206 Send Orders for Reprints to reprints@benthamscience.

ae

Current Rheumatology Reviews, 2017, 13, 206-218

REVIEW ARTICLE
ISSN: 1573-3971
eISSN: 1875-6360

Cardiovascular and Pulmonary Manifestations of Systemic Lupus

Erythematosus
BENTHAM
SCIENCE

Konstantinos Tselios and Murray B. Urowitz*

Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Lupus Clinic, University Health Network, Toronto,
Ontario, Canada
ARTICLE HISTORY
Received: December 27, 2016
Revised: February 02, 2017
Accepted: June 18, 2017
DOI:
10.2174/1573397113666170704102444
Current Rheumatology Reviews
Abstract: Background: Systemic lupus erythematosus (SLE) is characterized by various clinical manifesta-
tions and immunologic abnormalities. Cardiovascular and respiratory system involvement are increasingly
recognized as critical for patients’ prognosis. In this review, current knowledge concerning diagnosis, patho-
genesis and treatment of the cardiac and pulmonary lupus manifestations are discussed.
Method: Review of the literature.
Results: Although pericarditis is the most frequent heart manifestation in the context of lupus, valvular dis-
ease and less often myocarditis may be detected. In the latter, treatment should be prompt and aggressive to
prevent chronic sequelae like congestive heart failure. Later on disease course, accelerated atherosclerosis is
considered as one of the most important co-morbidities of SLE with cardiovascular events being one of the
leading causes of death at relatively young ages. Stratification of the patients at risk and stringent manage-
ment of the traditional risk factors are warranted.
Respiratory system involvement affects all anatomic structures of the lungs, pleura and pulmonary vascula-
ture while its severity ranges from asymptomatic pleural disease to acute respiratory failure. The most com-
mon features include pleuritis, interstitial lung disease and pulmonary embolism on the background of an-
tiphospholipid syndrome. Less usual complications include lupus pneumonitis, diffuse alveolar hemorrhage,
shrinking lung syndrome and pulmonary arterial hypertension.

Conclusion: There are no specific guidelines for the management of these manifestations and thera-
peutic approach remains empiric.
Keywords: Systemic lupus erythematosus, cardiovascular, pulmonary manifestations, viral, tuberculosis, uremic.

1. INTRODUCTION 2. CARDIOVASCULAR SYSTEM INVOLVEMENT

Systemic lupus erythematosus (SLE) is the prototype of
systemic autoimmune diseases, mainly affecting women of
reproductive age and characterized by various clinical mani-
festations as well as by multiple immunologic abnormalities.
Disease incidence ranges from 1 to 10 patients/100000 popu-
lation/year whereas prevalence is approximately 50 to 70 pa-
tients/100000 population [1]. The exact etiology of SLE re-
mains unknown; current pathogenetic theories involve a com-
plex interplay between certain genetic and environmental fac-
tors which may lead to immune system dysfunction, auto-
antibody production, immune complexes formation and,
eventually, tissue damage.
Among clinical manifestations, cardiovascular and pul-
monary features of SLE have an important impact on pa-
tients’ quality of life and prognosis. In this review, current
knowledge concerning their diagnosis, pathogenesis and
treatment is discussed.
*Address correspondence to this author at the University of Toronto Lupus
Clinic, Centre for Prognosis Studies in the Rheumatic Diseases Toronto
Western Hospital, 399 Bathurst St. 1E-410B, Toronto, Ontario, M5T 2S8,
Canada; Tel: 416-603-5828; Fax: 416-602-9387;
E-mail: m.urowitz@utoronto.ca
Heart involvement, in the course of SLE, most com-
monly presents with pericarditis. However, valvular disease
and less often myocarditis may be detected. Moreover, ac-
celerated atherosclerosis is currently considered as one of the
most important co-morbidities of SLE with cardiovascular
events being one of the leading causes of death in relatively
young ages.
3. PERICARDIUM
3.1. Pericarditis
Pericardial effusion is detected in 11-54% of patients
during disease course [2, 3], whereas acute cardiac tampo-
nade is rare and described mainly in case reports [4]. Peri-
carditis is usually recurrent and associated with positive an-
tinuclear antibodies (ANA) and fever [5]. In many cases,
pleural effusion may be concurrently found. Rarely, peri-
carditis may have other causes (viral, tuberculosis, uremic
etc) in the context of SLE, which should not be overlooked
[6].
Diagnostic approach of pericarditis in SLE does not dif-
fer from that in non-autoimmune patients. Chest pain (retros-

1875-6360/17 $58.00+.00 © 2017 Bentham Science Publishers

Cardiovascular and Pulmonary Manifestations
ternal or precordial) and/or discomfort, improved when lean-
ing forward and accompanied by dyspnea, palpitations or
fatigue are the cardinal symptoms. Physical examination
may reveal the characteristic pericardial rub whereas electro-
cardiogram (ECG) may show sinus tachycardia, widespread
ST elevation and PR depression in most of the limb and pre-
cordial leads. Secure diagnosis is achieved with transthoracic
echocardiogram (TTE), which can roughly estimate the vol-
ume of the pericardial fluid and assess the hemodynamic
impact of the effusion. In rare cases of dry or chronic con-
strictive pericarditis, cardiac computed tomography (CT)
and/or magnetic resonance imaging (MRI) might provide
further diagnostic information [7].
Autopsy studies have demonstrated the presence of
granular depositions of immunoglobulins and complement
C3 on the pericardium, suggesting the role of immune com-
plexes in promoting pericardial inflammation [8]. Pericardial
fluid is typically an exudate with neutrophil predominance;
autoantibodies, mainly ANA, might be detected although
this is not pathognomonic.
4. MYOCARDIUM AND CONDUCTION SYSTEM
4.1. Myocarditis
Primary myocardial involvement is uncommon and af-
fects approximately 3-9% of lupus patients depending on
definition; however, its frequency was reportedly greater in
autopsy studies performed in the 1950’s and 60’s reaching
15% [8]. In more recent post-mortem studies, after the wide
use of corticosteroids in lupus therapeutics, its prevalence
was estimated as 0-8% [9]. African-American patients are at
increased risk for development of myocarditis [10].
Typical clinical features include chest pain with tachy-
cardia, palpitations and/or symptoms of heart failure. History
of recent viral infection is usually absent. Cardiac troponins
and pro-B type natriuretic peptide are often elevated [3].
ECG commonly shows sinus tachycardia with widespread
non-specific ST alterations and T wave changes. Lupus
myocarditis may also present with arrythmias, conduction
abnormalities and ventricular dilatation [8]. TTE may assess
the extent of ventricular dysfunction (systolic and/or dia-
stolic) and hemodynamic compromise as low ejection frac-
tion is detected in the majority of the patients [11]. Rough
assessment of the texture of ventricular wall may be feasible.
Global hypokinesis is detected in 5-20%, however segmental
motion abnormalities may also occur. Cardiac MRI repre-
sents the imaging modality of choice in non-ischemic in-
flammation of the myocardium; inflammatory hyperemia
and edema, necrosis and/or scar, contractile dysfunction and
pericardium involvement may be thoroughly assessed [12].
Newer imaging techniques with positron emission tomogra-
phy (PET) may hold promise for the diagnosis and monitor-
ing of such patients [13].
Endomyocardial biopsy further supports the diagnosis of
myocarditis in complicated cases; however, its diagnostic
yield ranges from 10-30%. Typical findings include mono-
nuclear cell infiltration, perivascular inflammation and car-
diomyocyte necrosis [8]. Immunofluoresence studies have
demonstrated granular immunoglobulins and complement
deposition in the wall and perivascular tissue of myocardial
Current Rheumatology Reviews, 2017, Vol. 13, No. 3 207
blood vessels, supporting the hypothesis that lupus myo-
carditis is an immune complex-mediated disease [3, 8].
4.2. Cardiomyopathy
Cardiomyopathy in SLE, manifested as global hypokine-
sis and impaired contractility, is multifactorial in its etiology
since myocardial dysfunction may be caused by increased
global disease activity, concurrent infection, uremia, arterial
hypertension, thrombosis and other factors [8]. In later
stages, accelerated atherosclerosis leading to ischemic seque-
lae plays a key role. The most common initial echocardio-
graphic finding is that of mild diastolic dysfunction and de-
creased exercise tolerance [5]. This may remain undetected
and deteriorate, even in adolescents, since it is largely
asymptomatic and has been associated with disease duration,
renal impairment and abnormal nailfold microvasculature
[14]. More recently, it was shown that left atrial mechanical
function and volume are impaired in SLE, particularly in as-
ymptomatic patients with significant cumulative damage [15].
Chronic antimalarial use (chloroquine or hydroxychloro-
quine) has been linked to a specific form of cardiomyopathy
that resembles that of lysosomal storage diseases [16]. Se-
cure diagnosis requires endomyocardial biopsy and genetic
testing for the exclusion of Fabry’ s disease. Characteristic
findings include vacuolated cytoplasm with inclusion curvi-
linear bodies (lipid accumulation) on electron microscopy
[17]. Cardiac MRI is considered to reliably assess the extent
and distribution of hypertrophy, restrictive filling of the ven-
tricles and myocardial fibrosis. From a clinical perspective,
heart failure is the dominant syndrome.
More recently, Takotsubo cardiomyopathy was described
in lupus patients [18]. It is associated with physical and/or
emotional stress and most commonly affects post-
menopausal women. The typical echocardiographic presenta-
tion is that of apical ballooning of the left ventricle usually
accompanied by mural thrombus formation. Pathogenesis is
largely unknown; microcirculation disturbances, coronary
vasospasm, ischemia-reperfusion injury and catecholamine
overload are implicated. Management is supportive with
normalization of wall abnormalities within weeks.
4.3. Electrocardiographic (ECG) Abnormalities and Ar-
rhythmias
Rhythm disturbances are considered rare in SLE; how-
ever, it was recently demonstrated that non-specific ST-T
changes exist in 31% of newly diagnosed patients [19]. Re-
polarization abnormalities, mainly prolonged QT, were pre-
sent in 15% although that was severe (QTc>550msec) in less
than 1% of the patients. Other findings included ECG evi-
dence of left ventricular hypertrophy in 5.4%, supraventricu-
lar arrhythmias in 1.3% (atrial fibrillation in 0.13%), atriov-
entricular heart block in 0.6%, incomplete bundle branch
block (BBB) in 2.7%, right BBB in 0.8% and left BBB in
0.3% of the patients [19]. Increased cumulative damage was
strongly associated with these abnormalities. Antibodies
against the SSA/Ro antigen (the main autoantibodies impli-
cated in the atrioventricular block of neonatal lupus) were
not associated with any ECG findings [19]. Recently, QRS
fragmentation was described in higher frequency in SLE
208 Current Rheumatology Reviews, 2017, Vol. 13, No. 3
patients and was associated with older age, longer disease
duration and higher C-reactive protein levels [20].
From a pathogenetic standpoint, autopsy studies revealed
the presence of periarteritis of sinus nodal arteries and fibro-
sis of the atrioventricular node and conduction tissue [21].
The medications used in lupus therapeutics may also
have a role in ECG abnormalities. In this context, a cumula-
tive dose of hydroxychloroquine greater than 365 grams was
associated with decreased resting heart rate [22]. In line with
this observation, chloroquine (cumulative dose and duration
of use) was demonstrated to be protective against arrythmias
[23]. On the contrary, high disease activity was related to
increased rates of chronic tachycardia [24].
5. ENDOCARDIUM
5.1. Valvular Disease
Valvular involvement in SLE is detected echocardio-
graphically in almost 50% of the patients and usually pre-
sents as valve thickening, sterile vegetations and valve dis-
tortion and dysfunction. Nevertheless, its direct link to dis-
ease pathophysiology is uncertain. Many investigators have
reported an association between valvular abnormalities and
the presence of antiphospholipid antibodies [8]. In studies
using transesophageal echocardiography (TEE), the preva-
lence of valvular disease reached 82% (valve thickening in
63%) while this was highly correlated to the titer of IgG an-
ticardiolipin antibodies [25]. In one study, valvular involve-
ment was present in all patients with antiphospholipid syn-
drome (APS) who eventually developed cerebrovascular
disease (stroke), suggesting that the presence of valve ab-
normalities may be a significant risk factor for stroke, sei-
zures and other central nervous system (CNS) manifestations
[26].
From a functional standpoint, mild regurgitation of the
mitral and aortic valves is usually detected, while tricuspid
and pulmonary valves may be secondarily affected in cases
of pulmonary arterial hypertension. Clinically significant
valvular insufficiency and/or stenosis is rare and requires
surgical treatment in 4-6% of the patients [8]. The mortality
risk of surgical replacement is reportedly higher in patients
taking immunosuppressives or having APS [27]. There is no
direct evidence that treatment with corticosteroids and/or
immunosuppressives may prevent or improve valvular dis-
ease [3, 8].
The most characteristic valvulopathy of SLE is Libman-
Sacks endocarditis (LSE), which mainly affects the left car-
diac valves [28]. Its frequency is considered lower than pre-
viously reported, possibly due to more effective disease
management and estimated to vary widely between 11 and
74% [8]. In an echocardiographic study of 342 lupus pa-
tients, LSE was diagnosed in 38 cases (24 mitral, 13 aortic
and 1 tricuspid valve) [29]. Rarely, more than one valve may
be affected [30]. It is a non-infectious, verrucous, vegetative
endocarditis with a histopathological background of fibrin
and immune-complex deposits, neo-vascularization and
mononuclear cells infiltration [8]. Diagnosis is based on TTE
and TEE for the visualization of leaflet vegetations, as well
as in the real-time three dimensional heart ultrasound [31].
LSE is associated with antiphospholipid antibodies and
Tselios and Urowitz
clinically presents with acute embolic infarcts, mainly cere-
bral [3, 8].
6. CORONARY ARTERIES
6.1. Accelerated Atherosclerosis in SLE
The inflammatory nature of atherosclerosis has been well
established during the last 15 years [32]. In this context, an
initial insult causing endothelial dysfunction will drive the
accumulation of macrophages and T lymphocytes into the
arterial wall, which in turn will proliferate and activate other
cellular subpopulations through the secretion of proinflam-
matory cytokines. This mechanism will facilitate the forma-
tion of atherosclerotic plaques whose rupture will give rise to
the clinical equivalent, i.e cardiovascular events (CVEs).
The first studies on the impact of atherosclerotic CVEs
on SLE mortality date back to 1976 when it was demon-
strated that they were the major cause of death late in disease
course [33]. Subsequently, it was shown that 30% of the
overall patients’ deaths were attributed to coronary artery
disease (CAD) [34]. Pre-menopausal women with SLE were
shown to have a 50-fold increased risk for myocardial infarc-
tion (MI) when compared to age-matched healthy women
[35]. A recent population-wide study from Sweden showed
that hospitalized SLE patients had a 5-fold increased risk for
re-admission for a major CVE during the first year after ini-
tial admission [36]. Furthermore, SLE patients have a 5-fold
increased risk for MI within the first year after diagnosis [37]
or two years preceding diagnosis [38].
In the University of Toronto Lupus Clinic, 11% of all
patients (and 10% of 561 inception patients) developed a
CVE in an average time of 8 and 9 years since diagnosis,
respectively [39]. The mean age of a first CAD-related event
in a female lupus patient is between 48 and 50 [40], rather
earlier than her healthy counterpart. Moreover, the age-
difference at the time of cardiovascular death was approxi-
mately 15 years for females and 11 for male patients [41].
The precise pathophysiologic mechanisms underlying
accelerated atherosclerosis in SLE have not been fully eluci-
dated. Traditional, disease-related risk factors and the medi-
cations used for the long-term management of lupus have
been shown to be independent predictors both for clinical
(CVEs) and subclinical atherosclerosis.
Traditional risk factors are involved in the atherosclerotic
process in SLE in a proportion that was estimated to be
about 60% [42]. The most important non-modifiable factors
were age (particularly over 48 or in post-menopausal state),
positive family history (defined by the presence of a CVE in
a first-degree relative under the age of 55 for males or 65 for
females) and male sex [43]. Among modifiable risk factors,
obesity, arterial hypertension, diabetes, dyslipidemia, meta-
bolic syndrome, smoking and homocysteine were strongly
associated with the occurrence of CVEs in lupus patients
[43]. In addition, most of these traditional risk factors were
found to be associated with each stage of subclinical athero-
sclerosis, such as endothelial dysfunction, arterial stiffness,
arterial wall thickening and/or plaque formation, coronary
artery calcification and angiographically defined atheroscle-
rotic plaques [43]. Traditional risk factors, which may inde-
Cardiovascular and Pulmonary Manifestations Current Rheumatology Reviews, 2017, Vol. 13, No. 3 209

