Drs. Gonzalez-Gay and Gonzalez-Juanatey contributed equally to this work.
High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors
Article first published online: 30 JUL 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis Care & Research
Volume 57, Issue 6, pages 1074–1080, 15 August 2007
How to Cite
Gonzalez-juanatey, C., Llorca, J., Amigo-Diaz, E., Dierssen, T., Martin, J. and Gonzalez-Gay, M. A. (2007), High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis & Rheumatism, 57: 1074–1080. doi: 10.1002/art.22884
- Issue published online: 30 JUL 2007
- Article first published online: 30 JUL 2007
- Manuscript Accepted: 27 DEC 2006
- Manuscript Received: 28 AUG 2006
- Psoriatic arthritis;
- Cardiovascular disease;
- Carotid intima-media thickness;
- Carotid plaques
To assess the presence of subclinical atherosclerosis in patients with psoriatic arthritis (PsA) without clinically evident atherosclerosis or its complications, and to assess whether demographic or clinical factors affect the development of atherosclerotic disease in a series of patients with PsA attended to in a community hospital.
Fifty-nine patients with PsA who fulfilled the Moll and Wright criteria were recruited from Hospital Xeral-Calde (Lugo, Spain). Patients seen during the period of recruitment who had classic cardiovascular risk factors or had experienced cardiovascular or cerebrovascular events were excluded. Fifty-nine healthy matched controls were also studied. Carotid artery intima-media thickness (IMT) and carotid plaques were measured in the right common carotid artery. The study was performed using high-resolution B-mode ultrasound.
Patients with PsA exhibited greater carotid artery IMT than did matched controls (mean ± SD 0.699 ± 0.165 mm versus 0.643 ± 0.111 mm; P = 0.031; difference of means 0.056; 95% confidence interval 0.005–0.108). Adjusted for age, the carotid IMT was correlated with age at the time of PsA diagnosis (partial correlation coefficient [r] = −0.264, P = 0.04), disease duration (r = 0.264, P = 0.04), total cholesterol (r = 0.233, P = 0.01), and low-density lipoprotein cholesterol (r = 0.243, P = 0.01).
The present study demonstrates that patients with PsA without cardiovascular risk factors or clinically evident cardiovascular disease have a high prevalence of macrovascular disease in the form of increased carotid artery IMT compared with ethnically matched controls.
Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis (1, 2). Its recognition as an inflammatory disease distinct from rheumatoid arthritis (RA) (1) has put forward for consideration several questions regarding its specific mortality and morbidity (2). Information from a series of patients attended to in referral centers indicates that individuals with PsA have an increased mortality rate compared with the general population, and the mortality risk is related to disease severity at presentation to clinic (2–4). Highly experienced investigators have pointed out that cardiovascular disease is one of the leading causes of death in patients with PsA (2, 3). However, Mayo Clinic investigators reported that PsA was not associated with a significant increase in mortality in unselected patients (5). Likewise, a comprehensive review article published in 2004 unveiled limited available data related to the specific cardiovascular morbidity and mortality in unselected patients with PsA compared with the general population (6).
An important step forward in our understanding of whether PsA is associated with increased cardiovascular morbidity and mortality may be to determine the presence of subclinical data of atherosclerosis disease in unselected patients with PsA without overt cardiovascular complications or traditional cardiovascular risk factors. At present, several noninvasive imaging techniques offer an opportunity to study the relationship of surrogate markers to the development of atherosclerosis. The use of these techniques may help identify high-risk individuals who may benefit from active therapy to prevent clinical disease. One of these surrogate markers is the presence of endothelial dysfunction, considered as the earliest stage of atherosclerosis (7, 8). An assessment of endothelial function by postocclusion flow-mediated vasodilatation of the brachial artery using high-sensitivity brachial ultrasonography disclosed the presence of impaired endothelial function in patients with PsA without a history of cardiovascular events or traditional cardiovascular risk factors (9).
