Cardiovascular Risk and its Modification in Patients with Connective Tissue Diseases

Miriam O’Sullivan PhD MRCP

Visiting clinical research fellow*

Ian N Bruce MD FRCP

Professor of Rheumatology

Deborah PM Symmons MD FRCP

Professor of Rheumatology and Musculoskeletal Epidemiology

Arthritis Research UK Centre for Epidemiology

Centre for Musculoskeletal Research

University of Manchester

Stopford Building, Oxford Road

Manchester M13 9PT

NIHR Manchester Musculoskeletal Biomedical Research Unit

Central Manchester NHS Foundation Trust

Manchester Academic Health Science Centre

Manchester

Deborah.symmons@manchester.ac.uk

Telephone: +44 161 275 5044 / FAX: +44 161 275 5043

*Future address:

Sligo University Hospital

Sligo, Ireland

Corresponding author: Deborah Symmons

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Abstract

It is well documented that patients with SLE are at an increased risk of atherosclerotic cardiovascular

disease. There is evidence that traditional risk factors and disease-related factors are involved in this

increased risk. Less is known about cardiovascular (CV) risk and outcomes in other connective tissue

diseases (CTDs). Future longitudinal observational studies may help to answer these important

questions, however, because CTDs are rare, collaboration between clinicians with similar research

interests is needed to ensure large enough cohorts are available to address these issues.

Here we review the evidence available for CV risk in CTDs and discuss the benefits of longitudinal

observational studies in identifying CV outcomes. Structured care protocols for management of

cardiovascular risk in CTDs are lacking. We propose a target-based approach to assessing and

managing CV risk in CTDs.

Key words

Connective tissue diseases

SLE

Systemic sclerosis

Primary Sjogren’s syndrome

Idiopathic Inflammatory Myopathies

Cardiovascular disease

Cardiovascular risk management

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Introduction (Level A)

Patients with inflammatory musculoskeletal diseases have an excess risk of atherosclerotic cardiovascular

disease (ACVD) compared to the general population. A meta-analysis of 24 mortality studies in patients

with rheumatoid arthritis (RA) reported a weighted combined all-cause standardized mortality ratio (meta-

SMR) of 1.50 (95% 1.39-1.61) with similar increases for ischaemic heart disease (meta-SMR 1.59; 95%CI

1.46-1.73) and stroke (meta-SMR 1.52; 95% CI 1.40-1.67) (1). The bimodal pattern of death associated

with systemic lupus erythematosus (SLE) was first described in 1976 (2), with the first mortality peak

(within 1 year of diagnosis) being due mainly to active lupus and infection and the second peak (>5 years

from diagnosis) being due mainly to cardiovascular events (CVEs). In 1997 Manzi et al reported that the risk

of myocardial infarction (MI) was over 50 times higher in women aged 35-44 in the University of Pittsburgh

lupus cohort than in age-matched women from the Framingham offspring cohort (3).

In this chapter we summarise the most recent literature on the risk of ACVD and the risk factors for ACVD

in patients with SLE, systemic sclerosis, idiopathic inflammatory myopathies, mixed connective tissue

disease and primary Sjogren’s syndrome. We performed a Medline search up until 30th November 2015

searching for “ cardiovascular risk” and “cardiovascular mortality” and combined each with “ systemic

lupus erythematosus”, “ systemic sclerosis”, “Sjogren’s syndrome”, “idiopathic inflammatory myopathy”

and “mixed connective tissue disease”. We have focussed on reporting relevant systematic reviews and

papers published in the last 5 years.

We highlight the importance of longitudinal observational studies (LOS) in contributing to this knowledge

and on the value of embedding research into routine clinical practice. Finally we review strategies for

cardiovascular (CV) risk management in patients with connective tissue diseases (CTD).

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Cardiovascular disease in patients with SLE (Level A)

SLE is a chronic inflammatory autoimmune condition with significant morbidity and mortality. Survival

rates for SLE have improved dramatically in recent years (4). In an international study of 9547 patients

from 23 centres the all-cause SMR estimates decreased significantly between the 1970s and 2001.

However, the CV SMR increased slightly (5). CVEs remain one of the main causes of death in SLE.