pendently predict clinical or subclinical CAD, are presented
in Table 1.
Apart from traditional risk factors, SLE has been demon-
strated to be an independent predictor for CVEs, increasing
the risk of clinical cardiovascular disease about 5-8 times. In
this context, multiple disease-related factors have been asso-
ciated with that increased risk, such as global disease activ-
ity, cumulative damage and disease duration [43]. Clinical
activity was shown to be more crucial in increasing CV risk
since patients with serological activity but clinically quies-
cent disease were less likely to develop CAD [44]. In line
with these observations, certain disease phenotypes, such as
lupus nephritis and CNS involvement were independent pre-
dictors of CVEs [43].
Several autoantibodies, such as antiphospholipid (aPL),
anti-dsDNA and anti-endothelial cell antibodies (AECAs),
soluble mediators and specific lymphocyte populations, such
as the T-regulatory cells, have also been implicated in the
progression of subclinical atherosclerosis and CVEs [43, 45].
Disease-related risk factors with independent predictive abil-
ity for clinical and subclinical atherosclerotic vascular dis-
ease are shown in Table 2.
The role of the drugs used in SLE therapeutics should not
be overlooked. Corticosteroids may be directly atherogenic
(through the modification of the composition of plasma lipo-
proteins) and/or augment pre-existing risk factors such as
arterial hypertension, insulin resistance and increased body
weight. However, patients with higher cumulative doses are
usually those with increased disease severity, making the
latter an important risk factor. High doses of corticosteroids,
either as cumulative (reflecting active disease over time) or
current dose (reflecting an acute alteration in the vascular
microenvironment), were independent predictors for CVEs,
increased arterial stiffness, carotid IMT and plaque forma-
tion, as well as coronary calcification [46-51]. On the con-
trary, antimalarials were protective against CVEs and associ-
ated with a favorable metabolic profile concerning lipid and
glucose metabolism [52]. Moreover, they were associated
with a 68% reduction of thrombotic events further proving
their value in the chronic management of SLE. The precise
mechanism of antimalarial-related atheroprotection has not
been elucidated. It seems that the favorable effects on dis-
ease activity, steroid sparing effect, anti-thrombotic potency
and metabolic profile may play a role.
Despite the recognition of multiple independent predic-
tors for the occurrence of CVEs in lupus patients, a sepa-
rate composite score to assess cardiovascular risk has not
been developed. Both the Framingham Risk Score (FRS)
and the Systematic Coronary Risk Evaluation (SCORE) are
used to predict long-term cardiovascular risk in the general
population; however, their value in SLE is questionable. In
a study using coronary artery calcification as an end-point,
FRS and PDAY (Pathobiological Determinants for Athero-
sclerosis in the Youth, a modified score for younger pa-
tients) did not differ between lupus patients and controls

Table 1. Traditional (modifiable and non-modifiable) risk factors with an independent predictive ability for CVEs (cardiovascu-
lar events) or surrogate atherosclerosis measures in lupus patients.

Parameter PWV CP/IMT CAC SPECT CA CVEs

(Pooled HR) (Pooled HR) (Pooled HR) (Pooled HR) (Pooled HR) (Pooled HR)

Age 1.13 1.11-4.1 1.08-8.5 2.22 1.04-5.1

Positive Family History 3.6

Male sex 8.78 2.38 1.56-6.2

BMI>30 1.06-6.16

Arterial Hypertension 1.04-3 2.11-2.53 1.05-3.5

Diabetes Mellitus 1.54 60 4 1.5

TC 1.2-3 2.51 1.89 3.9-6.9

LDL 7.6

HDL 4.8 3.86

piHDL 9.1-12.8

TG 1.15-8

oxLDL

Metabolic Syndrome 3.11

Homocysteine 1.24

Smoking 7.7 3.8 2.2-3.7

FMD: flow mediated dilatation, PWV: pulse wave velocity, CP: carotid plaque, IMT: intima-media thickness, SPECT: single photon emission computed tomography, CA: coronary
angiography. For each end-point, the respective pooled hazard ratio range (HR) is shown.
Adapted from reference 43 Tselios et al. J Rheumatol 2016; 43: 54-65.
210 Current Rheumatology Reviews, 2017, Vol. 13, No. 3 Tselios and Urowitz

Table 2. SLE-related risk factors with an independent predictive ability for CVEs (cardiovascular events) or surrogate
atherosclerosis measures.

