximab (10 mg/kg)
can substantially increase the risk of adverse cardiovascular events
in the short-term [53].
It should be acknowledged that there are differences in the level
of evidence on adverse effects of different biologic agents. More
robust is the evidence on the cardiovascular profile of infliximab,
the oldest agent in use. A recent systematic review, largely based on
observational studies on infliximab therapy in RA, found a deterio-
ration of lipid profile due to anti-TNF-
therapies: a statistically
significant increase of total cholesterol (TC), low-density lipopro-
tein-cholesterol (LDL-C), high-density lipoprotein-cholesterol
(HDL-C), and triglycerides (TG) [54].
Infliximab-induced immunosuppression may reactivate oppor-
tunistic infections (eg, Listeria monocytogenes) causing rare but
fatal myocarditis [55]. Infliximab and other anti-TNF-
drugs also
alter the clearance of apoptotic cells and production of autoantibod-
ies, raising levels of anticardiolipin and triggering arterial and ve-
nous thrombogenesis [56]. The risk of thrombotic events is further
increased in those on concomitant glucocorticoid, methotrexate, or
COX-2 inhibitor therapy [57].
Short-term safety of the subcutaneously administered etanercept
is more favorable than that of infliximab [58]. A placebo-controlled
study of a 16-week etanercept therapy in 535 patients with RA re-
ported a slightly higher incidence of serious cardiovascular events,
including MI and heart failure, in the etanercept vs. the placebo
group (4.9% vs. 2.9%), occurring on the background of multiple
cardiovascular risk factors [59].
Adalimumab, a recombinant humanized IgG1 monoclonal anti-
body with minimized antigenicity and high affinity to TNF-
, has
also demonstrated an enhanced profile. Large studies on adalimu-
mab therapy in psoriatic arthritis distinguished hypertriglyceridemia
(2.3%) [60] and hypertension (0.9%) [61] as most frequent adverse
cardiovascular events. It is, however, suggested that adalimumab
may have a more favorable lipid profile than infliximab, particu-
larly in the long-term [62].
Golimumab is a new fully human anti-TNF-
monoclonal anti-
body approved by the US FDA for the treatment of RA, psoriatic
arthritis, and ankylosing spondylitis in 2009 [63]. Its main advan-
tage is the subcutaneous administration once monthly, with efficacy
and safety comparable to that of other anti-TNF agents [64]. In one
of the several recent phase III studies on RA, golimumab demon-
strated relatively safe profile, and was even considered a first-line
drug for the treatment of methotrexate-naïve patients with early RA
[65]. It was also shown to be effective in patients with RA previ-
ously treated with one or more anti-TNF agents [66]. A systematic
review of the trials with 1,231 patients with RA treated with go-
limumab proved its efficacy, compared with placebo [67]. When
safety of golimumab, golimumab plus DMARDs, and placebo plus
DMARDs arms of the recent phase III trials compared, the com-
bined incidence of MI, angina, heart failure, hypertension, and car-
diac arrest was less frequent in RA patients treated with golimumab
alone, though there were no statistically significant differences
between the arms [68].
Adverse Cardiovascular Effects of Antirheumatic Drugs
Certolizumab-pegol is a novel subcutaneously administered
PEGylated human anti-TNF antibody, consisting of a Fab
fragment
and lacking Fc region, which yield the prolonged plasma half-life of
2 weeks and enhanced safety in terms of autoimmune reactions. It
has demonstrated clinical efficacy and safety in patients with RA
and Crohn disease [69-71]. In a multicenter phase III trial with
more than 600 patients with RA, hypertension was among the most
frequently reported adverse events, particularly in those exposed to
high dose of certolizumab-pegol (2.4% and 3.7% in groups with
200 mg and 400 mg, respectively) [72]. It was, however, empha-
sized that these events are transient and closely related to preexis-
tent hypertension. A recent analysis of the results of placebo-
controlled phase III trials proved that certolizumab plus
methotrexate and certolizumab monotherapy are safer in terms of
cardiovascular events than respective comparators [73].
T-cell Costimulatory Modulation with Abatacept
Abatacept is a recombinant, fully human soluble fusion protein,
comprised of the cytotoxic T-lymphocyte associated antigen-4
(CTLA-4, CD152) immunoglobulin and a fragment of the Fc do-