Cardiovascular mortality in patients with SLE (Level B)

CV mortality is increased in SLE patients compared to the general population. In a meta-analysis of 27,123

SLE patients from 12 studies published prior to 2011, there was a 3-fold increased risk of all-cause

mortality (meta-SMR 2.98, 95% CI 2.32–3.83) and an increased risk of death from cardiovascular disease

(CVD) (meta-SMR 2.72, 95% CI 2.32- 3.83) (6). None of the studies of mortality published since 2011 has

had sufficient numbers of deaths to be able to report a CV specific SMR (7, 8). The most recent study

followed 2740 incident cases of SLE identified using the UK primary-care based Clinical Practice Research

Datalink and then linked to the national death register (9). The mortality rate ratio compared to age, sex

and practice matched controls was 1.67 (95%CI 1.43, 1.94). Another UK-based study followed an inception

cohort of 382 SLE patients recruited from 1989-2010. The all-cause SMR was 2.0 (95% CI 1.5, 2.8), with

CVEs being one of the most common causes of death ( 27%) (10).

Ethnicity may play a role in risk of cardiovascular mortality in SLE. A systematic review of 5 observational

studies involving 4469 Chinese patients with SLE found lower rates of death from CV causes than has been

documented in other ethnic groups (11). CVEs accounted for 11.5% of all deaths whereas death from

infection accounted for 33% of all deaths.

Traditionally mortality studies have focussed on the underlying cause of death as recorded on the death

certificate. A new methodology called multiple-cause-of-death analysis enables all the diagnoses recorded

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on the death certificate to be analysed. Two recently published studies have used this methodology in SLE.

One study included 4815 death certificates from Sao Paulo, Brazil on which SLE was listed as a cause of

death between 1985-2005 (12). The most common contributory causes of death were renal failure and

sepsis. Only in 2003-7, and in individuals aged less than 50 years when they died, was CVD a more

common cause of death than in the general population. The second study utilised the death certificates

from all 1593 adults who died in France between 2000 and 2009 and in whom SLE was mentioned on the

death certificate (13). The mean (SD) age at death of the SLE patients was 63.5 (18.4) years. The age-

standardised mortality rate fell from 4.1 per million in 2000 to 3.0 per million in 2009. Amongst patients in

whom SLE was listed as the underlying cause of death, 49.5% had CVD listed as another main cause. In

patients in whom SLE was listed as a non-underlying cause of death, CVD was listed as the underlying cause

of death more frequently than in the general population (relative risk (RR) 1.58; 95%CI 1.42-1.76).

Myocardial infarction in patients with SLE (Level B)

Patients with SLE have an increased risk of MI compared to the general population (3, 14). Using health

administrative databases from Canada between 1990-2007, Avina-Zubieta et al found that the overall

multivariable RR for MI in patients with physician-diagnosed SLE, compared with age and sex matched

controls, was 2.5 (95%CI 2.1, 3.1) (15). The subsequent incidence of MI in 1207 patients with SLE from

Taiwan, was 2.10 per 1000 person-years (pyrs) compared with 0.49 in age-and sex- matched controls,

adjusted hazard ratio (HR) 5.11 (95% CI 2.63, 9.92) (16).

Patients with SLE have a higher prevalence of CVD even before diagnosis. The prior incidence of CVD was

higher in 70 incident cases of SLE identified from The Marshfield Epidemiologic Study Area in Wisconsin,

USA than in matched controls (23% vs 10%); OR 3.7 (1.8, 7.9) (17).

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A study from the US National Heart, Lung and Blood Institute Dynamic Registry of patients undergoing

percutaneous coronary interventions (PCI) found no significant differences in the mean percent of

coronary artery stenosis and total occlusion in SLE vs non-SLE subjects (18). However, SLE patients had

significantly worse CV outcomes at one year following PCI including a higher risk of MI (15.6% vs. 4.8%,

p=0.01), and repeat PCI (31.3% vs. 11.8%, p=0.009). A retrospective cohort study from Taiwan found that

SLE was an independent predictor of inpatient mortality after PCI, OR 3.81 (95% CI 2.02, 7.16)(19).

Congestive Heart Failure in patients with SLE (Level B)

The risk of hospitalization for congestive heart failure (CHF) in SLE appears to be substantially increased.