Parameter PWV (HR) CP, IMT (Pooled HR) CAC (Pooled HR) SPECT (HR) CVEs (Pooled HR)

Disease Activity 12.3 1.05-1.2

Cumulative Damage 1.7 1.2 1.3-4.1

Disease duration 1.7-3.2 1.2-15.1 1.1-1.45

aCL 5.2 4.1 3.1-5.8

Anti-b2GPI 3.4

LA 5.2 4.4 1.74

Anti-oxPAPC 1.06

Anti-dsDNA 1.56

hsCRP 3 1.65-4.15 1.6-3.4

TWEAK 29

IL-6 1.07

Renal Disease 7.5 16.4 1.2-6.8

Proteinuria 2.4

Neuropsychiatric SLE 2.2-5.2

FMD: flow mediated dilatation, PWV: pulse wave velocity, CP: carotid plaque, IMT: intima-media thickness, SPECT: single photon emission computed tomography, CA: coronary
angiography, AZA: azathioprine. For each end-point, the respective pooled hazard ratio range (HR) is shown.
Adapted from reference 43 Tselios et al. J Rheumatol 2016; 43: 54-65.

[53]. In a prospective study of 250 female patients, the FRS
at baseline was higher, although insignificant, in patients
who developed a CVE [54]. In fact, it has been demon-
strated that the FRS underestimates the risk of CAD in SLE
by a factor of 7.5, underlining the importance of lupus-
specific risk factors [42]. In the Systemic Lupus Interna-
tional Collaboration Clinics (SLICC) inception cohort, the
mean FRS was lower than the original Framingham cohort
(2.55±3.38 vs. 3.29±4.5) with the same age and gender dis-
tribution [55]. More recently, it was shown that a multipli-
cation of FRS by 2 predicts CV risk in lupus patients more
accurately [56].
7. RESPIRATORY SYSTEM INVOLVEMENT
Respiratory system involvement in SLE affects all anat-
omic structures of the lungs, pleura and pulmonary vasculature
while its severity ranges from asymptomatic pleural disease to
acute respiratory failure. Depending on definition (clinical
criteria or histopathologic evidence), its prevalence ranges
from 20 to 90% and significantly affects prognosis [57, 58].
8. PLEURA
8.1. Pleural Involvement
Pleuritis is the most common feature, affecting up to 60%
of the patients during disease course [59]. It is the only pul-
monary manifestation currently included in the revised
American College of Rheumatology classification criteria for
SLE [60]. Pleural involvement may be asymptomatic or pre-
sented with the typical symptoms of pleuritic chest pain,
deteriorating with deep inhalation and causing dry cough
and/or dyspnea. It is usually unilateral and mild to moderate
in severity; seldomly it may be dry. Pleuritic fluid is sterile,
exudative and may contain ANA and inflammatory cells,
most commonly polymorphonuclear neutrophils. Positive
ANA should be interpreted cautiously since a high level
(1:160 with indirect immunofluoresence) in a known lupus
patient is highly suggestive of lupus pleuritis; on the other
hand, in the absence of SLE, it indicates paraneoplastic dis-
ease in half of the cases [61]. Histopathologic studies have
demonstrated non-specific lymphoplasmacytic infiltration of
the pleura with rare evidence of immune complex-mediated
vasculitis [62]. Although, pleural biopsy is not required for
diagnosis, it may rule out tuberculosis and/or pleural carci-
nomatosis in disputed cases.
9. LUNG PARENCHYMA
Lung parenchyma is affected in up to 13% of lupus pa-
tients, most commonly in the forms of interstitial lung dis-
ease (chronic interstitial pneumonia and bronchiolitis oblit-
erans with organizing pneumonia, BOOP) and acute lupus
pneumonitis.
9.1. Chronic Interstitial Pneumonia (CIP) and Organiz-
ing Pneumonia
This may be observed in 3-13% of SLE patients and it is
rarely severe [63]. In studies using high-resolution thorax CT
(HRCT), its prevalence was estimated to reach 70% [64]. It
is clinically manifested with exertional dyspnea, dry cough,
end-inspiratory crackles and gas-exchange disorders. Ini-
tially, there is a lymphocytic infiltration of the alveolar wall
with honeycombing formation in HRCT imaging [59].
Cardiovascular and Pulmonary Manifestations
Histopathologically, non-specific interstitial pneumonia is
the most common type [65]. Pulmonary function tests may
reveal a mild-to-moderate restrictive pattern with moderate
deterioration in CO transfer [66]. The severity of interstitial
lung disease does not correlate with lupus-specific serologic
markers, such as anti-dsDNA antibodies and complement
components C3/C4. However, a weak association with anti-
SSA/Ro antibodies has been reported [67].
Lymphoid interstitial pneumonia (LIP) is characterized
by diffuse infiltration of the interstitium by polyclonal lym-
phocytes and is commonly accompanied by lymphocytic
alveolitis. It cannot be differentiated from chronic interstitial
pneumonia (CIP) on clinical grounds; on imaging, diffuse
ground glass opacities are the dominant pattern [59, 63].
Organizing pneumonia has rarely been reported in SLE
without any clinical or radiological differences as compared
to other causes of BOOP. Usually, it follows local pulmo-
nary insult from infections, drugs, irradiation and chemical
agents. It has been described as the initial lupus manifesta-
tion and may occur regardless of disease activity [68, 69].
9.2. Acute Lupus Pneumonitis
This has been reported in up to 4% of lupus patients;
however, it is believed that its prevalence is overestimated
since most cases can be attributed to superimposed infec-
tions [70]. Acute lupus pneumonitis is a diffuse alveolar
inflammation without evidence of vasculitis or haemor-
rhage while hyaline membrane formation was occasionally
described [71]. Diagnosis is challenging since clinical (fe-
ver, cough, dyspnea, hypoxia) and radiologic features (uni-
or bilateral alveolar infiltrates) are non-specific. However,
it has been suggested that acute lupus pneumonitis usually
accompanies other active organ involvement, most com-
monly kidney disease, and is associated with anti-SSA/Ro
antibodies [71].
9.3. Diffuse Alveolar Hemorrhage
Diffuse alveolar hemorrhage (DAH) is the most severe
respiratory complication of SLE and affects approximately
2% of the patients [59]. Prompt recognition is of paramount
importance since mortality reaches 50-95% [72]. Most
commonly, it occurs in diagnosed cases whereas in 20% is
the initial manifestation of the disease [73]. DAH should be
suspected upon the abrupt appearance of dyspnea with he-
moptysis and pulmonary infiltrates on imaging; CT reveals
ground-glass opacifications. Bronchoscopy with bronchoal-
veolar lavage fluid analysis confirms diagnosis and may rule
out other possible causes such as infection [74].
The pathologic background is a diffuse, immune com-
plex-mediated pulmonary capillaritis [75]. Other characteris-
tics are non-specific and include interstitial infiltration by
mononuclear and polymorphonuclear cells, the presence of
hyalin membranes in later stages with hemosiderin-loaded
macrophages and microvascular thrombosis [75]. The patho-
physiologic basis of DAH is poorly understood albeit it has
been reported that certain similarities with acute lupus
pneumonitis do exist [59, 63]. In this context, severe in-
flammation of the alveolar-capillary unit may lead to in-
creased vascular permeability and direct damage to the ves-
Current Rheumatology Reviews, 2017, Vol. 13, No. 3 211
sel wall. Superimposed infections may further aggravate the
systemic inflammatory response and complicate the clinical
presentation. The presence of antiphospholipid antibodies
may also play a role in DAH development and severity [76].
Prognosis is poor with frequent development of adult respi-
ratory distress syndrome (ARDS) and respiratory failure
[77].
10. BRONCHIAL TREE
10.1. Bronchial Disease and Acute Reversible Hypoxemia
Bronchial involvement is rare and may affect the upper
and lower airways. Acute epiglottitis, laryngitis, tracheitis
and crico-arytenoid arthritis have been reported in isolated
cases [59]. Lower airway disease usually presents with an
obstructive pattern and was described in 6% of lupus pa-
tients; however, spirometric evidence of small airway dis-
ease was observed in 24% of the patients [78]. The histopa-
thologic basis is a non-specific bronchiolitis with obstruc-
tion of the bronchiole lumen and immunoglobulin (IgM and
IgG) and fibrinogen depositions [79]. Moreover, bronchiec-
tasis has been reported with increased frequency in lupus
patients; its attribution to the disease is doubtful [80].
Acute reversible hypoxemia refers to the onset of acute
dyspnea accompanied by chest pain, probably pleuritic, in
patients with an acute exacerbation of SLE [81]. Chest X-ray
is usually normal while pulmonary function tests reveal se-
vere hypoxemia with decreased vital capacity and carbon
monoxide diffusion [59]. Although it responds dramatically
to low-to-moderate doses of corticosteroids, several investi-
gators consider it as an indication of generalised lupus activ-
ity rather than a specific syndrome [82]. Its pathophysiology
is unclear; it is believed to involve neutrophil chemotaxis by
complement activation.
11. VASCULAR INVOLVEMENT
11.1. Thrombotic Manifestations of the Pulmonary Vas-
culature
Thrombotic manifestations are usually encountered in the
context of positive antiphospholipid antibodies (aPL) and
APS. Its diagnosis requires the detection of positive lupus
anticoagulant (LA) and/or anticardiolipin antibodies (aCL)
and/or anti-b2 glycoprotein I (anti-b2GPI) on two separate
occasions 12 weeks apart [83]. The prevalence of APS in
SLE is approximately 30%. The most common manifestation
is thrombosis of the pulmonary vasculature, ranging in se-
verity from massive pulmonary embolism to occlusion of the
small branches of the pulmonary arteries. The presence of
aPL increases the risk of pulmonary embolism by 6-fold as
compared to aPL(-) lupus patients [84]. Higher levels of IgG
aCL and IgG anti-b2GPI were associated with a higher risk
of thrombosis when compared to the IgM type of these
autoantibodies [59]. Multiple thrombotic episodes may lead
to chronic thromboembolic pulmonary disease and, eventu-
ally, pulmonary arterial hypertension.
In the rare cases of catastrophic APS, multi-organ failure
may occur due to diffuse thrombotic micro-angiopathy. Lung
involvement has been reported in two thirds of the patients
212 Current Rheumatology Reviews, 2017, Vol. 13, No. 3
and, most commonly, exhibits with multiple pulmonary em-
bolisms and/or diffuse alveolar hemorrhage [76].
11.2. Pulmonary Artery Hypertension
SLE is the second most common systemic autoimmune
disease with concurrent pulmonary arterial hypertension
(PAH) after progressive systemic sclerosis [85]. PAH can be
detected with non-invasive measures in 6-14% of lupus pa-
tients; half of them do not have a clear risk factor besides
SLE, while in the other half PAH is considered secondary
[85]. In such cases, the most common primary causes are
heart disease (cardiomyopathy, valvular disease), chronic
thromboembolic pulmonary disease and pulmonary fibrosis
[59, 63]. SLE diagnosis precedes PAH in the vast majority of
patients; rarely, PAH may lead to lupus diagnosis [86]. Sev-
eral studies have demonstrated an association of PAH with
Raynaud’ s phenomenon rheumatoid factor positivity, anti-
ribonucleoprotein antibodies and endothelin-1 [87, 88].
The pathologic basis is immune complex-mediated vas-
culitis with thickening of the intima and media layers of
pulmonary artery branches and subsequent lumen narrowing
[85, 88]. Other mechanisms that may contribute to PAH in-
clude hypoxia due to lung disease (in cases of pulmonary
fibrosis), in situ thrombosis (in cases of positive antiphos-
pholipid antibodies) and pulmonary veno-occlusive disease.
In addition, disequilibrium between vasoconstrictors (endo-
