Objective Data regarding cardiovascular comorbidity and cardiovascular risk factors in patients with psoriatic arthritis (PsA) are limited. To evaluate the cardiovascular risk profile, a systematic literature search was performed to provide an extensive summary of all studies available on cardiovascular risk in PsA.
Methods Medline, EMBASE and the Cochrane library were searched from January 1966 to April 2011 for English language articles on data concerning cardiovascular diseases and cardiovascular risk factors in PsA. Review articles, case reports and studies on psoriasis alone were excluded.
Results Twenty-eight articles were included in this review. Studies on all-cause mortality revealed mixed results. Available data on cardiovascular disease appeared more consistent, indicating an increased cardiovascular mortality and morbidity in PsA. Commensurate with this, surrogate markers of subclinical atherosclerosis, arterial stiffness and cardiovascular risk factors, for example hypertension, dyslipidaemia, obesity and metabolic-related factors, were more prominent in PsA compared with controls. Suppression of inflammation was linked with a favourable effect on cardiovascular surrogate markers, for example carotid intima media thickness and endothelial dysfunction, in several (un)controlled studies.
Conclusion Most studies point towards an increased cardiovascular risk in PsA, broadly on a par with the risk level in rheumatoid arthritis, emphasising the need for similar cardiovascular risk management in both conditions. Further studies are needed to indicate whether inflammatory suppression or modification of traditional cardiovascular risk factors, or both, will reduce cardiovascular risk.
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There is now abundant evidence demonstrating a higher cardiovascular risk in several rheumatic diseases, best exemplified in rheumatoid arthritis (RA).1,–,3 There are several potential reasons for the higher cardiovascular risk in rheumatic diseases, but inflammation is considered to play a crucial role.4 Inflammation accelerates atherosclerosis directly, but also by effects on classic and non-classic cardiovascular risk factors, such as lipid levels, blood pressure and insulin resistance.2 ,4 ,5
Psoriatic arthritis (PsA) is a chronic inflammatory disease characterised by synovial and entheseal inflammation and psoriasis. The clinical presentation of PsA can manifest as peripheral arthritis, asymmetrical oligoarthritis, arthritis mutilans or an axial form similar to that of ankylosing spondylitis (AS).6 In terms of cardiovascular risk, several studies have demonstrated a higher cardiovascular risk in psoriasis,7,–,10 but data on cardiovascular disease in PsA specifically are limited and not sufficiently separated from primary psoriasis populations. Given the co-existence of skin and joint involvement, PsA may be associated with a greater inflammatory load and as a consequence it is theoretically possible that the cardiovascular disease burden may emerge more strongly compared with patients with only skin involvement.7
To evaluate the cardiovascular risk profile, we performed a systematic literature search to provide an extensive summary of all studies available on cardiovascular risk in PsA. Furthermore, we aimed to examine the influence of classic (eg, blood pressure and hypercholesterolaemia) and non-classic (eg, inflammation and uric acid) cardiovascular risk factors and the impact of antirheumatic treatment on cardiovascular risk in PsA.
We performed a systemic literature search using the scientific literature databases Medline, EMBASE and the Cochrane library. In Medline, we used both MeSH terms and relevant free-text terms. The following search terms (synonyms and combinations) were used: ‘psoriatic arthritis’ AND ‘cardiovascular disease’, OR ‘lipid profile’, OR ‘obesity’, OR ‘metabolic syndrome’, OR ‘hypertension’, OR ‘smoking’, OR ‘diabetes’, OR ‘anti-inflammatory treatment’ (table 1). The search was conducted from January 1966 to April 2011. The references of the reviewed articles were manually scanned for other relevant studies.
Studies were included if they were written in English and contained data on cardiovascular disease and/or risk factors in PsA. Review articles, case reports and studies on psoriasis alone were excluded. Selected articles were screened for eligibility by AJ. After completing the literature search all screened literature was summarised and presented at the European League Against Rheumatism (EULAR) meeting, where all members gave their comments on the available literature presented. All literature and comments were included in the systematic review.
The original search identified a total of 444 articles. A total of 28 articles met the inclusion criteria (see figure 1).
Mortality in PsA
Three observational cohort studies11,–,13 (n=1561 patients) and an equal number of population-based studies were identified (n=894 patients),7 ,14 ,15 which studied mortality. They are summarised in table 2.
Two out of three observational cohort studies demonstrated a higher standardised mortality rate (SMR): 1.6 and 1.4, respectively.11 ,13 Data from these two studies were derived from the same cohort, but from different time periods, demonstrating an increased overall mortality risk over nearly four decades of follow-up, but the mortality risk declined over time.11 ,13 Moreover, increased mortality appeared to be associated with disease severity, as indicated by a high erythrocyte sedimentation rate (ESR) and radiological damage.16 In contrast, a more recent cohort study following 453 patients with PsA for 22 years did not observe increased mortality with a combined SMR for men and women of 81.82% (95% CI 57.61 to 112.78).12 However, cardiovascular disease was the leading cause of death (38%).12
With regard to the available population-based studies, only one out of three studies reported increased mortality.7 ,14 ,15 The Danish Nationwide cohort reported a significantly increased overall mortality (RR 1.74; 95% CI 1.32 to 2.30), particularly arising from cardiovascular disease (RR 1.84; 95% CI 1.11 to 3.06).7 Remaining studies contained a low number of patients with PsA15 and SMR were not presented.14 In all, data regarding survival in patients with PsA are inconclusive. This might be explained by a small sample size in some studies14 ,15 and differences in the length of follow-up. A study with shorter follow-up13 demonstrated higher SMR compared with the studies with longer follow-up,11 ,12 as it is not correlated for when during the follow-up death occurs.