main of human IgG-1. It is the first in a new class of intravenously
administered selective costimulation modulators [74]. The drug
modulates costimulation of T-lymphocytes and disrupts subsequent
activation of B-lymphocytes and macrophages, with a resultant
decrease of proinflammatory cytokines and complement fixation
[75]. Abatacept is approved by the US FDA for the treatment of
patients with moderate to severe RA who failed to respond to one
or more DMARDs or anti-TNF agents [76]. Its use is also recom-
mended in methotrexate-naïve patients with early RA and aggres-
sive course of the disease [77], as well as in case of inadequate
response to several biologic agents, including rituximab [78]. A
meta-analysis of 7 randomized controlled trials with 2,908 patients
showed that it had been efficacious in reducing pain and rheuma-
toid activity and improving physical activity at 6 and 12 months of
treatment, compared with placebo [79].
The recent integral analysis of the phase III trials on abatacept
in RA, compared with abatacept plus DMARDs and placebo plus
DMARDs, proved its relatively safe cardiovascular profile in terms
of the combined incidence of angina, cardiac arrest, MI, hyperten-
sion, and heart failure (no significant difference between the arms)
[68]. Serious adverse events were more likely to develop when
other biologic agents were concurrently used [79]. Of mild to mod-
erate adverse cardiovascular events, hypertension was the most
frequent (6.6%) [80].
CD20-targeted Therapy with Rituximab
Rituximab is a human-murine chimeric monoclonal antibody
against B-lymphocyte-specific CD20 surface protein that depletes
these cells and suppresses cytotoxic-antibody and immune-complex
mediated reactions. Rituximab therapy holds promise for the treat-
ment of autoimmune rheumatic disorders, such as SLE, RA, an-
tiphospholipid syndrome, Sjögren syndrome, and some vasculitides,
particularly those refractory to conventional antirheumatic drugs
[81, 82]. In fact, a recent systematic review of randomized placebo-
controlled trials with a total of 938 RA patients resistant or intoler-
ant to DMARDs or anti-TNF agents demonstrated efficacy in terms
of reducing disease activity and safety of rituximab (two infusions
of 1,000 mg each) in combination with methotrexate [83]. Serious
adverse events of rituximab were comparable to those of placebo
over 24-48 weeks of follow-up.
Safety and efficacy of rituximab have also been tested in lupus
patients with or without nephritis enrolled in phase III randomized
controlled trials [84, 85]. Even though serious adverse events in
patients treated with rituximab were not more frequent than in the
placebo arm and rituximab had a greater positive effect on lupus-
specific antibodies, clinical efficacy of the drug was not superior to
that of placebo. Several small studies have assessed safety of ri-
Current Pharmaceutical Design, 2012, Vol. 18, No. 11 1545
tuximab in combination with cyclophosphamide for the treatment
of refractory lupus, which yielded conflicting results [86, 87]. Even
more uncertain are issues of long-term efficacy of rituximab, par-
ticularly in patients with lupus nephritis [88].
Preliminary longitudinal studies have shown beneficial effects
of rituximab on lipid profile, surrogate markers of atherosclerosis
(i.e., common carotid artery intimal-medial thickness) and endothe-
lial dysfunction assessed by flow-mediated dilation of the brachial
artery in RA [89, 90]. However, these studies are limited in statisti-
cal power and duration (4-6 months).
Given the crucial role of B-cell-mediated autoimmune reactions
and inconclusive evidence on safety, clinical efficacy, and vascular
effects, larger scale and longer prospective studies on rituximab are
warranted [91, 92].
Importantly, cardiovascular events frequently occurring during
rituximab infusions, such as hypotension (10%) and peripheral
edema (8%) [93], prompted premedication with methylprednisolone
and regulation of the infusion rate [94]. The US FDA issued a
boxed warning indicating the risk of severe infusion-related cardio-
vascular events, usually occurring within the first 24 hours. These
may include fatal MI, ventricular fibrillation, other life-threatening
arrhythmias, and cardiogenic shock [95]. Therefore, rituximab
should be used with caution in patients with established cardiovas-
cular or pulmonary diseases, in whom close cardiovascular moni-
toring is required throughout the infusion at the slowest possible
rate.
Interleukin (IL)-1