thelin-1, thromboxane A2) and vasodilators (prostacyclin)
has been described in SLE [85].
Main clinical manifestations include exertional dyspnea,
chest pain, dry cough and syncope. Further features develop
upon right ventricular strain or failure such as elevated jugular
pressure, liver enlargement, ascites and lower limb edema.
Diagnosis of PAH can be obtained through Doppler
echocardiography, which may reliably assess the estimated
pulmonary artery pressure through the right ventricular sys-
tolic pressure and/or tricuspid insufficiency. Right heart
catheterization confirms diagnosis and evaluates PAH sever-
ity while it adds useful information for the responsiveness to
vasodilators. Exclusion of secondary causes of PAH should
include thorax CT (for pulmonary fibrosis), ventilation-
perfusion scan (for chronic thromboembolic pulmonary hy-
pertension) and pulmonary function tests since isolated im-
pairment of diffusing capacity for carbon monoxide (DLCO)
may be an early indicator of PAH.
12. SYNDROMES DUE TO EXTRA-PULMONARY
CAUSES
12.1. Shrinking Lung Syndrome
Respiratory muscle involvement may lead to hemidia-
phragm dysfunction and shrinking lung syndrome [59, 63]. It
is considered rare and may occur at any time after SLE diag-
nosis. Diaphragm paresis as a cause has been questioned by
a small study that reported a non-specific restriction in chest-
wall expansion rather than sole diaphragm dysfunction [89].
Clinical features include pleuritic-type chest pain, dyspnea
with orthopnea and reduced chest expansion while imaging
reveals elevated hemi-diaphragms without pleural involve-
ment. Pulmonary function tests indicate a restrictive ventila-
tory disorder with normal diffusing lung capacity. Differen-
Tselios and Urowitz
tial diagnosis includes pleural disease, lupus and corticoster-
oid-induced myopathy, as well as other causes of phrenic
nerve dysfunction [90].
The pathogenesis of shrinking lung syndrome has not
been elucidated. A weak association with anti-SSA/Ro anti-
bodies has been suggested [91] although with no direct link-
age. Diaphragm muscle fibrosis has been reported [92] while
a more generalized respiratory muscle dysfunction has also
been described [89]. Lupus-related phrenic nerve paresis
may also play a role in some cases [93].
13. THERAPEUTIC APPROACH TO HEART IN-
VOLVEMENT IN SLE
Non-steroidal anti-inflammatory drugs (NSAIDs) are
considered by most rheumatologists as the first choice in
mild cases with minimal pericardial effusion [94]. Corticos-
teroids should be used in refractory cases with or without an-
timalarials. The recommended dose has not been established;
however, it is suggested that this should be 0.5-1mg/kg of
prednisone with a stable dose for a month, followed by slow
tapering [95]. If symptoms persist or deteriorate, colchicine
(0.5-1mg/day) was shown to be effective in reducing disease
severity and recurrence rate [96]. Other approaches include the
addition of immunosuppressive drugs, such as azathioprine,
mycophenolate mofetil or methotrexate [95]. In isolated cases,
tocilizumab has been used successfully [97]. Pericardiotomy
represents the last resort, particularly in cases of constrictive
pericarditis with hemodynamic compromise or cardiac tam-
ponade.
Treatment of lupus myocarditis consists of corticoster-
oids in high doses (0.5-1mg/kg of prednisone or intravenous
pulses of methylprednisolone, e.g. 1000mg/day for 3 con-
secutive days) in combination with immunosuppressives
[98]. Cyclophosphamide and intravenous immunoglobulins
(IVIGs) have been shown to improve cardiac function and
mortality [99, 100]. Plasmapheresis is conserved for refrac-
tory cases. Supportive treatment in cases of overt heart fail-
ure is also recommended.
Therapeutic approach in cases with cardiomyopathy is
guided by the etiologic classification of the disease. Ischemic
cardiomyopathy should be treated with optimization of anti-
platelet/anticoagulant therapy and supportive measures (an-
giotensin converting enzyme inhibitors/receptor blockers,
beta-blockers, diuretics etc.) [101]. Intervention with coro-
nary angioplasty and by-pass graft should be considered in
cases of severe obstructive CAD according to the guidelines
for the general population. In the rare cases of antimalarial-
induced cardiomyopathy, withdrawal of the offending agent
is warranted; however, the rate of improvement has not been
defined [16].
Therapeutic approach to LSE remains controversial.
This valvulopathy is considered to be associated with dis-
ease activity and increased levels of aPL. Conservative
management with corticosteroids and anticoagulation may
be beneficial in selected patients with no hemodynamic
instability. However, in some cases corticosteroids may
increase the extent of fibrosis and ultimately worsen valvu-
lar deformity [102]. In addition, rapid deterioration of mi-
tral valve regurgitation was reported in a case after a few
Cardiovascular and Pulmonary Manifestations
weeks on high-dose corticosteroids [103]. Anticoagulants
are recommended for the prevention of embolic sequelae.
Of note, anticoagulation failed to regress valvular lesions in
primary APS after 5 years of follow-up, although intensive
therapy with an INR>3 was associated with less new le-
sions [104, 105]. Clinically significant valvular dysfunc-
tion, requiring surgical management, develops in 1-18% of
the patients. Surgical treatment is warranted in cases with
hemodynamic instability, preferably with valve replace-
ment instead of valvuloplasty, particularly in cases with
involvement of the subvalvular apparatus [106]. At the ex-
pense of life-long anticoagulation, mechanic valves are
supposed to perform better than bio-prosthetic ones since
the latter have been associated with recurrent valvulitis,
fibrosis and perforation and/or massive valve thrombosis
[107, 108].
Although the efficacy of antimalarials in SLE-related
heart disease has not been tested in randomized controlled
trials, it has been shown that these agents exert a protective
effect on the occurrence of primary heart disease (pericardi-
tis, myocarditis and valvular disease) [2].
13.1. Reduction of CV Risk in SLE
Early recognition and modification of the factors contrib-
uting to accelerated atherosclerosis in lupus patients are of
paramount importance since CVEs are one of the leading
causes of death in this population, even in relatively young
ages [58]. A thorough monitoring of these factors is recom-
mended upon disease diagnosis and on regular intervals
thereafter [43]. The goal is the minimization of the effect of
modifiable risk factors, such as hypertension, dyslipidemia,
diabetes, obesity and smoking; however no specific recom-
mendations currently exist [109].
Arterial hypertension should be treated early with a target
of 130/80mmHg, particularly for patients with renal in-
volvement [110]. Angiotensin converting enzyme inhibitors
(ACEIs) and/or angiotensin receptor blockers (ARBs) are
considered the drugs of choice, especially for patients with
lupus nephritis (LN) and concomitant proteinuria [110].
ACEIs non-use was associated with increased carotid athero-
sclerosis, as assessed by total plaque area, in African-
American lupus patients [111]. However, these agents failed
to exhibit an atheroprotective effect with regard to clinical
CVEs in lupus patients [112].
Concerning dyslipidemia, several randomized con-
trolled trials with statins in SLE patients failed to prove a
clear benefit in terms of halting atherosclerosis progres-
sion [113]. Atorvastatin (10-20mg/day) did not prevent
the progression of subclinical atherosclerosis, assessed by
carotid intima-media thickness (IMT), in children and
adolescents with SLE, over a 3-year period, in the Athero-
sclerosis Prevention in Paediatric Lupus Erythematosus
Study [114]. Use of higher doses (40mg/day) in adults
stabilized the coronary artery calcium score but had no
effect on perfusion defects [115]. Similarly, Lupus Athe-
rosclerosis Prevention Study (LAPS) reported no benefit,
in terms of coronary artery calcium and carotid IMT, us-
ing atorvastatin 40mg/day for 2 years. Moreover, no
changes were observed concerning disease activity and
inflammation or endothelial cell activation markers [116].
Current Rheumatology Reviews, 2017, Vol. 13, No. 3 213
Rosuvastatin (10mg/day) decreased carotid IMT in lupus
patients following a 24-month administration [117]
whereas fluvastatin significantly reduced CVEs in a sub-
group of kidney transplanted SLE patients [118]. In ado-
lescent lupus patients, atorvastatin failed to reduce carotid
IMT, although subgroup analysis showed that it might
reduce the progression rate of the atherosclerotic plaque
in patients with high CRP [119].
Aspirin in low doses is recommended for the primary
prevention of thrombotic events in SLE patients with posi-
tive aPL [120], although there is no strong evidence for this.
The regular use of low-dose aspirin in lupus patients without
any specific indication is not currently recommended.
In some studies, antimalarial treatment was associated
with a reduction in the rate of atherosclerotic cardiovascular
events [43].
14. THERAPEUTIC APPROACH TO RESPIRATORY
INVOLVEMENT IN SLE
Corticosteroids (prednisone dose 0.5mg/kg) are usually
effective in the treatment of moderate to severe pleural effu-
sions. In refractory cases, antimalarials and immunosuppres-
sive agents, such as azathioprine and mycophenolate mofetil
are recommended for flare prevention and steroid-sparing
effect [121-123]. Belimumab has also demonstrated efficacy
in isolated cases (unpublished observations) while thoracen-
tesis is indicated for symptomatic relief.
Treatment of interstitial lung disease (chronic and/or non-
specific interstitial pneumonia) is controversial since most
likely this does not deteriorate over time [121]. However, in
progressive cases, corticosteroids are the first choice along
with steroid-sparing agents, such as mycophenolate mofetil,
azathioprine or cyclophosphamide [124, 125]. The same
approach is recommended for the rare cases of bronchiolitis
obliterans with organizing pneumonia [126].
The therapeutic approach to acute lupus pneumonitis
and diffuse alveolar hemorrhage is largely based on clinical
experience and limited case reports and case series. Intra-
venous pulses of methylprednisolone (1g/day for three con-
secutive days) or high doses of prednisone (1-2mg/kg) in
less critically ill patients are recommended [121-123]. Im-
munosuppressive agents like cyclophosphamide (most
commonly in pulse therapy), IVIGs and azathioprine are
likely to provide clinical benefit [121, 127, 128]. Plas-
mapheresis has been used in approximately one third of the
published cases with diffuse alveolar hemorrhage and it did
not appear to influence the clinical outcome [129]. Suppor-
tive treatment with mechanical ventilation is warranted in
cases with ARDS.
Therapeutic approach to shrinking lung syndrome is
based on limited evidence and consists primarily of gluco-
corticoids with or without immunosuppressives [130, 131].
The precise dose of glucocorticoids or the duration of treat-
ment has not been specified. Most commonly used immuno-
suppressives include azathioprine, methotrexate and cyclo-
phosphamide. In cases where diaphragmatic weakness is
implied, theophylline and beta-agonists should also be con-
sidered [132, 133]. Isolated reports also demonstrated im-
provement of refractory cases with rituximab [134].
214 Current Rheumatology Reviews, 2017, Vol. 13, No. 3 Tselios and Urowitz