Cardiovascular morbidity in PsA
Four studies reported cardiovascular morbidity in a total of 4810 patients with PsA.7 ,17,–,19 There were large differences in study design and in cardiovascular composite endpoints (table 3). For example, data on cardiovascular morbidity were gathered prospectively in one17 and cross-sectionally in the remaining studies.7 ,18 ,19 All studies reported an increased cardiovascular morbidity in PsA, including ischaemic heart disease, congestive heart failure, cerebrovascular and peripheral vascular disease.
Ahlehoff et al7 included patients with PsA as well as patients with psoriasis alone, and reported a similar cardiovascular risk in patients with severe psoriasis and in patients with PsA. In addition, cardiovascular risk in PsA seemed broadly comparable with diseases with well-known increased cardiovascular risks, such as diabetes mellitus or RA.7 ,19
Surrogate markers of atherosclerosis
Surrogate markers of atherosclerosis were all unfavourable in PsA in terms of the conferred increase in cardiovascular risk (table 4).20,–,25 Postocclusion flow-mediated vasodilatation (FMD) was impaired in patients with PsA without pre-existing cardiovascular risk factors when compared with healthy controls.22 In addition, carotid intima-media thickness (IMT) appeared consistently greater in PsA.20 ,21 ,23,–,25
Traditional cardiovascular risk factors
Lipid abnormalities were commonly found in PsA,18 ,24 ,28,–,30 best exemplified by lower serum levels of high-density lipoprotein (HDL)-cholesterol and higher serum levels of triglycerides.26 ,28 ,30 Dyslipidaemia seemed to be more prominent in PsA patients with active disease, suggesting a potential relationship between the degree of inflammation and the lipid profile.28 ,30 Hypertension was found in 30% of all PsA patients.18 ,29 After adjustment for blood pressure-lowering agents, blood pressure remained significantly higher in PsA patients compared with controls.28 Also, obesity and hyperuricaemia appeared to be more prevalent in PsA.24 ,26 ,28 ,29 ,31 ,32 Although smoking is frequently reported in patients with psoriasis, only a few studies reported smoking habits in patients with PsA.24 ,28 ,29 There was no statistical difference in smoking prevalence between patients and controls.24 ,28 Diabetes mellitus was more often present in patients with PsA compared with controls.18 ,24 ,26 ,28 ,29 One study found a higher prevalence of dyslipidaemia, hypertension and metabolic syndrome in PsA than in other rheumatic diseases such as RA and AS.26 OR adjusted for age, sex, smoking, body mass index, disease duration and current treatment with biological agents was 2.44 (95% CI 1.48 to 4.01) compared with RA and AS.26
Treatment of PsA in relation to cardiovascular risk
Traditional cardiovascular risk factors
Serum levels of HDL-cholesterol increased after 6 months' treatment with infliximab in 60 patients with rheumatic diseases, including 10 patients with PsA.33 A double-blind placebo controlled trial with tumour necrosis factor (TNF; inhibitor onercept, a TNF receptor-based inhibitor that was not ultimately marketed), including 127 patients with PsA and active psoriasis, reported an increment in serum levels of apolipoprotein A-I, apolipoprotein B and triglycerides, and a decline of lipoprotein-a after 12 weeks in patients treated with onercept.34 The effect of anti-TNF treatment on other traditional cardiovascular risk factors in PsA has not yet been studied.
Taken together, the effect of antirheumatic treatment, ie, steroidal and non-steroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs (DMARD), on cardiovascular risk factors is unknown, while data from studies evaluating the effect of TNFα blockade therapy on cardiovascular risk factors are scarce.