Using the California Hospital Discharge Database, Ward found that the proportionate morbidity ratio for

CHF in women with SLE compared to women without SLE was 3.22 (95%CI 2.55, 4.05) in those aged 18-44

years; 1.34 (95%CI 1.14, 1.56) in those aged 45-64 years; and 1.30 (95% 1.16, 1.45) in those aged 65 years

and over (20). The nature of CHF in SLE is likely to be multifactorial. Of 24 episodes of CHF in a large

international inception cohort of SLE followed for up to 8 years, only 5 (21%) were attributed to

atherosclerosis (21). CHF is more common in patients with SLE admitted with an MI compared to controls

admitted with an MI (20% vs 15%) and the presence of CHF in SLE patients admitted with an MI is a risk

factor for mortality (17.9% vs 5.8%) (22).

Stroke in patients with SLE (Level B)

In a recent meta-analysis of 10 population-based cohort studies the pooled RR in patients with SLE for all

types of stroke combined was 2.53 (95%CI 1.96, 3.26) (23). The risks of ischaemic stroke (RR 2.10; 95%CI

1.68, 2.62), intracerebral haemorrhage (RR 2.72; 95%CI 2.15, 3.44) and subarachnoid haemorrhage (RR

3.85; 95%CI 3.20, 4.64) were all increased. The RR for stroke was highest in adults aged less than 50 years.

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Peripheral arterial disease in patients with SLE (Level B)

Peripheral arterial disease (PAD) is more common in SLE than the general population (24, 25). A study from

the National Health Insurance Research Database of Taiwan of over 10,000 SLE patients reported a 9-fold

higher incidence of PAD compared with non-SLE patients (26).

Subclinical atherosclerosis in patients with SLE (Level B)

Subclinical atherosclerosis may manifest as endothelial dysfunction, arterial stiffness, a high carotid intima

media thickness (cIMT), and plaque or coronary artery calcification (CAC). A recent meta-analysis showed

that patients with SLE have a higher cIMT and an increased prevalence of carotid plaque compared with

controls (27). Plaque and IMT measurement on carotid ultrasound in SLE can independently predict CVEs

(28).

Risk factors for CVD in patients with SLE (Level B)

The aetiology of the premature atherosclerosis seen in SLE is incompletely understood. Traditional

cardiovascular risk factors (TRFs), disease-related factors and certain treatments all play a part. Tselios et

al recently published a systematic review in which they identified 101 papers which explored risk factors

for the development of atherosclerosis in SLE and which satisfied their inclusion criteria (29). The following

section summarises the results of this systematic review.

Traditional risk factors for CVD in patients with SLE (Level C)

Classic TRFs include increasing age, male gender, smoking status, diabetes, hypertension and

dyslipidaemia. A number of these factors are more common in patients with SLE including hypertension

and diabetes, but not smoking or hypercholesterolaemia (30). More recently described TRFs in the general

population include a positive family history of CVD, high levels of high sensitivity C-reactive protein (hs-

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CRP), ethnicity, low levels of physical activity, obesity and the metabolic syndrome (MetS). MetS is a

clustering of CV risk factors including abdominal (central) obesity, elevated blood pressure, elevated fasting

plasma glucose, high serum triglycerides, and low high-density lipoprotein (HDL) levels. There is a higher

prevalence of MetS in patients with SLE compared with matched controls (31). There is evidence that SLE-

related factors including active disease, damage and renal involvement are independently associated with

MetS and that MetS is prevalent early in the course of the disease (32).

Among the non-modifiable TRFs, there is evidence that increasing age, postmenopausal status, male

gender and a positive family history are independent risk factors for subclinical atherosclerosis and CVEs in

patients with SLE (29).

Among the modifiable TRFs, obesity and arterial hypertension are independent risk factors for CVEs and

subclinical atherosclerosis in patients with SLE (29). Smoking has been shown to be associated with CVEs,

carotid plaque and CAC in SLE. Total cholesterol has been shown to be an independent risk factor for CVEs

and subclinical atherosclerosis. Although not an independent risk factor for CVE or CAC, high LDL levels

were an independent predictor of increased cIMT and plaque formation (33). MetS is associated with

increased cIMT, CAC and arterial stiffness.

Disease specific risk factors for CVD in patients with SLE (level C)

TRFs alone do not fully explain the increased risk of CVD seen in patients with SLE (34) either as a group or

individually. What is more, in a study from the Toronto clinic, lupus patients with CVEs had more TRFs than

those without events but they did not have a higher Framingham risk score (35). SLE disease activity has

been shown to be an independent risk factor for CVEs and subclinical atherosclerosis (29). Cumulative

damage; long disease duration; dsDNA antibodies, anti-cardiolipin antibodies and lupus anticoagulant have

also been shown to be independent predictors of CVEs and subclinical atherosclerosis (29, 36-38).