Inhibitors
IL-1
is a proinflammatory cytokine released by activated
monocytes/macrophages after the cleavage of its amino-terminal
region by caspase-1. The cytokine takes part in the inflammatory
pathways of a wide range of rheumatic diseases by stimulating
matrix metalloproteinases and other destructive enzymes, adhesion
molecules, cytokines, and other inflammatory agents in the synovial
and cartilaginous tissues [96, 97]. Animal and human studies on
arthritis have also suggested IL-1
involvement in bone resorption
[98]. Improved understanding of the role of IL-1
in inflammation
has enabled using the IL-1 inhibitors anakinra, rilonacept, and ca-
nakinumab in several rheumatic diseases.
Initially, anakinra, a recombinant human IL-1 receptor antago-
nist with binding affinity similar to that of IL-1, was tested in large
cohorts of patients with RA, and was approved by the US FDA for
the treatment of moderate to severe RA unresponsive to DMARDs
in 2001 [99]. Subsequent comparative studies with anti-TNF
agents, however, revealed less potent antirheumatoid activity of IL-
1 inhibitors [100] and prompted the search for other clinical condi-
tions where these agents can be more efficacious [101, 102]. As a
result, a series of studies have proved efficacy and relative safety of
IL-1 inhibitors in autoinflammatory disorders, characterized by the
absence of high-titer autoantibodies and antigen-specific T-cells
and ranging from periodic fever syndromes, such as FMF, BD,
Tumour Necrosis Factor Receptor-Associated Periodic Syndrome
(TRAPS), Cryopyrin-Associated Periodic Syndrome (CAPS), to
gout, type 2 diabetes, and chronic heart failure [103-109]. Anakinra
has been particularly useful in patients with autoinflammatory dis-
orders unresponsive to conventional drug therapies (eg, colchicine
in FMF) [110, 111].
Large trials on anakinra have suggested that this and possibly
other IL-1 inhibitors are much safer than anti-TNF agents, with the
only common mild and transient injection site reaction developing
in 67% of cases [100], and the absence of strong evidence on wors-
ening heart failure or other cardiovascular events [112]. Actually,
cardiopulmonary arrest [113] and death because of preexistent heart
failure [114] were reported in rare cases of anakinra administration
in RA.
1546 Current Pharmaceutical Design, 2012, Vol. 18, No. 11
On the contrary, a pilot study suggested that anakinra, adminis-
tered in the post-infarction period, prevents adverse cardiac remod-
eling [115]. Another 1-month longitudinal study with RA patients
treated with anakinra demonstrated a significant improvement of
endothelial function, cardiac contractility and diastolic function
[116], thus providing a pathophysiological justification of its safety
in patients with RA, failing heart, diabetes, and other comorbidities
[117].
Recently, studies on CAPS and FMF have also demonstrated
the short-term cardiovascular safety of rilonacept, a fusion protein
consisting of the extracellular fragments of IL-1 receptor and Fc of
IgG1, and canakinumab, a fully human anti-IL-1
monoclonal anti-
body [118, 119]. Both drugs are now approved by the US FDA for
the treatment of CAPS [120-122]. To date, the raise of total choles-
terol, triglycerides, HDL-cholesterol, and LDL-cholesterol as a
result of the anti-inflammatory effect of rilonacept is the only re-
ported adverse cardiovascular event of IL-1 blockade (<1%), re-
quiring regular monitoring of lipids and, rarely, lipid-lowering ther-
apy [123].
IL-6 receptor Inhibitor Tocilizumab
Tocilizumab is a recombinant human monoclonal antibody,
blocking soluble and membrane-bound IL-6 receptors, thereby
suppressing IL-6-induced immune reactions and inflammation,
particularly at the synovial space and the endothelium. The drug
targets hepatic production of acute-phase proinflammatory proteins,
T-lymphocyte activation, and immunoglobulin synthesis [124]. In
the US, EU and Japan, it has been approved for combined use with
methotrexate in the treatment of patients with moderate to severe
RA with inadequate response or intolerance to DMARDs or other
biologic therapies [125, 126]. It may be also useful as monotherapy
and for the treatment of other rheumatic diseases such as adult-
onset Still disease [127].
Several recent phase III studies have proved efficacy and safety
of tocilizumab (4-8 mg/kg monthly) in combination therapy of RA,
which yielded profound suppression of systemic inflammation and
activity of arthritis, improvement of general health and remission of