Anti-TNF treatment may have a favourable effect on the progression of surrogate markers of atherosclerosis. Aortic stiffness measured by aortic pulse wave velocity improved 0.50±0.78 m/s in patients with rheumatic diseases, including six patients with PsA, after 3 months of anti-TNF treatment.35 In the same study, a correlation was found between a reduction in C-reactive protein levels and aortic pulse wave velocity. Administration of etanercept or infliximab resulted in a short-term (8–12 weeks) improvement of FMD in 25 patients with RA and 11 patients with PsA.36 In another case–control study, 120 PsA patients with at least 1 year anti-TNF treatment were compared with 104 PsA patients receiving traditional DMARD therapy matched for age, gender, cardiovascular risk factors and disease activity.20 The mean post-treatment IMT was 0.70±0.18 mm in anti-TNF-treated patients and 0.80±0.26 mm in DMARD-treated patients (p=0.002). Also, the prevalence of carotid plaque was significantly higher in patients on DMARD 40% versus those on anti-TNF 16% (p<0.0001). A small cohort study of 20 PsA patients reported lower carotid IMT in anti-TNF-treated patients compared with patients on DMARD (on average 0.70 mm vs 0.79 mm) and even demonstrated a decline in carotid IMT (0.63 mm) in those who stayed on anti-TNF treatment for 2 years, while the carotid IMT progressed in patients who discontinued anti-TNF treatment or in those receiving DMARD therapy.37
The results of this review suggest an increased prevalence of cardiovascular diseases in patients with PsA compared with the general population as well as an increased prevalence of cardiovascular risk factors. Studies on all-cause mortality revealed mixed results. A comparison of those studies is difficult due to differences in PsA definition, patient population, disease duration, length of follow-up and study design across the separate investigations. In addition, it is important to take into account time trends and differential treatment of PsA, as cohorts in earlier years11 ,13 showed an increased mortality compared with a more recently studied cohort.12 Nevertheless, overall studies indicate that PsA is associated with increased mortality compared with the general population. This increased cardiovascular mortality is particularly prominent in observational cohort studies and therefore seems to be associated with disease severity. In agreement with this, a higher inflammatory burden, illustrated by a high ESR and/or the presence of radiological damage, was associated with increased all-cause mortality.16
Available data on cardiovascular disease appeared more consistent, indicating a higher cardiovascular mortality and morbidity in PsA.7 ,11 ,13 ,17 ,18 Again, inflammatory load as inferred by disease severity correlated with increased cardiovascular morbidity.7 ,16 In line with a higher cardiovascular risk, surrogate markers on subclinical atherosclerosis and arterial stiffness and established cardiovascular risk factors, for example hypertension, dyslipidaemia, obesity and type 2 diabetes were more prominent in PsA.17 ,18 ,20 ,22 ,23 ,26 With regard to surrogate markers, we would like to emphasise that the method of obtaining IMT data is crucial to the validity of the findings when comparing IMT in patients and controls. The process needs to be rigorous and robust, and patients and controls need to be recruited similarly. Moreover, IMT measurement should be conducted according to existing well-validated protocols and in a blinded manner to minimise bias. Unfortunately, information regarding most of these aspects is generally lacking in published studies.
Many studies linked the suppression of inflammation with a favourable effect on cardiovascular surrogate markers, for example carotid IMT and endothelial dysfunction.20 ,35 ,37 Those studies, although different in study design and comprising low numbers of patients, may be clinically relevant as they provide indirect evidence to support the inflammatory hypothesis. Obviously, appreciation of shared inflammatory mechanisms in atherosclerosis and rheumatic diseases, such as PsA, and placebo controlled studies with hard cardiovascular endpoints are urgently needed for a better understanding of the cardiovascular burden in this population. Notably, several studies reported a significant weight gain in patients with psoriasis during anti-TNF treatment.38 ,39 However, whether the increase in body weight was in the form of fat or fat-free mass is unanswered because of a lack of body composition assessments. This should be explored further, but nevertheless there is evidence that weight gain in the context of treatments for autoimmune conditions is not necessarily harmful but rather concurs with less inflammation.40
The choice of an appropriate comparator group for patients with PsA is complex. In most studies, cardiovascular risk in PsA is compared with the general population,11 ,13 ,17 illustrating an increased cardiovascular disease burden in PsA patients. However, to assess whether the co-existence of skin and joint involvement in PsA may be associated with a greater inflammatory load, and as a consequence, an even greater cardiovascular disease burden compared with patients with only skin involvement, a direct comparison between PsA and psoriasis is needed. One study showed an increased prevalence of hypertension in PsA patients compared with patients with psoriasis alone.41 Moreover, one direct comparison revealed that the risk of a myocardial infarction, in comparison with the general population, was doubled in patients with severe psoriasis and PsA.7
A EULAR taskforce recently provided recommendations for cardiovascular risk management in patients with RA, PsA and AS.3 The recommendations were based on the methodological strength of the existing literature, which was stronger for RA than PsA.3 Although a substantial number of studies identified increased cardiovascular risk in patients with PsA, the methodological strength of the existing literature is low. This systematic literature search identified one randomised clinical trial34 (evidence category 1B), and the remaining studies are descriptive studies (evidence category 3). The guidelines for the determination of the level of evidence are provided as a supplementary file (table S1, available online only). Therefore, this review reaffirms that the level of evidence is still insufficient to provide definitive recommendations.
As recently emphasised,42 to achieve conclusive evidence long-term well-controlled data and larger numbers are needed. At present, differences in the study design and composite cardiovascular endpoint definitions complicate interpretation. Therefore, we advise, in line with previously published EULAR guidelines, adequate cardiovascular risk management according to local guidelines and aggressive suppression of inflammation to lower cardiovascular risk in PsA.
The authors are grateful to the Clinical Research Bureau of the Jan van Breemen Research Institute/READE, which receives support from the Dutch Arthritis Association.
Review history and Supplementary material
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Funding This project was financially supported by the European League Against Rheumatism.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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