Treatment of pulmonary arterial hypertension in the Table 3. Main cardiac and pulmonary manifestations of SLE
context of SLE should be prompt and aim at PAP normali- and antiphospholipid syndrome and recommended
zation in order to maximize survival. Thorough diagnostic treatment.
evaluation is of utmost importance since patients with other
causes (e.g. left heart failure, chronic thromboembolic Pericarditis NSAIDs, corticosteroids, colchicine, immu-
PAH) should be treated accordingly (diuretics, anticoagu- nosuppressives (AZA, MMF, MTX), pericar-
lants etc). Subgroup analysis of several randomized trials diotomy
with PAH-targeted therapies in patients with connective
tissue disease-associated PAH has provided some evidence Myocarditis Corticosteroids (± IV pulses), cyclophos-
for a positive outcome in lupus patients [135-141]. These phamide, IVIGs, plasmapheresis, supportive
approaches included endothelin receptor antagonists treatment for HF
(bosentan), phosphodiesterase type 5 inhibitors (PDE5 in- Cardiomyopathy Guided by the etiology (e.g. antiplate-
hibitors, sildenafil) and vasodilators. Primary end points let/anticoagulation therapy, invasive ap-
included the change in functional class (New York Heart proach in ischemic cardiomyopathy)
Association), exercise tolerance (assessed with the 6 min-
ute walk distance) and PAH hemodynamics. In parallel, Libman-Sacks Corticosteroids, immunosuppressives (?),
observational cohort studies have shown that immunosup- endocarditis anticoagulation, surgery
pressive therapies have a considerable benefit in such pa-
Accelerated Optimal control of modifiable risk factors
tients [142-148]. Corticosteroids in high doses (0.5-
atherosclerosis (hypertension, dyslipidemia, diabetes, obe-
1mg/kg/day with slow tapering) were used in all these stud-
sity, smoking), minimization of glucocorti-
ies, usually in combination with cyclophosphamide (intra-
coids, antimalarials, aspirin in patients with
venous pulses 500-1000mg/m2 /month). More recently, it
positive antiphospholipid antibodies
was demonstrated that the addition of vasodilators and sup-
portive treatment with diuretics and anti-coagulants may Pleuritis Corticosteroids, antimalarials, immunosup-
benefit patients with more severe PAH at diagnosis; in that pressives (AZA, MMF)
study, patients with mixed connective tissue disease were
also included [145]. Interstitial lung Corticosteroids, immunosuppressives (AZA,
disease MMF), cyclophosphamide in cases of rapid
progression
15. TREATMENT OF THROMBOTIC MANIFESTA-
TIONS IN APS Bronchiolitis obliterans Corticosteroids, immunosuppressives (AZA,
with organizing MMF), cyclophosphamide in cases of rapid
Therapeutic management of APS is based on anticoagu-
pneumonia progression
lants and/or antiplatelet drugs and depends on the initial
clinical manifestations and concurrent co-morbidities. In the Acute lupus IV pulses of corticosteroids, cyclophos-
case of non-symptomatic presence of antiphospholipid anti- pneumonitis phamide, plasmapheresis, mechanical venti-
bodies (particularly high titers of IgG aCL, IgG anti-b2GPI lation if ARDS
or persistently positive lupus anticoagulant), the use of low
dose aspirin (75-100 mg/day) is recommended [149], al- Diffuse alveolar IV pulses of corticosteroids, cyclophos-
though not based on solid evidence. hemorrhage phamide, plasmapheresis, mechanical venti-
lation if ARDS
In the case of venous thrombosis/pulmonary embolism,
initial management does not differ from patients without Shrinking lung Corticosteroids, immunosuppressives (AZA,
APS; heparin (unfractionated or low molecular weight syndrome MTX), 2-agonists, theophylline
heparin or fondaparinux) should be administered for 4-5
Pulmonary arterial Corticosteroids, cyclophosphamide, PAH-
days followed by warfarin or other vitamin K inhibitors. hypertension targeted therapy
Therapy is recommended indefinitely, aiming at an INR
(international normalized ratio) between 2.0 and 3.0 [150]. Presence of aPL Low dose aspirin (75-100mg/day)
Initial management of an arterial thrombotic event (stroke, without clinical event
myocardial infarction etc.) should be guided by the existing
Venous thrombosis LMWH in the initial stages, anticoagulation
recommendations. Chronic anticoagulant therapy with war-
and pulmonary (target INR 2.0-3.0 if warfarin is used)
farin aiming at an INR between 3.0 to 4.0 is warranted; in
embolism
patients with high risk for recurrence, aspirin should be co-
administered. Arterial thrombosis Anticoagulation (target INR 3.0-4.0)
Immunosuppressive medications are usually recom- NSAIDs: non-steroidal anti-inflammatory drugs, AZA: azathioprine, MMF: mycophe-
mended in secondary APS aiming at suppressing aPL titers nolate mofetil, MTX: methotrexate, IV: intravenous, IVIGs: intravenous immuno-
globulins, HF: heart failure, ARDS: acute respiratory distress syndrome, PAH: pulmo-
and the vascular inflammation from the underlying disease. nary arterial hypertension, LMWH: low molecular weight heparin, INR: international
High doses (or intravenous pulses) of corticosteroids, cyclo- normalized ratio.
phosphamide, rituximab and/or plasma exchange are used in
cases of refractory disease (in the context of severe SLE) or
catastrophic APS [149]. CONSENT FOR PUBLICATION
Therapeutic approach to the main cardiovascular and Not applicable.
respiratory manifestations of SLE is presented in Table 3.
Cardiovascular and Pulmonary Manifestations
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1] Tsokos GC. Systemic lupus erythematosus. N Eng J Med 2011;
365: 2110-21.
[2] Garcia MA, Alarcon GS, Boggio C, Hachuel L, Marcos AI, Marcos
JC et al. Primary cardiac disease in systemic lupus erythematosus
patients: protective and risk factors- data from a multi-ethnic Latin
American cohort. Rheumatology (Oxford) 2014; 53: 1431-8.
[3] Miner JJ, Kim AH. Cardiac manifestations of systemic lupus
erythematosus. Rheum Dis Clin North Am 2014; 40: 51-60.
[4] Topaloglou S, Aras D, Ergun K, Altay H, Alyan O, Akgul K. Sys-
temic lupus erythematosus: an unusual case of cardiac tamponade
in a young man. Eur J Echocardiogr 2006; 7: 460-2.
[5] Doria A, Iaccarino L, Sarzi-Puttini P, Atzeni F, Turriel M, Petri M.
Cardiac involvement in systemic lupus erythematosus. Lupus 2005;
14: 683-6.
[6] Buppajamrntham T, Palavutitoai N, Katchamart W. Clinical mani-
festation, diagnosis, management and treatment outcome of peri-
carditis in patients with systemic lupus erythematosus. J Med As-
soc Thai 2014; 97: 1234-40.
[7] Oh JY, Chang SA, Choe YH, Kim DK. Transient constrictive peri-
carditis in systemic lupus erythematosus. Eur Heart J Cardiovasc
Imaging 2012; 13: 793.
[8] Tincani A, Rebaioli CB, Taglietti M, Shoenfeld Y. Heart involve-
ment in systemic lupus erythematosus, antiphospholipid syndrome
and neonatal lupus. Rheumatology (Oxford) 2006; 45 suppl 4: iv8-
iv13.
[9] Bulkley BH, Roberts WC. The heart in systemic lupus erythemato-
sus and the changes induced in it by corticosteroid therapy: a study
of 36 necropsy patients. Am J Med 1975; 58: 243.
[10] Apte M, McGwin G Jr, Vilá LM, Kaslow RA, Alarcón GS,
Reveille JD; LUMINA Study Group. Associated factors and impact
of myocarditis in patients with SLE from LUMINA, a multiethnic
US cohort (LV). Rheumatology (Oxford). 2008; 47: 362-7.
[11] Zhang L, Zhu YL, Li MT, Gao N, You X, Wu QJ et al. Lupus
myocarditis: a case control study from China. Chin Med J (Engl)
2015; 128: 2588-94.
[12] Mavrogeni S, Bratis K, Markoussis V, Spargias C, Papadopoulou
E, Papamentzelopoulos S et al. The diagnostic role of cardiac mag-
netic resonance imaging in detecting myocardial inflammation in
systemic lupus erythematosus. Differentiation from viral myocardi-
tis. Lupus 2013; 22: 34-43.
[13] Alchammas J, Al-Faham Z, Roumayah Y, Wong OC. The evalua-
tion of lupus myocarditis with 13N-Ammonia and 18F-FDG PET. J
Nucl Med Technol 2016; 44: 210-1.
[14] Chung HT, Huang YL, Yeh KW, Huang JL. Subclinical deteriora-
tion of left ventricular function in patients with juvenile-onset sys-
temic lupus erythematosus. Lupus 2015; 24: 263-72.
[15] Li K, Wang R, Dai M, Lu J, Zou Y, Yang X. Evaluation of left
atrial function by real time 3-D echocardiography in patients with
systemic lupus erythematosus. J Rheumatol 2015; 42: 196-201.
[16] Yogasundaram H, Putko BN, Tien J, Paterson I, Cujec B, Ringrose
J et al. Hydroxychloroquine-induced cardiomyopathy: case report,
pathophysiology, diagnosis and treatment. Can J Cardiol 2014; 30:
1706-15.
[17] Tselios K, Gladman DD, Harvey P, Mak S, Chantal M, Butany J,
Urowitz MB. Hydroxychloroquine-induced cardiomyopathy in sys-
temic lupus erythematosus-a case report. J Clin Rheumatol 2016;
22: 287-8.
[18] Shim IK, Kim BJ, Kim H, Lee JW, Cha TJ, Heo GH. A case of
persistent apical ballooning complicated with apical thrombus in