RA during a 6-12 month period [128-131].
One of the frequently reported adverse effects of tocilizumab is
dyslipidemia with elevation of TC, LDL-C, HDL-C, and triglyc-
erides [132], which is presumably the result of blocking the IL-6-
dependent inflammatory pathway and lipid metabolism [133]. In
the Tocilizumab in Combination With Traditional DMARD Ther-
apy (TOWARD) study on 1,220 RA patients, 23% of those on to-
cilizumab had elevated total cholesterol as an adverse event [129].
Nonetheless, it has been shown that tocilizumab does not adversely
affect the atherogenic index (TC/HDL-C ratio), and there has not,
thus far, been any report on related increase of cardiovascular
events during short- and long-term follow-ups [134, 135].
Importantly, tocilizumab reverses the suppression of the
CYP450 system induced by IL-6 and modulates effects of some
cardiovascular drugs metabolized through this system (e.g., simvas-
tatin) [124]. Cardiovascular events can also develop during intrave-
nous infusion of tocilizumab. Of these, hypertension was reported
in 1% of cases [124]. The mechanism of this effect is not entirely
clear.
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
Methotrexate
Methotrexate is an analogue of folic acid, acting as an antifolate
agent. Over the past three decades, it has been widely used in the
treatment of inflammatory arthritides and RA, in particular [136].
Methotrexate is now recognized as the drug of choice for the treat-
ment of RA [137]. The drug provides immunosuppression and inhi-
bition of neutrophil chemotaxis and synthesis of proinflammatory
cytokines [138], which contribute not only to antirheumatoid but
Gasparyan et al.
also to antiatherogenic and cardioprotective effects [139]. In fact, it
has been shown that methotrexate retards atherogenesis [140, 141]
and dampens the heightened cardiometabolic risk in RA [142]. Not
surprisingly, in a large prospective cohort study with 107,908 pa-
tients with RA, methotrexate therapy was associated with a signifi-
cantly reduced rate of MI (RR 0.81, 95%CI 0.60-1.08) [143]. Addi-
tionally, recent systematic reviews on cardiovascular mortality in
RA provided solid evidence on cardioprotection due to the long-
term low-dose methotrexate therapy [12, 144].
Although numerous reports confirm the efficacy of methotre-
xate, the issue of its toxicity and the associated hyperhomocys-
teinemia are still subjects of ongoing clinical investigations [145].
Most experts strongly advocate folic acid supplementation on top of
methotrexate to treat hyperhomocysteinemia and to decrease car-
diovascular morbidity and mortality in arthritides [146-148].
Cardiovascular adverse events rarely develop in the course of
methotrexate therapy. The US FDA reported that about 3% of those
on methotrexate presented with pericarditis, pericardial effusion,
hypotension, myocardial ischemia, and thromboembolic events (ie,
cerebral, deep vein, retinal vein thromboses, and pulmonary embo-
lus) [149]. Methotrexate-induced immunosuppression, presenting
with neutropenia and reactivation of opportunistic infections, may
trigger myocarditis [149]. The risk of adverse effects is especially
high due to drug-drug interactions and profound immunosuppres-
sion in the course of combined antirheumatic therapy (eg,
methotrexate plus azathioprine, or cyclosporine, or minocycline, or
infliximab) [150-152].
Antimalarial Drugs
Chloroquine and hydroxychloroquine have been used for the
treatment of autoimmune manifestations in SLE, RA, primary
Sjögren syndrome and some other rheumatic diseases for decades
[153-156]. Although the mechanisms of action of both agents are
not fully clarified, it is suggested that the antirheumatic effects
largely derive from targeting autoantigen processing in macro-
phages and suppressing T-lymphocytes [157]. Antimalarials offer
significant advantages by disrupting complexes between antiphos-
pholipid antibodies and
2-glycoprotein I [158] and annexin A5
anticoagulant [159], thereby neutralizing prothrombotic effects of
antiphospholipid antibodies [160]. These agents also enhance lipid
and glycemic profiles, elasticity of peripheral arteries and systemic
vascular resistance, and reduce the associated cardiovascular risk in
SLE and RA [161-163]. A recent systematic review provided evi-
dence on varying degrees of protection against venous and arterial
thromboses, bone loss, and dyslipidemia in patients with moderate