Carotid intima-media thickness (IMT) of the common carotid artery, determined by high-resolution B-mode ultrasound of the common carotid artery, is another useful noninvasive surrogate marker of macrovascular atherosclerosis disease. Case–control studies have demonstrated that increased common carotid artery IMT determined by high-resolution B-mode ultrasound is a good indicator of generalized atherosclerosis and coronary artery disease (10–12), providing early information on atherosclerosis in subclinical stages of the disease in individuals at risk (13, 14). IMT corresponds to the width of the vessel intima and media, which consists of endothelium, connective tissue, and smooth muscle (14). This is also the site of lipid deposition and plaque formation (15). In the present study, we assessed whether carotid IMT was increased in a cohort of patients with PsA without overt cardiovascular disease or classic cardiovascular risk factors attended to in a community hospital.
PATIENTS AND METHODS
Patients and controls.
A series of patients with PsA and the same number of matched controls were assessed in the present study. Consecutive patients attending hospital outpatient clinics over a period of 8 months (March to October 2002) who fulfilled the Moll and Wright criteria (presence of an inflammatory arthritis [peripheral arthritis and/or sacroiliitis or spondylitis], presence of psoriasis, and absence of serologic tests for rheumatoid factor [RF] ) were included. Patients were treated by the same group of rheumatologists and were recruited from the Hospital Xeral-Calde (Lugo, Spain). This hospital is the single referral center for rheumatic diseases for a well-defined, stable and ethnically homogenous, mixed rural and urban, white population living in the region of Lugo, central Galicia (northwestern Spain) (16, 17). The main characteristics of the Lugo population have previously been reported (18–20).
Patients were divided into different disease groups according to the Moll and Wright classification criteria (1). As previously reported, peripheral arthritis was defined by the history or presence of ≥1 swollen joint for at least 3 months (21). Based on the criteria by Moll and Wright, patients were included into one of the following categories according to the predominant rheumatic manifestation: 1) distal joint disease affecting the distal interphalangeal joints only; 2) oligoarthritis involving ≤4 joints; 3) polyarthritis affecting ≥5 joints; 4) arthritis mutilans, a severely deforming form of arthritis manifesting with either joint lysis or ankylosis; and 5) spondylarthropathy, an inflammatory arthritis of the back.
As previously reported (9), because PsA may evolve from oligoarticular to polyarticular over time (22), in keeping with a former report (23) and for the purpose of this study, patients with an oligoarticular presentation that evolved into polyarticular distribution over the course of the disease and who displayed this polyarticular pattern at the time of assessment were included in the category of polyarticular. Also, for the purpose of this study, patients with inflammatory arthritis of the back who presented with a predominant polyarticular pattern were included in the category of polyarthritis.
Only patients who had been treated for at least 1 year at the outpatient rheumatology clinic at the time of this study were included. Patients seen during the period of recruitment who had hypertension (systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg), dyslipidemia (total cholesterol and/or triglyceride levels in fasting plasma >240 mg/dl and >160 mg/dl, respectively), diabetes mellitus (fasting overnight venous plasma glucose concentration in all individuals included in this study had to be <110 mg/dl), renal insufficiency (serum creatinine values in all individuals included in this study had to be <1.3 mg/dl, which is considered the upper normal range in our laboratory), or obesity (body mass index >30 kg/m2), had developed cardiovascular or cerebrovascular events, had evidence of cardiovascular disease or received drugs affecting the cardiovascular system (antihypertensive or antiaggregant drugs, nitrates, and statins), or were being treated with estrogens at the time of the study were excluded. Also, for the purpose of inclusion patients had to be nonsmokers or have stopped smoking at least 5 years previously. The definition of cardiovascular disease comprised 1) ischemic heart disease (IHD), which included acute coronary syndromes with or without persistent ST-segment elevation and chronic coronary heart disease (IHD was diagnosed as previously reported ), and 2) congestive heart failure, which was defined according to the Framingham Heart Study criteria (25). Also, as previously reported (26, 27), a patient was considered to have a cerebrovascular event when he or she had a stroke and/or transient ischemic attacks. At the time of the study only 59 patients with PsA who were seronegative for RF fulfilled the inclusion criteria described above. In this regard, based on the inclusion and exclusion criteria described, 31 patients with PsA were excluded.