Takotsubo cardiomyopathy of a systemic lupus erythematosus pa-
tient. J Cardiovasc Ultrasound 2013; 21: 137-9.
[19] Bourre-Tessier J, Urowitz MB, Clarke AE, Bernatsky S, Krantz
MJ, Huynh T et al. Electrocardiographic findings in systemic lupus
Current Rheumatology Reviews, 2017, Vol. 13, No. 3 215
erythematosus: data from an international inception cohort. Arthri-
tis Care Res 2015; 67: 128-35.
[20] Demir K, Avci A, Yilmaz S, Demir T, Ersecqin A, Altunkeser BB.
Fragmented QRS in patients with systemic lupus erythematosus.
Scand Cardiovasc J 2014; 48: 197-201.
[21] Teixeira RA, Borba EF, Bonfa E, Filho MM. Arrhythmias in sys-
temic lupus erythematosus. Bras J Rheumatol 2010; 50: 81-9.
[22] Cairoli E, Danese N, Teliz M, Bruzzone MJ, Ferreira J, Rebella M
et al. Cumulative dose of hydroxychloroquine is associated with a
decrease of resting heart rate in patients with systemic lupus e-
rythematosus: a pilot study. Lupus 2015; 24: 1204-9 .
[23] Teixeira RA, Borba EF, Pedrosa A, Nishioka S, Viana VS, Ramires
JA et al. Evidence for cardiac safety and antiarrhythmic potential
of chloroquine in systemic lupus erythematosus. Eurospace 2014;
16: 887-92.
[24] Utset TO, Ward AB, Thompson TL, Green SL. Significance of
chronic tachycardia in systemic lupus erythematosus. Arthritis Care
Res (Hoboken) 2013; 65: 827-31.
[25] Turiel M, Muzzupappa S, Gottardi B, Crema C, Sarzi-Puttini P,
Rossi E. Evaluation of cardiac abnormalities and embolic sources
in primary antiphospholipid syndrome by transesophageal echocar-
diography. Lupus 2000; 9: 406-12.
[26] Erdogan G, Goren MT, Diz Kucukkaya R, Inanc M. Assessment of
cardiac structure and left atrial appendage functions in primary an-
tiphospholipid syndrome: a transesophageal echocardiographic
study. Stroke 2005; 36: 592-6.
[27] Foroughi M, Hekmat M, Ghorbani M, Ghaderi H, Majidi M, Be-
hesti M. Mitral valve surgery in patients with systemic lupus
erythematosus. Sci World J 2014; 2014: 216291.
[28] Libman E, Sacks B. A hitherto undescribed form of valvular and
mural endocarditis. Arch Intern Med 1924; 33: 701-37.
[29] Moyssakis I, Tektonidou MG, Vasilliou VA, Samarkos M, Votteas
V, Moutsopoulos HM. Libman-Sacks endocarditis in systemic lu-
pus erythematosus: prevalence, associations and evolution. Am J
Med 2007; 120: 636-42.
[30] Hachiya K, Wakami K, Tani T, Yoshida A, Suzuki S, Suda H et al.
Double-valve replacement for mitral and aortic regurgitation in a
patient with Libman-Sacks endocarditis. Intern Med 2014; 53:
1769-73.
[31] Plastiras SC, Pamboucas CA, Tektonidou M, Toumanidis ST. Real-
time three-dimensional echocardiography in evaluating Libman-
Sacks vegetations. Eur J Echocardiogr 2010; 11(2): 184-5.
[32] Hansson GK. Inflammation, atherosclerosis and coronary artery
disease. N Engl J Med 2005; 352: 1685-95.
[33] Urowitz MB, Bookman AA, Hoehler BE, Gordon DA, Smythe HA,
Ogryzlo MA. The bimodal mortality pattern of systemic lupus
erythematosus. Am J Med 1976; 60: 221-5.
[34] Aranow C, Ginzler EM. Epidemiology of cardiovascular disease in
systemic lupus erythematosus. Lupus 2000; 9: 166-9.
[35] Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA Jr, Jan-
sen-McWilliams L et al. Age-specific rates of myocardial infarc-
tion and angina in women with systemic lupus erythematosus:
comparison with the Framingham study. Am J Epidemiol 1997;
145: 408-15.
[36] Zoller B, Li X, Sundquist J, Sundquist K. Risk of subsequent coro-
nary heart disease in patients hospitalized for immune-mediated
diseases: a nation-wide follow up study from Sweden. PLoS One
2012; 7: e33442.
[37] Avina-Zubieta JA, Sayre EC, Kopec J. Risk of myocardial infarc-
tion in patients with systemic lupus erythematosus: a population-
based study. Lupus 2013; 22: 20 (abstract).
[38] Bartels CM, Buhr KA, Goldberg JW, Bell CL, Visekruna M, Nek-
kanti S et al. Mortality and cardiovascular burden of systemic lupus
erythematosus in a US population-based cohort. J Rheumatol 2014;
41: 680-7.
[39] Urowitz MB, Ibanez D, Gladman DD. Atherosclerotic vascular
events in a single large lupus cohort: prevalence and risk factors. J
Rheumatol 2007; 34: 70-5.
[40] Bruce IN, Gladman DD, Urowitz MB. Premature atherosclerosis in
systemic lupus erythematosus. Rheum Dis Clin North Am 2000;
26: 257-78.
[41] Scalzi LV, Hollenbeak CS, Wang L. Racial disparities in age at
time of cardiovascular events and cardiovascular-related death in
patients with systemic lupus erythematosus. Arthritis Rheum 2010;
62: 2767-75.
216 Current Rheumatology Reviews, 2017, Vol. 13, No. 3
[42] Esdaile JM, Abrahamowicz M, Grodzicky T, et al. Traditional
Framingham risk factors fail to fully account for accelerated athe-
rosclerosis in systemic lupus erythematosus. Arthritis Rheum 2001;
44: 2331-7.
[43] Tselios K, Sheane BJ, Gladman DD, Urowitz MB. Optimal moni-
toring for coronary heart disease risk in systemic lupus erythemato-
sus patients. A systematic review. J Rheumatol 2016: 43: 54-65.
[44] Steiman A, Gladman DD, Ibanez D, Urowitz MB. Outcomes in
patients with systemic lupus erythematosus with and without a pro-
longed serologically active clinically quiescent period. Arthritis
Care Res (Hoboken) 2012; 64: 511-8.
[45] Tselios K, Sarantopoulos A, Gkougkourelas I, Boura P. T regula-
tory cells: A promising new target in atherosclerosis. Crit Rev Im-
munol 2014; 34: 389-97.
[46] Karp I, Abrahamowicz M, Fortin PR, Pilote L, Neville C, Pineau
CA et al. Longitudinal evolution of coronary heart disease in sys-
temic lupus erythematosus. J Rheumatol 2012; 39: 968-73.
[47] Magder LS, Petri M. Incidence of and risk factors for adverse car-
diovascular events among patients with systemic lupus erythemato-
sus. Am J Epidemiol 2012; 176: 708-19.
[48] Doria A, Shoenfeld Y, Wu R, Gambari PF, Puato M, Ghirardello A
et al. Risk factors for subclinical atherosclerosis in a prospective
cohort of patients with systemic lupus erythematosus. Ann Rheum
Dis 2003; 62: 1071-7.
[49] Schanberg LE, Sandborg C, Barnhart HX, Ardoin SP, Yow E,
Evans GW et al. Premature atherosclerosis in pediatric systemic
lupus erythematosus: risk factors for increased carotid intima-
media thickness in the atherosclerosis prevention in pediatric lupus
erythematosus cohort. Arthritis Rheum 2009; 60: 1496-507.
[50] Rho YH, Chung CP, Oeser A, Solus J, Raggi P, Gebretsadik T et
al. Novel cardiovascular risk factors in premature coronary athero-
sclerosis associated with systemic lupus erythematosus. J Rheuma-
tol 2008; 35: 1789-94.
[51] Sacre K, Escoubet B, Pasquet B, Chauveheid MP, Zennaro MC,
Tubach F et al. Increased arterial stiffness in systemic lupus
erythematosus (SLE) patients at low risk for cardiovascular dis-
ease: a cross-sectional controlled study. PLoS One 2014; 9:
e94511.
[52] Jung H, Bobba R, Su J, Shariati-Sarabi Z, Gladman DD, Urowitz
M et al. The protective effect of antimalarial drugs on thrombovas-
cular events in systemic lupus erythematosus. Arthritis Rheum
2010; 62: 863-8.
[53] Chung CP, Oeser A, Avalos I, Raggi P, Stein CM. Cardiovascular
risk scores and the presence of subclinical coronary artery athero-
sclerosis in women with systemic lupus erythematosus. Lupus
2006; 15: 562-9.
[54] Goldberg RJ, Urowitz MB, Ibanez D, Nikpour M, Gladman DD.
Risk factors for development of coronary artery disease in women
with systemic lupus erythematosus. J Rheumatol 2009; 36: 2454-
61.
[55] Urowitz MB, Gladman DD, Ibanez D, Fortin P, Sanchez-Guerrero
J, Bae S et al. Clinical manifestations and coronary artery disease
risk factors at diagnosis of systemic lupus erythematosus: data from
an international inception cohort. Lupus 2007; 16: 731-5.
[56] Urowitz MB, Ibanez D, Su J, Gladman DD. Modified Framingham
Risk Factor score for systemic lupus erythematosus. J Rheumatol
2016; 43: 875-9.
[57] Carmier D, Marchand-Adam S, Diot P, Diot E. Respiratory in-
volvement in systemic lupus erythematosus. Rev Maladie Respirat
2010; 27: e66-e78.
[58] Abu-Shakra M, Urowitz MB, Gladman DD, Gough J. Mortality
studies in systemic lupus erythematosus. Results from a single cen-
tre. I. Causes of death. J Rheumatol 1995; 22: 1259-64.
[59] Swigris JJ, Fischer A, Gilles J, Meehan RT, Brown KK. Pulmonary
and thrombotic manifestations of systemic lupus erythematosus.
Chest 2008; 133: 271-80.
[60] Hochberg MC. Updating the American College of Rheumatology
revised criteria for the classification of systemic lupus erythemato-
sus. Arthritis Rheum 1997; 40(9): 1725.
[61] Wang DY, Yang PC, Yu WL, Kuo SH, Hsu NY. Serial antinuclear
antibodies titre in pleural and pericardial fluid. Eur Respir J 2000;
15: 1106-10.
[62] Crestam B. The respiratory system in connective tissue disorders.
Allergy 2005; 60: 715-34.
[63] Keane MP, Lynch JP. Pleuropulmonary manifestations of systemic
lupus erythematosus. Thorax 2000; 55: 159-66.
Tselios and Urowitz