SLE treated with antimalarials [164]. The review also evaluated the
outcomes of prospective studies on cardiotoxicity in patients ex-
posed to antimalarials over a period of 7 months – 7.9 years, which
yielded no cases of clinically significant adverse events. Likewise,
another study on 85 patients with connective tissue diseases, with-
out cardiovascular disease, treated with hydroxychloroquine for at
least 1 year, demonstrated that the effects of this particular agent on
the conduction, evaluated by measuring PR and QT intervals and
heart rate on standard 12-lead electrocardiograms, are within a safe
range [165].
Nonetheless, there have been more than 20 case reports on car-
diotoxicity presenting as potentially life-threatening restrictive car-
diomyopathy and conduction disorders in patients on prolonged use
(7 months – 25 years) of either chloroquine or hydroxychloroquine
at large cumulative doses (292g - 4380g) [166, 167]. In most cases,
discontinuation of the therapy allowed improving myocardial re-
laxation, contractility, and conduction within several months.
Cyclosporine
Cyclosporine is a cyclic polypeptide immunosuppressive agent
which binds to cyclophilin molecules and thus inhibits calcineurin,
a key protein phosphatase involved in T-lymphocyte activation. The
Adverse Cardiovascular Effects of Antirheumatic Drugs
results of open-label trials have supported its use as a second-line or
alternative drug in severe psoriatic arthritis [168], early severe RA
[169], lupus nephritis [170], and ocular lesions in BD [171]. Due to
neurotoxicity, the drug should be avoided in patients with neu-
rologic manifestations. The long-term use of cyclosporine is limited
by its nephrotoxicity, presenting as glomerular arteriolopathy and
tubulo-interstitial changes with hyperuricemia and electrolyte dis-
turbances, such as hyperkalemia and hypomagnesemia [172]. Cy-
closporine is also known as a drug causing thrombotic thrombocy-
topenic purpura and hemolytic uremic syndrome [173]. Distur-
bances in glomerular circulation, including vasoconstriction and
thrombosis, lead to hypertension (8%-53%) [174] and increase the
risk of arrhythmias, MI, and heart failure [175]. Cardiovascular
events may also develop due to the concurrent anticoagulant, potas-
sium-sparing diuretic, statin, calcium channel blocker, amiodarone,
digoxin, NSAID, and some other drug therapies, all of which re-
quire close monitoring of blood pressure and kidney functions in a
properly equipped facility by doctors experienced in immunosup-
pressive therapy [174].
Leflunomide
Leflunomide is an inhibitor of pyrimidine synthesis with a
proven efficacy in RA and psoriatic arthritis [176]. It inhibits pro-
liferation of CD4+ T-lymphocytes, thereby providing antiinflam-
matory and immunomodulatory effects. Its efficacy and tolerability
are comparable to those of methotrexate and sulfasalazine [177].
Even though preliminary experimental studies suggested some
antiatherogenic and antiproliferative properties of leflunomide,
implicated in successful coronary angioplasty with leflunomide-
eluting stents [178], strong evidence is lacking to recommend the
drug for cardiovascular risk reduction in rheumatic diseases. On the
contrary, some experts consider leflunomide along with cy-
closporine, NSAIDs, and COX-2 inhibitors as drugs worsening
cardiovascular risk [179].
The most common cardiovascular adverse effect of leflunomide
is hypertension, which was reported in 2.1%-10.6% of cases in
phase II and III trials [180]. A recent cohort study on 325 RA pa-
tients also linked hypertension with leflunomide therapy (HR 1.02,
95%CI 1.00-1.05) [181]. The precise mechanisms of this adverse
effect remain unknown, although, based on the pharmacokinetics of
the drug and the pathophysiology of hypertension in RA [182], it is
possible to speculate that interactions with concurrently adminis-
tered NSAIDs, sodium and fluid retention, and increased sympa-
thetic activity are the major players in leflunomide-induced hyper-
tension. Blood pressure monitoring and antihypertensive treatment
may be needed in some cases (eg, in patients with preexistent hy-
pertension and combined drug therapy) [183].
Cyclophosphamide
Cyclophosphamide is a nitrogen mustard alkylating agent from
the oxazophorine group. It has been successfully used as an induc-
tion and maintenance therapy for lupus nephritis for many years,
though the optimal dosage regimens have not been established
[153]. In spite of its efficacy in lupus nephritis and systemic vascu-