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Antiphospholipid syndrome (APS) frequently co-exists with SLE (39). Patients who have a diagnosis of both

SLE and APS represent a more severe disease phenotype with higher risk of CVD (40). Both proteinuria and

renal impairment are independent predictors of CVE (29).

Treatment related factors and the risk of CVD in patients with SLE (Level C)

The negative effects of corticosteroids on CVE, hypertension, lipid profile and weight are well known. High

cumulative steroid dose predicts plaque formation in patients with SLE (41). Current steroid use,

independent of disease activity, also predicts CVE (38).

The protective role of hydroxychloroquine has been demonstrated in a number of studies. In a Chinese SLE

cohort, lack of use of hydroxychloroquine was an independent risk factor for CVD (42). In a prospective

study in the Toronto lupus cohort, patients who developed coronary artery disease (CAD) were significantly

less likely to have been treated with hydroxychloroquine than those who did not develop CAD (43).

Cardiovascular disease in patients with systemic sclerosis (Level A)

Systemic sclerosis (SSc) is an autoimmune CTD characterised by multiorgan fibrosis, vasculopathy triggered

by endothelial injury, and autoantibody production. Inflammation plays a less prominent role in SSc than

in SLE. SSc may directly affect the heart leading to myocardial fibrosis, conduction defects, left ventricular

systolic and diastolic dysfunction and pericardial disease (44). Heart disease may also occur secondary to

pulmonary hypertension in SSc. Although microvascular disease is the hallmark of SSc, there is growing

evidence that macrovascular damage, resulting in ACVD is contributing to excess morbidity and mortality

(45).

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Cardiovascular mortality in patients with SSc (Level B)

A meta-analysis including 9239 SSc patients from 17 studies published prior to 2005 reported an all-cause

meta-SMR of 2.72 (95%CI 1.93, 3.83) (46). CVD specific SMR was not reported. In the EULAR Scleroderma

Trials and Research (EUSTAR) database, 55% of 234 deaths in SSc were directly attributable to the disease

and 41% due to non-SSc causes; 26% of the deaths directly attributed to SSc and 29% of the non-SSc causes

of death were due to CVD (47).

There is evidence of a higher case fatality for MI but not for stroke in patients with SSc compared with

patients without CTD. Using the US Nationwide Inpatient Survey, Dave et al found that 5.5% of 61,734

admissions in patients with SSc were for a CVD diagnosis or procedure compared with 4.9% of SLE

admissions, 7.1% of RA admissions and 6.7% of control admissions. Patients with SSc and MI were more

likely to die during that admission than patients with SLE and MI, patients with RA and MI, or controls with

MI (48).

Atherosclerotic CVD in patients with SSc (Level B)

A number of large studies have reported an increased risk of ACVD in patients with SSc compared to the

general population. A study of 850 patients with SSc from the Australian Scleroderma Cohort Study

reported an odds ratio (OR) for self-reported coronary heart disease, after adjusting for TRFs, of 3.2 (95%

CI: 2.3-4.5) compared with a control group from the Australian Diabetes, Obesity and Lifestyle Study and of

2.0 (95% CI: 2.3- 4.5) when compared with a cohort from the National Health Survey (49). In a study of 865

patients with SSc identified from a UK primary care database, the HR for MI, after adjusting for TRFs and

steroid use, was 1.8 (95% CI: 1.07- 3.05), for stroke was 2.61 (95%CI: 1.54-4.44) and for PAD was 4.35

(95%CI: 2.74- 6.93) compared to age and sex matched controls (50). The adjusted HR for MI between 1344

incident cases of SSc and 13440 controls from Taiwan was 2.45 (95%CI 1.60, 3.75) (51).

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Subclinical atherosclerosis in patients with SSc (Level B)

A recent systematic review and meta-analysis reported on 31 studies which had examined angiography,

cIMT, carotid plaque, computed tomography or magnetic resonance imaging, flow mediated dilatation,

ankle-brachial index or autopsy in patients with SSc and controls (52). Compared to controls, patients with

SSc had a higher prevalence of coronary atherosclerosis, peripheral vascular disease and cerebrovascular

calcification.