[64] Fenlon HM, Doran M, Sant SM. Breatnach E. High resolution
chest CT in systemic lupus erythematosus. Am J Roentgenol 1996;
166: 301-7.
[65] Anto JM, Cullinan P. Clusters, classification and epidemiology of
interstitial lung diseases: concepts, methods and critical reflections.
Eur Respir J Suppl 2001; 32: 101s-106s .
[66] Eichacker PQ, Pinsker K, Epstein A, Schiffenbauer J, Grayzel A.
Serial pulmonary function testing in patients with systemic lupus
erythematosus. Chest 1988; 94: 129-32.
[67] Hedgpeth MI, Boulware DW. Interstitial pneumonitis in antinu-
clear antibody-negative systemic lupus erythematosus: a new clini-
cal manifestation and possible association with anti-Ro (SSA) anti-
bodies. Arthritis Rheum 1988; 31: 545-8.
[68] Takada H, Saito Y, Nomura A, Ohga S, Kuwano K, Nakashima N
et al. Bronchiolitis obliterans organizing pneumonia as an initial
manifestation in systemic lupus erythematosus. Pediatr Pulmonol
2005; 40: 257-60.
[69] Gammon RB, Bridges TA, Al-Nezir H, Alexander CB, Kennedy Jr
JI. Bronchiolitis obliterans organizing pneumonia associated with
systemic lupus erythematosus. Chest 1992; 102: 1171-4.
[70] Haupt HM, Moore GW, Hutchins GM. The lung in systemic lupus
erythematosus. Analysis of the pathologic changes in 120 patients.
Am J Med 1981; 71: 791-8.
[71] Matthay RA, Schwartz MI, Petty TL, Stanford RE, Gupta RC,
Sahn SA et al. Pulmonary manifestations of systemic lupus
erythematosus: review of twelve cases of acute lupus pneumonitis.
Medicine (Baltimore) 1975; 54: 397-409.
[72] Schwab EP, Schumacher Jr HR, Freundlich B, Callegari PE. Pul-
monary alveolar hemorrhage in systemic lupus erythematosus.
Semin Arthritis Rheum 1993; 23: 8-15.
[73] Zamora MR, Warner ML, Tuder R, Schwarz MI. Diffuse alveolar
hemorrhage and systemic lupus erythematosus. Clinical presenta-
tion, histology, survival and outcome. Medicine (Baltimore) 1997;
76: 192-202.
[74] Orens JB, Martinez FJ, Lynch 3rd JP. Pleuropulmonary manifesta-
tions of systemic lupus erythematosus. Rheum Dis Clin North Am
1994; 20: 159-93.
[75] Myers JL, Katzenstein AA. Microangiitis in lupus-induced pulmo-
nary hemorrhage. Am J Clin Pathol 1986; 85: 552-6.
[76] Boura P, Papadopoulos S, Tselios K, Skendros P, Dioritou O, Ma-
lamis G et al. Intracerebral hemorrhage in a patient with SLE and
catastrophic antiphospholipid syndrome (CAPS): report of a case.
Clin Rheumatol 2005; 24: 420-4.
[77] Kim WU, Kim SI, Yoo WH, Park JH, Min JK, Kim SC et al. Adult
respiratory distress syndrome in systemic lupus erythematosus:
causes and prognostic factors: a single center, retrospective study.
Lupus 1999; 8: 552-7.
[78] Andonopoulos AP, Constantopoulos SH, Galanopoulou V, Drosos
AA, Acritidis NC et al. Pulmonary function of non-smoking pa-
tients with systemic lupus erythematosus. Chest 1988; 94: 312-5.
[79] Kinney WW, Angelillo VA. Bronchiolitis in systemic lupus
erythematosus. Chest 1982; 82: 646-9.
[80] Ooi GC, Ngan H, Peh WC, Mok MY, Ip M. Systemic lupus
erythematosus patients with respiratory symptoms: the value of
HRCT. Clin Radiol 1997; 52: 775-81.
[81] Abramson SB, Dobro J, Eberle MA, Benton M, Reibman J, Epstein
H et al. Acute reversible hypoxemia in systemic lupus erythemato-
sus. Ann Intern Med 1991; 114: 941-7.
[82] Martinez-Taboada VM, Blanco R, Armona J, Fernandez-Sueiro JL,
Rodriguez-Valverde V. Acute reversible hypoxemia in systemic
lupus erythematosus: a new syndrome or an index of disease activ-
ity? Lupus 1995; 4: 259-62.
[83] Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL,
Cervera R et al. International consensus statement on an update of
the classification criteria for definite antiphospholipid syndrome
(APS). J Thromb Haemost 2006; 4: 295-306.
[84] Wahl DG, Guillemin E, de Maistre E, Perret C, Lecompte T, Thi-
baut G. Risk for venous thrombosis related to antiphospholipid an-
tibodies in systemic lupus erythematosus- a meta-analysis. Lupus
1997; 6: 467-73.
[85] Dhala A. Pulmonary arterial hypertension in systemic lupus
erythematosus: current status and future direction. Clin Dev Immu-
nol 2012; 2012: 854941.
[86] Johnson SR, Gladman DD, Urowitz MB, Ibanez D, Granton JT.
Pulmonary hypertension in systemic lupus. Lupus 2004; 13: 506-9.
Cardiovascular and Pulmonary Manifestations
[87] Shen JY, Chen SL, Wu XY et al. Pulmonary hypertension in sys-
temic lupus erythematosus. Rheumatol Int 1999; 18: 147-51.
[88] Guillevin L. Vasculopathy and pulmonary arterial hypertension.
Rheumatology 2009; 48 suppl3: iii54-7.
[89] Laroche CM, Mulvey DA, Hawkins PN, Walport MI, Strickland B,
Moxham J et al. Diaphragm strength in the shrinking lung syn-
drome of systemic lupus erythematosus. Q J Med 1989; 71: 429-39.
[90] Allen D, Stoller JK, Minai OA. A 45-year-old woman with sys-
temic lupus erythematosus and progressive dyspnea. Chest 2007;
131: 1252-5.
[91] Isbii M, Uda H, Yamagami T, Katada Y. Possible association of
“shrinking lung” and anti-Ro/SSA antibody. Arthritis Rheum 2000;
43: 2612-3.
[92] Rubin LA, Urowitz MB. Shrinking lung syndrome in SLE: a clini-
cal pathologic study. J Rheumatol 1983; 10: 973-6.
[93] Hardy K, Herry I, Attali V, Cadranel J, Similowski T. Bilateral
phrenic paralysis in a patient with systemic lupus erythematosus.
Chest 2001; 119: 1274-7.
[94] Muangchan C, Van Vollenhoven RF, Bernatsky SR, Smith CD,
Hudson M, Inanc M et al. Treatment algorithms in systemic lupus
erythematosus. Arthritis Care Res (Hoboken) 2015; 67: 1237-45.
[95] Kruzliak P, Novak M, Piler P, Kovacova G. Pericardial involve-
ment in systemic lupus erythematosus: current diagnosis and ther-
apy. Acta Cardiol 2013; 68: 629-33 .
[96] Imazio M, Bobbio M, Cecchi E, Demarie D, Demichelis B, Pomari
F et al. Colchicine in addition to conventional therapy for acute
pericarditis: results of the COlchicine for acute PEricarditis
(COPE) trial. Circulation 2005; 112: 2012-6.
[97] Ocampo V, Haaland D, Legault K, Mittoo S, Aitken E. Successful
treatment of recurrent pleural and pericardial effusions with tocili-
zumab in a patient with systemic lupus erythematosus. BMJ Case
Rep 2016 Aug 8; 2016 pii: bcr2016215423.
[98] Zhang L, Zhu YL, Li MT, Gao N, You X, Wu QJ et al. Lupus
myocarditis: a case-control study from China. Chin Med J (Engl)
2015: 128: 2588-94.
[99] Azzam ZS, Maza I, Zeidan-Shwiri T, Lorber M. Cyclophos-
phamide restores heart function in a patient with lupus myocarditis.
Isr Med Assoc J 2005; 7: 266-7.
[100] Micheloud D, Calderon M, Caparros M, D’Cruz DP. Intravenous
immunoglobulin therapy in severe lupus myocarditis: good out-
come in three patients. Ann Rheum Dis 2007; 66: 986-7.
[101] Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG,
Fletcher BJ et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS fo-
cused update of the guideline for the diagnosis and management of
patients with stable ischemic heart disease: a report of the Ameri-
can College of Cardiology/American Heart Association Task Force
on practice guidelines and the American Association for Thoracic
Surgey, Preventive Cardiovascular Nurses Association, Society for
Cardiovascular Angiography and Interventions and Society of Tho-
racic Surgeons. Circulation 2014; 130: 1749-67.
[102] Hojnik M, George J, Ziporen L, Shoenfeld Y. Heart valve in-
volvement (Libman-Sacks endocarditis) in the antiphospholipid
syndrome. Circulation 1996; 93: 1579-87.
[103] Hoffman R, Lethen H, Zunker U, Schondube FA, Maurin N, Sie-
berth HG. Rapid appearance of severe mitral regurgitation under
high-dosage corticosteroid therapy in a patient with systemic lupus
erythematosus. Eur Heart J 1994; 15: 138-9.
[104] Zavaleta NE, Montes RM, Soto ME, Vanzzini NA, Amigo MC.
Primary antiphospholipid syndrome: a 5-year transesophageal
echocardiographic follow-up study. J Rheumatol 2004; 31: 2402-7.
[105] Turiel M, Sarzi-Puttini P, Peretti R, Bonizzato S, Muzzupappa S,
Atzeni F et al. Five-year follow-up by transesophageal echocardio-
graphic studies in primary antiphospholipid syndrome. Am J Car-
diol 2005; 96: 574-9 .
[106] Bai Z, Hou J, Ren W, Guo Y. Diagnosis and surgical treatment for
isolated tricuspid Libman-Sacks endocarditis: a rare case report and
literature review. J Cardiothorac Surg 2015; 10: 93 .
[107] Gordon RJ, Weilbaecher D, Davy SM, Safi HJ, Quinines MA,
DeFelice CA et al. Valvulitis involving a bio-prosthetic valve in a
patient with systemic lupus erythematosus. J Am Soc Echocardiogr
1996; 9: 104-7 .
[108] Da Silva AN, Ferreira LD, Monaco CG, Silva CE, Gil MA, Peixoto
LB et al. Intracardiac thrombosis and mitral prosthesis dysfunction
in systemic lupus erythematosus. A case report. Rev Port Cardiol
2003; 22:213-9.
Current Rheumatology Reviews, 2017, Vol. 13, No. 3 217
[109] Bertsias G, Ioannidis JPA, Boletis J, Bombardieri S, Cervera R,
Dostal C et al. EULAR recommendations for the management of
systemic lupus erythematosus. Report of a Task Force of the EU-