litides, evidence has emerged indicating the associated high risk of
infections, malignancies, and other toxicities, giving, in some in-
stances, preference to the less toxic agents with comparable effi-
cacy (eg, mycophenolate mofetil) [184].
Rare cases of cardiotoxicity with acute heart failure have been
reported in association with high-dose (50 mg/kg) cyclophos-
phamide therapy in severe autoimmune diseases [185]. High risk of
cardiotoxicity and acute heart failure in patients on cyclophos-
phamide requires close monitoring of heart function, with a special
attention to QT dispersion and its prolongation on ECG [186].
Current Pharmaceutical Design, 2012, Vol. 18, No. 11 1547
Azathioprine
Azathioprine is a purine analogue, which has a certain role in
the maintenance therapy of lupus nephritis [187]. Cardiovascular
adverse events of azathioprine include rare cases of angina, renal
vein thrombosis, subclavian vein thrombosis [188], hypotension,
and cardiogenic shock [189].
Sulfasalazine
Sulfasalazine is a folate antagonist primarily used in the treat-
ment of inflammatory bowel disease, as well as in early RA and
spondyloarthritides [190, 191]. The drug’s adverse effects include
rare cases of myelosuppression and thrombocytopenia, interfering
with antiplatelet and anticoagulant therapies [192].
COLCHICINE
Colchicine is an alkaloid derived from Colchicum autumnale
with a narrow therapeutic window. The drug disrupts polymeriza-
tion of microtubulin in inflammatory cells, predominantly in neu-
trophils where it accumulates [193]. Its antichemotactic action plays
a crucial role in the treatment of disorders where neutrophils are
target cells (eg, FMF, BD, and gout) [193, 194]. Also, it has been
reported that colchicine suppresses inflammatory pathways linked
to monocytes/macrophages, T-lymphocytes, and provides an antifi-
brotic effect, substantially widening its therapeutic indications
[195]. Colchicine is used as first-line therapy in FMF, and in some
cases of gout, pericarditis, and arthritis in BD [193]. Importantly,
prevention of flares and suppression of subclinical inflammation in
FMF by regular 1-2 mg/daily colchicine therapy are believed to
contribute to antiatherosclerotic and cardioprotective effects of the
drug [10].
There have been a few reports on colchicine overdosage and
poisoning-induced cardiotoxicity [196, 197]. Lethal cases are usu-
ally associated with acute ingestion of colchicine at doses exceed-
ing 0.5 mg/kg [198]. In critical cases, colchicine-induced cardiotox-
icity present with hypotension and cardiac arrest [199]. Toxicity,
however, may develop with even low doses in patients with hepatic
or renal failure and in cases of the concurrent use of drugs interfer-
ing with P-glycoprotein (increasing intracellular accumulation of
the drug) and with the cytochrome (CYP) 450 3A4 system (de-
creasing production of the drug metabolites). In fact, combination
of therapeutic doses of colchicine with cyclosporine, macrolides,
such as erythromycin and clarithromycin (but not spiramycin), and
statins, affecting both P-glycoprotein and CYP450 3A4, was asso-
ciated with toxicity [200]. Critical pancytopenia may arise in pa-
tients on combined treatment with colchicine and macrolides, while
myopathy may be a consequence of the combination with lipid-
lowering drugs (ie, statins and fibrates) [201].
GLUCOCORTICOIDS
It has been long known that glucocorticoids exert permissive
effects on other hormones and anti-inflammatory effects, reducing
vascular permeability and inhibiting proinflammatory cytokines and
adhesion molecules [202]. For more than half a century, these
agents have been successfully used in the treatment of cardiovascu-
lar and autoimmune disorders to provide anti-inflammatory, immu-
nosuppressive and, to some extent, cardioprotective effects [203].
Evidence has accumulated suggesting benefits of adding low-dose
glucocorticoids (below 7.5 mg/daily prednisone) to DMARDs in
early RA in terms of radiological progression of bone destruction
[204, 205]. A recent meta-analysis of six randomized controlled
trials with 689 patients with RA, followed for more than 2 years,
revealed an acceptable safety profile of glucocorticoids compared
with placebo [206]. Nonetheless, glucocorticoids in a dose (mainly
above 7.5 mg/daily) and time-dependent (more than 2.7-5 years)
manner increase the incidence of hypertension, hyperglycemia,
1548 Current Pharmaceutical Design, 2012, Vol. 18, No. 11 Gasparyan et al.