Risk factors for CVD in patients with SSc (Level B)

TRFs have been less studied in SSc than in SLE. Overall there appear to be fewer differences between SSc

patients and general population controls than is the case for SLE. In the study from the UK database (50),

the SSc cohort had a lower frequency of overweight and obesity than matched controls, but a higher

frequency of past smoking and oral corticosteroid use. The frequency of hypertension, dyslipidaemia and

diabetes were similar in the SSc group and matched controls. Hypercholesterolaemia, diabetes and obesity

were less prevalent in the Australian Scleroderma Cohort than in community-based controls, while past

smoking was more prevalent. The prevalence of hypertension was similar (49).

Cardiovascular disease in patients with Idiopathic Inflammatory Myopathies (Level A)

Idiopathic inflammatory myopathies (IIM) such as dermatomyositis and polymyositis are rare autoimmune

diseases characterized by inflammation of skeletal muscle, proximal muscle weakness and elevated muscle

enzymes. IIM can directly affect the heart causing myocarditis, myocardial fibrosis and arrhythmias (53).

Until recently evidence on the risk of ACVD in IIM has been scarce.

The all-cause SMR was 1.75 (95%CI 1.41, 2.15) in 370 patients diagnosed with IIM since 1980 from the

South Australian Myositis Database (54). CVD accounted for 30.5% of deaths. A meta-analysis, published in

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2014, identified 4 LOS that had examined CAD as an outcome in 13,201 IIM patients (55). There was a

significantly increased risk of CAD in patients with IIM compared with controls (pooled risk ratio 2.24 (95%

CI: 1.02, 4.92)). In a more recent study from Taiwan the risk of acute coronary syndrome was significantly

higher in patients with IIM than in controls, adjusted hazard ratio 1.98 (95% CI: 1.17 -3.35)(56).

There is evidence of an increased risk of ischaemic stroke in patients with dermatomyositis. In a study of

907 patients with dermatomyositis from Taiwan, the adjusted HR for ischaemic stroke over the first 2 years

of disease was 1.67 (95% CI: 1.19, 2.34) compared to controls (57). A study using a health administrative

database from Quebec followed 607 patients with IIM for a mean of 4 years. The stroke rate (5.2/1000

pyrs) was similar to that reported in patients with RA (58). In this study, dyslipidaemia and hypertension

were associated with arterial events, while immunosuppressive therapy was inversely associated.

There is some evidence that TRFs are more prevalent in patients with IIM than in the general population. A

cross-sectional study of 84 dermatomyositis patients identified 47% with MetS compared with 7% of

healthy controls (59). Diabetes was also more prevalent in the dermatomyositis group. Other cross-

sectional studies have found higher rates of obesity, hypertension, diabetes and dyslipidaemia in patients

with IIM compared with controls (60-62). High CAC scores on cardiac computed tomography were also

more frequent in the IIM cohort (62).

Cardiovascular disease in patients with mixed connective tissue disease (Level A)

Mixed connective tissue disease (MCTD) has features of several CTDs including SLE, SSc, PM and RA in

association with high titre antibody to U1 ribonucleoprotein (anti-RNP). A recent systematic review of 11

studies, including 616 patients with MCTD, found that the prevalence of cardiac involvement varied from

13% to 65% depending on the methodology used. Pericarditis was the most common cardiac

manifestation (63). By far the largest included study followed 280 patients for a mean of 13 years; 7.8% of

the cohort died with one third of deaths attributed to CVEs (64). Bodolay et al reported more endothelial

dysfunction and increased cIMT in patients with MCTD compared with healthy controls (65).

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Evidence on the prevalence of TRFs in MCTD is limited. One study reported significantly higher levels of

total cholesterol and triglycerides in 37 patients with MCTD compared to 30 controls (66). A large

proportion of the MCTD group were taking corticosteroids.

Cardiovascular disease in patients with primary Sjogren’s syndrome (Level A)

Primary Sjogren’s syndrome (pSS) is an auto-immune disease characterised by lymphocytic infiltration of

exocrine glands and associated with a wide range of auto-antibodies, in particular anti-SS-A/Ro and anti-SS-

B/La antibodies.

Mortality in pSS is increased compared to the general population. In 1045 Spanish patients with pSS

followed for a mean of almost 10 years the SMR was 4.66 (95%CI 3.85, 5.60) (67). CVD was the main cause

of death.