C-reactive protein (CRP; nephelometry) level, erythrocyte sedimentation rate (ESR; Westergren), serum glucose, creatinine, total cholesterol, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol, and triglycerides (fasting overnight determinations) were assessed in all patients at the time of the study. Information about CRP level and ESR at the time of disease diagnosis was also reviewed.
From the time of diagnosis of PsA, all patients included in this study were actively treated with nonsteroidal antiinflammatory drugs (indomethacin 100 mg/day, naproxen 500–1,000 mg/day, or diclofenac 100–150 mg/day) but none was treated with cyclooxygenase 2 selective inhibitors. Thirty-four patients had received or were being treated with prednisone (≤10 mg/day) because of disease severity. The mean ± SD cumulative prednisone dosage in the 34 patients was 3.2 ± 2.4 gm (median 2.4, interquartile range 1.4–4.5, range 0.2–8.3 gm). At the time of this study, 51 patients were receiving methotrexate therapy, either alone (n = 43) or in combination with sulfasalazine (n = 3), oral cyclosporine (n = 3), or anti–tumor necrosis factor α monoclonal antibody infliximab (n = 2). When this study was conducted, 21 of the 59 patients presented with bone erosions in the hands and/or feet and 15 had radiologic findings of sacroiliitis.
Healthy controls from the Lugo region matched on age, body mass index, and sex without family history of psoriasis, PsA, RA, or any other inflammatory rheumatic disease were also studied. All controls (n = 59) were also ethnically matched, and none of the controls included in this study had a history of hypertension, diabetes mellitus, dyslipidemia, renal insufficiency, obesity, or cardiovascular or cerebrovascular events, or had smoked within the 5 years prior to the study.
Informed consent was obtained from all cases and controls. The local institutional committee approved the study.
Carotid IMT was measured in the right common carotid artery as previously reported (28, 29). Atherosclerotic plaque in the common carotid artery was defined as a distinct protrusion, >1.5 mm, into the vessel lumen. The study was performed using high-resolution B-mode ultrasound (Hewlett-Packard SONOS 5500, Palo Alto, CA) with a 10-MHz linear transducer. In all cases a single cardiologist (CG-J) who was blinded to clinical information performed all the studies. The reproducibility of the IMT measurements was evaluated in 15 patients and 15 controls within 1 week of the first ultrasonographic examination. The correlation coefficient for carotid IMT was 0.98.
Continuous data were expressed as the mean ± SD and categorical variables were expressed as percentages. Continuous variables were compared using Student's t-test or Mann-Whitney U test. Proportions were compared by chi-square test or Fisher's exact test.
Correlation between carotid IMT and continuous variables was tested via estimation of Pearson's partial correlation coefficient adjusted by age at the time of the study. Two-sided P values less than 0.05 were considered to indicate statistical significance. Analyses were performed with Stata 8/SE (StataCorp, College Station, TX).
Clinical and characteristics of the patients.
Clinical information on 50 of the 59 patients with PsA included in the present study has previously been reported (9). The main demographic and clinical features of this series of patients are shown in Table 1. The mean ages at psoriasis onset and diagnosis of PsA were 29.4 and 41.0 years, respectively. The mean PsA duration was 7.8 years.