diabetes, osteoporosis, and MI throughout various cohorts of rheu-
matic patients [207-209].
Importantly, the US-based Rochester population-based study
identified rheumatoid factor seropositivity as a critical contributor
to the composite risk of MI, heart failure, and cardiovascular mor-
tality in RA patients exposed to glucocorticoids at high cumulative
doses (HR 3.06 vs. 0.85 in patients with and without rheumatoid
factor positivity) [210]. A number of other factors may also in-
crease the incidence of cardiovascular adverse effects of glucocorti-
coids, with electrolyte disturbances and fluid retention among the
most likely contributors. The role of electrolytes is of critical im-
portance in case of pulse therapy with glucocorticoids, requiring
close monitoring of blood electrolytes, electrocardiograms, and
blood pressure recordings to timely detect various life-threatening
arrhythmias [211]. Rarely, pulse therapy causes supraventricular
and ventricular arrhythmias, hypotension, shock, and sudden death
[212].
NONSTEROIDAL ANTIINFLAMMATORY DRUGS
(NSAIDS)
NSAIDs form a large group of agents, differing in chemical
structure, pharmacodynamics, and pharmacokynetics, which block
different isoenzymes of COX and provide antiinflammatory and
analgesic effects in a wide range of rheumatic diseases. Whilst the
blockade of COX-1 brings about a decrease of prostaglandins at
inflammatory sites and gastrointestinal, renal, and cardiovascular
adverse events, the blockade of COX-2 is associated with allevia-
tion of pain, partly due to reducing levels of prostaglandins in the
central nervous system [213]. Mechanisms of adverse events are
not fully explored. Yet, it is possible that the imbalance between
by-products of the COX-1 (thromboxane A2) and COX-2 (prosta-
glandin I2) pathways, with an increase of the former and a decrease
of the latter, may be responsible for vasoconstriction, platelet acti-
vation, subsequent hypertension, and accelerated atherosclerosis
[214]. The inhibition of renal prostaglandins may also lead to the
sodium retention, peripheral edema, and decompensation of heart
failure [215].
Currently, two subgroups of NSAIDs are marketed: traditional
agents blocking both COX-1 and COX-2 and selective COX-2
blockers. Cardiovascular safety of both subgroups still warrants
evaluation in the context of each agent, different age and gender
groups, doses of NSAIDs, drug combinations, and duration of the
treatment.
An inflammatory polyarthritis inception cohort study with 923
subjects followed from 1990 to 2004 demonstrated an inverse asso-
ciation between NSAIDs (predominantly diclofenac, naproxen, and
ibuprofen) and cardiovascular mortality (adjusted Odds Ratio 0.54,
95%CI 0.34-0.86) [216]. The majority of other epidemiological
studies, however, indicated the heightened cardiovascular risk asso-
ciated with most nonselective and selective NSAIDs. In a study
with 49,711 subjects aged 65 years and older the relative risk of MI
within 180 days after the initiation of therapy with nonselective
(diclofenac, ibuprofen, and naproxen) and selective NSAIDs (ro-
fecoxib and celecoxib) was the highest for diclofenac and rofecoxib
and the lowest for naproxen [217]. A nationwide study from Fin-
land with 33,039 subjects exposed to NSAIDs found a similarly
increased risk of first-time MI within 180 days after the initiation of
both nonselective and selective agents [218].
Comparative systematic reviews of randomized controlled stud-
ies confirmed that diclofenac and rofecoxib have the worst cardio-
vascular safety profiles [219, 220]. Furthermore, these systematic
reviews demonstrated that rofecoxib at either low or high dose tops
the list of NSAIDs, with substantially increased risk of thrombotic
events. In fact, the results of the Vioxx Gastrointestinal Outcomes
Research (VIGOR) [221] and the Adenomatous Polyp Prevention
on Vioxx (APPROVe) trials [222] comparing 50 mg/daily ro-
fecoxib with 1,000 mg/daily naproxen and 25 mg/daily rofecoxib
with placebo, respectively, led to the withdrawal of this COX-2
selective inhibitor from the market, based on the established risk of
thrombotic events.
Despite the wealth of evidence on unfavorable cardiovascular
profile of most NSAIDs, these agents are still recommended by
experts for symptomatic treatment of rheumatic diseases after care-
ful evaluation of the risk/benefit ratio in each individual case (eg, in
patients without gastrointestinal and cardiovascular risk all cur-
rently marketed NSAIDs can be used, while in those with high
cardiovascular risk - naproxen only) [223].