Reports on the occurrence of ACVD in patients with pSS have been inconsistent. A study of 5205 patients

with a new diagnosis of pSS and no prior history of MI from Taiwan found similar numbers of acute MIs in

the patients with pSS compared with age, gender and comorbidity matched controls: HR 0.86 (95%CI 0.55,

1.35) (68). These researchers also found a similar incidence of ischaemic stroke in both groups: HR 0.84

(95% CI 0.63-1.12) (69). Contrary to these findings, Bartoloni et al reported a higher prevalence of self-

reported cerebrovascular events (2.5% vs 1.4%) and MI (1.0% vs 0.4%) in 788 Italian women with pSS

compared to 4774 age-matched female controls (70). There is some evidence of an increased prevalence

of subclinical atherosclerosis in pSS.

In a study of 200 women with pSS and 200 age matched female controls from the UK, hypertension

(adjusted RR 2.02; 95%CI 1.19, 3.44) and hypertriglyceridaemia (adjusted RR 2.26; 1.26, 4.08) were more

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common in pSS (71) whereas smoking was less common (3.8% vs 10.1%; p= 0.026). Bartoloni et al also

found that smoking was less common in women with pSS (70). This may be because smoking exacerbates

the symptoms of xerostomia. Much of the excess hypertension found in the UK study was previously

undiagnosed, suggesting that patients with pSS should have their blood pressure monitored regularly.

Mechanisms for the accelerated development of atherosclerosis in patients with CTD

In addition to TRFs, there are other important mechanisms related to CTDs that contribute to the increased

CV risk. Chronic inflammation is a cornerstone of the pathogenesis of many CTDs and is also central to the

development of atherosclerosis (72). Immune-mediated changes play a role in the pathogenesis of both

CTD and atherosclerosis. Autoantibody formation, which is a hallmark of CTD, contributes to vascular

damage and risk of thrombosis (72).

The mechanisms at play in the development of ACVD in SSc have not being fully elucidated and

microvascular disease may also contribute. Endothelial cell injury induced by anti-endothelial antibodies,

ischaemia/reperfusion damage, and immune-mediated cytotoxicity represent the main causes of vascular

injury together with an impaired vascular repair mechanism (45).

Contribution of LOS to understanding the development of CVD in the clinical course of CTD (level A)

The clinical course of treated CTD can be studied in a number of contexts including randomised controlled

trials (RCTs) and longitudinal observational studies (LOS).

LOS comprise cohorts of patients with the CTD of interest, with few exclusion criteria, followed

prospectively. Investigation and treatment will be according to local practice and may or may not be

protocol driven. The cohort may either be assembled as close as possible to disease onset (inception

cohorts) or assembled from prevalent cases, or both. The quality of a LOS is determined by (i) the

representativeness of the cohort (and thus the generalisability of the results); (ii) the breadth, quality and

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completeness of the data; and (iii) the comprehensiveness of the capture and validation of outcome data.

LOS may recruit specifically for research purposes or may be derived from disease registers compiled

within clinical practice. Some studies are a hybrid. Alternatively CTD cohorts may be assembled from

within large administrative health databases or from national disease registers. Each of these sources has

its own strengths and weaknesses. As illustrated earlier in this Chapter, most of the information on the

incidence and prevalence of fatal and non-fatal CVEs in CTD is derived from LOS and administrative

datasets.

Modifying cardiovascular risk in clinical practice (Level A)

Evidence-based protocols for the screening and management of CV risk factors in CTD do not currently

exist. However, the elevated risk of CVD in SLE and the need to address this risk has been acknowledged by

experts in two consensus documents (73, 74). The EULAR recommendation for monitoring patients with

SLE advises screening for TRFs at baseline and at least annually thereafter (73). The American Heart

Association Guidelines for the prevention of CVD in women have included SLE as a group at increased CVD

risk (74). There is evidence that composite risk scores such as the Framingham risk score underestimate

risk in SLE (30, 34, 75). In one study, a multiplication of the Framingham risk score components by 2 was

shown to improve accuracy (76).

In the absence of evidence-based guidelines for CV risk assessment in CTDs in general, we propose using

previously published recommendations for CV risk management in SLE (77, 78) and more recent

recommendations for coronary heart disease risk assessment also in SLE by Tselios et al(29) as a

framework to guide CV risk evaluation in CTDs.