LAR Standing Committee for International Clinical Studies includ-
ing Therapeutics. Ann Rheum Dis 2008; 67: 195-205.
[110] Tselios K, Koumaras C, Gladman DD, Urowitz MB. Do current
arterial hypertension treatment guidelines apply to systemic lupus
erythematosus patients? A critical appraisal. Semin Arthritis
Rheum 2014; 43: 521-5.
[111] Ravenell RL, Kamen DL, Spence JD, Hollis BW, Fleury TJ, Jan-
ech MG et al. Premature atherosclerosis is associated with hypovi-
taminosis D and angiotensin converting enzyme inhibitor non-use
in lupus patients. Am J Med Sci 2012; 344: 268-73.
[112] Tselios K, Gladman DD, Su J, Urowitz MB. Does renin-
angiotensin system blockade protect lupus nephritis patients from
atherosclerotic cardiovascular events? A case-control study. Arthri-
tis Care Res (Hoboken) 2016; 68: 1497-504.
[113] Tselios K, Koumaras C, Gladman DD, Urowitz MB. Dyslipidemia
in systemic lupus erythematosus: just another comorbidity? Semin
Arthritis Rheum 2016; 45: 604-10.
[114] Schanberg LE, Sandborg C, Barnhart HX, Ardoin SP, Yow E,
Evans GW et al. Use of atorvastatin in systemic lupus erythemato-
sus in children and adolescents. Arthritis Rheum 2012; 64: 285-96.
[115] Plazak W, Gryga K, Dziedzic H, Tomkiewicz-Pajak L, Konieczyn-
ska M, Podolec P et al. Influence of atorvastatin on coronary calci-
fications and myocardial perfusion defects in systemic lupus
erythematosus patients: a prospective, randomized, double-masked,
placebo-controlled study. Arthritis Res Ther 2011; 13: R117.
[116] Petri MA, Kiani AN, Post W, Christopher-Stine L, Magder LS.
Lupus Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis
2011; 70: 760-5.
[117] Mok CC, Wong CK, To CH, Lai JP, Lam CS. Effects of rosuvas-
tatin on vascular biomarkers and carotid atherosclerosis in lupus: a
randomized, double-blind, placebo-controlled trial. Arthritis Care
Res (Hoboken) 2011; 63: 875-83.
[118] Norby GE, Holme I, Fellstrom B, Jardine A, Cole E, Abedini S et
al. Effect of fluvastatin on cardiac outcomes in kidney transplant
patients with systemic lupus erythematosus: a randomized placebo-
controlled study. Arthritis Rheum 2009; 60: 1060-4.
[119] Ardoin SP, Schanberg LE, Sandborg CI, Barnhart HX, Evans GW,
Yow E et al. Secondary analysis of the APPLE study suggests
atorvastatin may reduce atherosclerosis progression in pubertal pa-
tients with higher C reactive protein. Ann Rheum Dis 2014; 73:
557-66.
[120] Arnaud L, Mathian A, Ruffatti A, Erkan D, Tektonidou M, Cervera
R et al. Efficacy of aspirin for the primary prevention of thrombo-
sis in patients with antiphospholipid antibodies: an international
and collaborative meta-analysis. Autoimmun Rev 2014; 13: 281-
91.
[121] Mira-Avendano IC, Abril A. Pulmonary manifestations of Sjogren
syndrome, systemic lupus erythematosus and mixed connective tis-
sue disease. Rheum Dis Clin North Am 2015; 41: 263-77.
[122] Memet B, Ginzler EM. Pulmonary manifestations of systemic
lupus erythematosus. Semin Respir Crit Care Med 2007; 28: 41-50.
[123] Torre O, Harari S. Pleural and pulmonary involvement in systemic
lupus erythematosus. Presse Med 2011; 40: e19-29.
[124] Fischer A, Brown KK, Du Bois RM et al. Mycophenolate mofetil
improves lung function in connective tissue-associated interstitial
lung disease. J Rheumatol 2013; 40: 640-6.
[125] Eiser AR, Shanies HM. Treatment of lupus interstitial lung disease
with cyclophosphamide. Arthritis Rheum 1994; 37: 428-31.
[126] Takada H, Saito Y, Nomura A et al. Bronchiolitis obliterans organ-
izing pneumonia as an initial manifestation in systemic lupus
erythematosus. Pediatr Pulmonol 2005; 40: 257-60.
[127] Isbister JP, Ralston M, Hayes JM et al. Fulminant lupus pneumoni-
tis with acute renal failure and RBC aplasia. Successful manage-
ment with plasmapheresis and immunosuppression. Arch Intern
Med 1981; 141: 1081-3.
[128] Winder A, Molad Y, Ostfeld I et al. Treatment of systemic lupus
erythematosus by prolonged administration of high dose intrave-
nous immunoglobulins: report of 2 cases. J Rheumatol 1993; 20:
495-8.
[129] Ednalino C, Yip J, Carsons SE. Systematic review of diffuse alveo-
lar haemorrhage in systemic lupus erythematosus: focus on out-
come and therapy. J Clin Rheumatol 2015; 21: 305-10.
218 Current Rheumatology Reviews, 2017, Vol. 13, No. 3
[130] Duron L, Cohen-Aubart F, Diot E, Borie R, Abad S, Richez C et al.
Shrinking lung syndrome associated with systemic lupus erythema-
tosus: A multicenter collaborative study of 15 new cases and a re-
view of the 155 cases in the literature focusing on treatment re-
sponse and long-term outcomes. Autoimmun Rev 2016; 15: 994-
1000.
[131] Borrell H, Narváez J, Alegre J, Castellví I, Mitjavila F, Aparicio M
et al. Shrinking lung syndrome in systemic lupus erythematosus.
Medicine 2016; 95: e4626.
[132] Van Veen S, Peeters AJ, Sterk PJ, Breedveld FC. The “shrinking
lung syndrome” in SLE: treatment with theophylline. Clin Rheu-
matol 1993; 12: 462-5.
[133] Muñoz-Rodríguez FJ, Font J, Badia JR, Miret C, Barbera JA,
Cervera R et al. Shrinking lungs syndrome in systemic lupus
erythematosus: improvement with inhaled beta-agonist therapy.
Lupus 1997; 6: 412-4.
[134] Benham H, Garske L, Veccio P, Eckert BW. Successful treatment
of shrinking lung syndrome with rituximab in a patient with sys-
temic lupus erythematosus. J Clin Rheumatol 2010; 16: 68-70.
[135] Robbins IM, Gaine SP, Schilz R, Tapson VE, Rubin LJ, Loyd JE.
Epoprostenol for treatment of pulmonary hypertension in patients
with systemic lupus erythematosus. Chest 2000; 117: 14-8.
[136] Shirai Y, Yasuoka H, Takeuchi T, Satoh T, Kuwana M. Intrave-
nous epoprostenol treatment of patients with connective tissue dis-
ease and pulmonary arterial hypertension at a single centre. Mod
Rheumatol 2013; 23: 1211-20.
[137] Denton CP, Humbert M, Rubin L, Black CM. Bosentan treatment
for pulmonary arterial hypertension related to connective tissue
disease: a subgroup analysis of the pivotal clinical trials and their
open-label extensions. Ann Rheum Dis 2006; 65: 1336-40.
[138] Mok MY, Tsang PL, Lam YM, Lo Y, Wong WS, Lau CS. Bosen-
tan use in systemic lupus erythematosus patients with pulmonary
arterial hypertension. Lupus 2007; 16: 279-85.
[139] Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A et
al. Bosentan therapy for pulmonary arterial hypertension. N Engl J
Med 2002; 346: 896-903.
[140] Badesch DB, Hill NS, Burgess G, Rubin LJ, Barst RJ, Galie N et
al. Sildenafil for pulmonary arterial hypertension associated with
connective tissue diseases. J Rheumatol 2007; 34: 2417-22.
Tselios and Urowitz
[141] Oudiz RJ, Schilz RJ, Barst RJ, Galie N, Rich S, Rubin LJ et al.
Treprostinil, a prostacyclin analogue, in pulmonary arterial hyper-
tension associated with connective tissues disease. Chest 2004;
126: 420-7.
[142] Tanaka E, Harigai M, Tanaka M, Kawaguchi Y, Hara M, Kamatani
M. Pulmonary hypertension in systemic lupus erythematosus:
evaluation of clinical characteristics and response to immunosup-
pressive treatment. J Rheumatol 2002; 29: 282-7.
[143] Gonzalez-Lopez L, Cardona-Munoz EG, Celis A, Garcia-de la
Torre I, Orozco-Barocio G, Salazar-Paramo M et al. Therapy with
intermittent pulse cyclophosphamide for pulmonary hypertension
associated with systemic lupus erythematosus. Lupus 2004; 13:
105-12.
[144] Sanchez O, Sitbon O, Jais X, Simonneau G, Humbert M. Immuno-
suppressive therapy in connective tissue diseases-associated pul-
monary arterial hypertension. Chest 2006; 130: 182-9.
[145] Jais X, Launay D, Yaici A, Le Pavec J, Tcherakian C, Sithon O et
al. Immunosuppressive therapy in lupus- and mixed connective tis-
sue disease-associated pulmonary arterial hypertension: a retro-
spective analysis of twenty-three cases. Arthritis Rheum 2008; 58:
521-31.
[146] Miyamichi-Yamamoto S, Fukumoto Y, Sugimura K, Ishii T, Satoh
K, Miura Y et al. Intensive immunosuppressive therapy improves
pulmonary hemodynamics and long-term prognosis in patients with
pulmonary arterial hypertension associated with connective tissue
disease. Circ J 2011; 75: 2668-74.
[147] Kommireddy S, Bhyravavajhala S, Kurimeti K, Chennareddy S,
Kanchinadham S, Rajendra Vara Prasad I et al. Pulmonary arterial
hypertension in systemic lupus erythematosus may benefit by addi-
tion of immunosuppression to vasodilator therapy: an observational
study. Rheumatology (Oxford) 2015; 54: 1673-9.
[148] Hennigan S, Channick RN, Silverman GJ. Rituximab treatment of
pulmonary arterial hypertension associated with systemic lupus
erythematosus: a case report. Lupus 2008; 17: 754-6.
[149] Giannakopoulos B, Krilis SA. How I treat the antiphospholipid
syndrome. Blood 2009; 114: 2020-30.
[150] Konstantinides SV, Torbicki A, Agnalli G, Danchin N, Fitzmaurice
D, Galie N et al. 2014 ESC guidelines on the diagnosis and man-
agement of acute pulmonary embolism. Eur Heart J 2014; 35:
3033-69.