Table 1. Cardiovascular Safety Profile of Biologic Agents in Rheumatic Diseases

Drugs Adverse Events

TNF-
blockers (infliximab, etanercept, adalimumab, Worsening of heart failure

golimumab, and certolizumab-pegol) Arrhythmias, conduction disorders
Dyslipidemia
Hypertension
Arterial and venous thromboses
Acute coronary syndrome
Cardiomyopathy
Myocarditis

T-cell costimulatory modulator abatacept Hypertension

Anti-CD20 monoclonal antibody rituximab Infusion-related reactions (hypotension, peripheral edema, MI, arrhythmias, and cardiogenic
shock)

IL-1
inhibitor rilonacept Dyslipidemia

IL-6 receptor inhibitor tocilizumab Dyslipidemia

Infusion-related reactions (hypertension)
Adverse Cardiovascular Effects of Antirheumatic Drugs Current Pharmaceutical Design, 2012, Vol. 18, No. 11 1549

Table 2. Cardiovascular Safety Profile of DMARDs

Drugs Adverse Events

Methotrexate Pericarditis
Pericardial effusion
Hypotension
Myocardial ischemia
Arterial and venous thromboses
Pulmonary embolus
Myocarditis

Antimalarials Restrictive cardiomyopathy

Conduction disorders

Cyclosporine Hypertension
Hyperuricemia
Hypokalemia
Hypomagnesemia
Thrombocytopenia

Leflunomide Hypertension
Angina
Thrombocytopenia

Cyclophosphamide Acute heart failure

Azathioprine Hypotension
Angina
Cardiogenic shock
Renal and subclavian veins thromboses

Sulfasalazine Thrombocytopenia

restrictive cardiomyopathy. Cardiotoxicity has also been reported in

CONCLUSION
The management of most rheumatic diseases has undergone
dramatic changes in the recent decades. Better understanding of the
autoimmune and autoinflammatory pathways, coupled with ad-
vances in drug design, has led to more targeted therapies in a vari-
ety of rheumatic diseases. Suppressing diverse mediators of in-
flammation by DMARDs, biologic agents, and glucocorticoids has
been shown to be cardioprotective, mostly in retrospective and
short-term prospective studies employing surrogate markers of
atherogenesis. While large prospective studies on the implications
of most antirheumatic agents on cardiovascular morbidity and mor-
tality are still pending, evidence is accumulating suggestive of ad-
verse effects of potent immunosuppressive and anti-inflammatory
therapies with biologic agents on lipid profile Table 1. Moreover,
some new monoclonal antibodies with proven antirheumatic effi-
cacy may cause infusion-related adverse cardiovascular events,
such as hypotension, peripheral edema, MI, arrhythmias, and car-
diogenic shock Table 1.
For decades, clinicians have been using DMARDs for mono
and combination therapy of rheumatic diseases, which have led to
substantial improvements in the quality of life and survival of pa-
tients with SLE, RA, and systemic vasculitides. These successes,
however, have come with reports on the “dark” side of DMARD
therapy Table 2. In particular, leflunomide and cyclosporine fre-
quently cause hypertension, long-term therapy with antimalarials
may be associated with very rare but potentially life-threatening
those treated with colchicine Table 3, the essential drug for target-
ing activated neutrophils in autoinflammatory disorders, but exhib-
iting adverse profile when used in subjects with renal failure or in
those on combined drug therapies.
Uncertainties surround the issue of glucocorticoid therapy in
rheumatic diseases. It is particularly unclear which dosage regimens
and how long should be used to minimize or avoid events, such as
hypertension, hyperglycemia, and diabetes Table 3.
Perhaps the most challenging is the symptomatic pain manage-
ment with NSAIDs Table 3. Preliminary evidence indicates the
relative cardiovascular safety of naproxen and strongly contraindi-
cates the use of rofecoxib that is no longer marketed due to the well
documented prothrombotic effects.
In conclusion, clinicians should be alert of the wide variety of
cardiovascular adverse effects of individual antirheumatic drugs,
and should carefully monitor blood pressure and markers of in-
flammation, thrombosis, myocardial ischemia, electrolytes, and
lipids while administering these drugs. Future prospective studies
should specifically investigate cardiovascular safety of most antir-
heumatic drugs as part of mono- or combination therapy in relation
to different dosage regimens, duration of therapy, age, and gender.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
1550 Current Pharmaceutical Design, 2012, Vol. 18, No. 11
Table 3. Cardiovascular Safety Profile of other Drugs Used in the Treatment of Rheumatic Diseases
Drugs
Colchicine Hypotension and cardiac arrest due to cardiotoxicity
Glucocorticoids Hypertension
Hyperglycemia
Diabetes
Heart failure
Arrhythmias
NSAIDs Hypertension
Decompensated heart failure
Thromboses
Arrhythmias
ACKNOWLEDGMENT
AYG and GDK thank The Dudley Group NHS Foundation
Trust (A Teaching Trust of the University of Birmingham, UK) for
providing support during the preparation of this review.
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