We suggest that a target-based approach is appropriate to assess and manage CV risk for these patients

(Table 1). Such an approach will pay attention to TRFs and disease specific factors. Prompt screening for

TRFs early in the course of the CTD is advisable. Thereafter, assessment of TRFs should be performed

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annually in all patients and more frequently (6-12 monthly) in those with already identified CV risk factors.

A high index of suspicion for clinical CV disease is also recommended.

Hypertension (Level C)

There is an increased prevalence of hypertension in most CTDs (71, 79). Hypertension is defined as values

>140mmHg systolic and/or >90mmHg diastolic blood pressure. Tselios et al point out that current

hypertension guidelines may not apply to patients with SLE (33). Patients with CTDs have not, however,

been previously included in treatment recommendations.

We recommend that blood pressure should be measured at each clinic visit. When elevated, it should be

monitored closely and an assessment of steroid use and renal function should be made (77). Advice should

be given on non-pharmacological interventions such as exercise, weight loss and dietary salt restriction.

Pharmacological treatment should be initiated if blood pressure remains consistently elevated above

140/90mmHg (80).

Anti-hypertensive choice will vary depending on the presence of co-morbidities such as renal disease,

diabetes and left ventricular hypertrophy. ACE inhibitors and angiotensin receptor blockers, because of

their advantages beyond solely correcting hypertension, are useful agents to consider in CTD patients (80).

Smoking (Level C)

We believe that smoking status should be ascertained in all CTD patients. In SLE, smoking may increase

disease activity (81). It also interferes with the response to anti-malarial medications (82, 83). In SSc,

smokers are prone to more severe Raynaud’s phenomenon and digital ulceration (84, 85).

In general, it is important to establish patients’ willingness to stop smoking and methods available to assist

them. We hope that reminding patients repeatedly of the risks associated with smoking will improve

cessation rates. Pharmacological treatments and nicotine replacement therapy may be offered (86). In

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addition to drugs, referral to smoking cessation clinics to provide and support behavioural interventions

improves the likelihood of success.

Dyslipidaemia (Level C)

An abnormal lipid profile is prevalent in SLE and has also been reported in some studies in pSS (87, 88). A

meta-analysis of 3 trials in SLE found that despite significant reductions in cholesterol with statin therapy,

measures of subclinical atherosclerosis did not improve (89). Therefore, whilst ‘all’ patients with SLE should

not automatically be prescribed a statin, we believe that statins still have a key role in CTD patients to

enable patients to achieve their ideal target LDL.

We recommend that CTD patients have a baseline and annual lipid profile measured. If dyslipidaemia is

discovered, treatment should be initiated and the lipid profile repeated to ensure normalisation.

Therapeutic lifestyle changes, including reduction in dietary saturated fat content, weight loss and

moderate physical activity should be employed and may be sufficient to enable the patient to achieve an

ideal LDL in those with moderate LDL elevations, i.e. LDL of 2.6 to 3.4mmol/L. This step is particularly

relevant in SLE as steroid dose modification and the introduction of an antimalarial (where appropriate)

may both add to lipid lowering in such patients. When the LDL cholesterol is > 3.4 mmol/L, unless the

patient is on high dose glucocorticoids, it is unlikely that lifestyle modification alone will be sufficient to

achieve an ideal LDL; such patients most likely will require statin therapy. The Adult Treatment Panel III

guidelines recommend an LDL target of 2.6mmol/L for diabetic patients (90). Given the high CV risk nature

of SLE, we recommend using these diabetic treatment targets. If LDL is >2.6mmol/L despite lifestyle

changes, lipid lowering therapy should be commenced and titrated according to response (77). Currently,

we recommend following lipid target guidelines as for the general population in patients with other CTDs.

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Obesity and the metabolic syndrome (MetS) (Level C)

We recommend that weight, height and calculation of body mass index (BMI) should be measured at

baseline. Measurement of waist circumference gives additional information about CV risk. A BMI of

<25Kg/m2 and a waist circumference of < 40 inches for males and <35 inches for females are ideal targets

in Caucasian patients. If patients are overweight or have a high waist circumference, advice regarding a

healthy diet low in saturated fat and the importance of regular exercise should be given.

MetS in SLE can be present without central obesity. Therefore it is important to consider this diagnosis in

patients whose waist circumference is normal but have clustering of other factors (31, 32). There is

evidence that the risk of MetS is reduced in patients taking hydroxychloroquine (32).

Diabetes Mellitus (DM) (Level C)

DM is more prevalent in CTD than the general population(30). Patients should therefore have a baseline

and annual fasting glucose (and/or HbA1C) measured. A fasting glucose >7.0mmol/L and/or a random

glucose > 11.1mmol/L confirms a diagnosis of DM. Such patients should be managed in conjunction with

their primary care physician and /or a diabetologist. A glucose tolerance test should be considered in

patients with a fasting glucose of >6.1mmol/L. Hydroxychloroquine can help to improve glycaemic control

(91). In established DM, the addition of an anti-malarial can potentially induce hypoglycaemia and the

patient should be informed that their insulin or oral hypoglycaemic agent dosing may need some

adjustment.

Exercise prescription (Level C)

Physicians should discuss the benefits of exercise with their CTD patients. Three to 5 hours of moderate

intensity aerobic activity per week is recommended in healthy individuals. There is evidence of

improvements in disease activity and vascular function with regular exercise in patients with CTD (92).

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However, exercise recommendations should be individualized, as factors such as fatigue, CVD and

musculoskeletal manifestations of the disease will alter patient’s ability to participate in regular physical

activity.

Disease-related risk factor modification (Level C)

Early control of disease activity is very important. At each clinic visit, patients should have a renal function

assessment and urine quantified for proteinuria. Chronic kidney disease is a CVD-risk equivalent so early

diagnosis and management is imperative.

All patients with a CTD should also be screened for the presence of co-existing antiphospholipid antibodies,

i.e. antibodies to lupus anticoagulant, anti-cardiolipin antibodies and where available, β2-microglobulin, at

time of diagnosis. The opportunity to rationalize corticosteroid dose and use should be taken at every

clinical assessment to minimise negative CV effects. Use of hydroxychloroquine is recommended in all SLE

patients unless there is a contraindication, as it is proposed to have cardio protective properties (38, 43).

Patient Involvement (Level C)

Patient education is a vital part of CV risk management in CTD, as their involvement is more likely to result

in success. Evidence in the lupus literature shows limited awareness amongst patients of their CV risk

factors and of their increased CV risk (93).

Future considerations (Level C)

Dedicated CV screening clinics for CTD may be the way forward, with evidence of their benefit in other

inflammatory rheumatic conditions already available (94). Another consideration for the future is the use

of screening tools such as carotid ultrasound to assess cIMT and presence of plaque as these markers have

been shown to be independent predictors of CVEs (28).

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Summary (Level A)

Information on the risk of ACVD and risk factors for the development of CVD in patients with CTDs other

than SLE is sparse. This is, in part, because the study of cause-specific mortality and morbidity requires

large cohorts of patients followed over long periods of time with robust identification of the outcomes of

interest. Assembling such cohorts is a challenge in rare CTDs and often requires multi-centre collaboration.

There is an increasing body of evidence that TRFs, disease specific factors and treatment all contribute to

the excess risk of CVD in patients with SLE. It is probable that a similar pattern will emerge in non-SLE CTDs

although the relative contribution of these factors is likely to differ. The minimisation of CV risk in the

individual patient with CTD will require attention to optimise TRFs and control of disease activity whilst

minimising exposure to steroids.

Practice points (Level C)

CTD patients should have a CV risk assessment, ideally at baseline and annually thereafter

TRFs and disease related factors, including medications, must be considered when assessing CV risk

If TRFs are identified they should be managed at least as stringently as recommended in guidelines

for the general population

As a validated composite CV risk assessment model for CTD is not currently available, we

recommend a target-based approach to the assessment and management of CV risk for these

patients

Research agenda (Level C)

Further research is necessary to expand on what is known with respect to CV risk in CTDs other than

SLE.

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Whether CV outcomes in SLE and other CTDs improve with the use of more stringent targets than is

recommended in the general population needs to be determined.

When disease activity is controlled and TRF have been addressed, research will be important to

investigate whether CV risk in CTD is then level with that in the general population or whether

other non-modifiable risk factors are involved.

Conflict of interest statement (Level C)

Miriam O’Sullivan, Ian Bruce and Deborah Symmons have no conflicts of interest

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