|Variable||Patients (n = 59)||Controls (n = 59)||P|
|At the time of study||48.8 ± 12.4||48.8 ± 12.0||0.99|
|At the time of psoriasis onset||29.4 ± 12.3|
|At the time of PsA diagnosis||41.0 ± 12.7|
|Disease duration at the time of study, years||7.8 ± 6.5|
|Patients presenting with arthritis before cutaneous manifestations, no. (%)||8 (13.5)|
|Patterns of PsA, no. (%)|
|Distal interphalangeal joints only||1 (1.7)|
|Blood pressure at the time of study, mm Hg|
|Systolic||122.6 ± 13.6||122.2 ± 12.6||0.85|
|Diastolic||77.4 ± 8.1||75.8 ± 9.2||0.31|
|Heart rate at the time of study, beats per minute||72.5 ± 8.3||71.4 ± 7.8||0.47|
|Body mass index, kg/m2||25.6 ± 1.9||25.4 ± 2.1||0.65|
|DAS28 score||2.4 ± 0.7|
|Serum creatinine at the time of study, mg/dl||1.00 ± 0.15||0.98 ± 0.16||0.59|
|CRP level, mg/liter|
|At the time of disease diagnosis||20.2 ± 28.9|
|At the time of study||8.4 ± 5.6||3.3 ± 1.3||< 0.001|
|At the time of disease diagnosis||29.3 ± 23.5|
|At the time of study||17.7 ± 9.9||11.2 ± 5.5||< 0.001|
|Cholesterol or triglycerides at the time of study, mg/dl|
|Total cholesterol||194.7 ± 31.5||185.9 ± 30.2||0.12|
|HDL cholesterol||53.8 ± 11.9||51.9 ± 11.5||0.37|
|LDL cholesterol||116.8 ± 24.7||111.5 ± 24.1||0.25|
|Triglycerides||90.0 ± 30.9||97.4 ± 33.9||0.68|
|Fasting serum glucose at the time of study, mg/dl||92.3 ± 10.1||90.6 ± 10.8||0.38|
|Carotid IMT, mm||0.699 ± 0.165||0.643 ± 0.111||0.031|
|Carotid plaques, no. (%)||9 (15)||3 (5)||0.068|
PsA frequently evolved from oligoarticular to polyarticular over the course of the disease. Therefore, at the time of the study 38 (64.4%) of the 59 patients presented with a polyarticular pattern. Other disease patterns are shown in Table 1.
Disease activity in patients with PsA with peripheral arthritis was assessed by the Disease Activity Score in 28 joints (DAS28) used in patients with RA (30). DAS28 scores in the 54 patients with predominant peripheral patterns (the patient who only had distal interphalangeal joint involvement was not included) are also shown in Table 1. Laboratory markers of inflammatory response (CRP level and ESR) at the time of PsA diagnosis and at the time of the study, as well as glucose, creatinine, and lipid profile data at the time of the study are also described in Table 1.
Differences between patients with PsA and controls.
A cross-sectional study was performed to establish clinical and ultrasonographic differences between patients and controls (Table 1). Patients with PsA exhibited greater carotid IMT than did matched controls (mean ± SD 0.699 ± 0.165 mm versus 0.643 ± 0.111 mm; P = 0.031; difference of means 0.056; 95% confidence interval 0.005–0.108) (Figure 1). In addition, although carotid plaques were more commonly observed in patients with PsA (9 patients [15%]) than controls (3 patients [5%]), the difference did not achieve statistical significance (P = 0.068) (Table 1).
Correlation between carotid artery IMT and epidemiologic and laboratory variables in patients with PsA.
As expected, a positive strong correlation between age at the time of study and the carotid artery IMT in patients with PsA was observed (r = 0.522, P < 0.001). Also, a significant age-adjusted correlation between carotid IMT and age at the time of diagnosis of PsA (r = −0.264, P = 0.04), disease duration (r = 0.264, P = 0.04), total cholesterol (r = 0.233, P = 0.01), and LDL cholesterol (r = 0.243, P = 0.01) was found (Table 2). However, there was no significant correlation between carotid IMT and DAS28 score, the laboratory markers of inflammation assessed at the time of the study or at the time of disease diagnosis, or the cumulative corticosteroid dose (Table 2).
|At the onset of psoriasis||0.009||0.95|
|At the time of diagnosis of PsA||−0.264||0.04|
|DAS28 for patients with peripheral arthritis†||−0.112||0.43|
|Systolic blood pressure†||−0.031||0.74|
|Diastolic blood pressure†||0.045||0.63|
|ESR at the time of disease diagnosis||−0.095||0.48|
|CRP level at the time of disease diagnosis||−0.071||0.60|
|ESR at the time of the study||0.024||0.80|
|CRP level at the time of the study||0.118||0.21|
|Cumulative prednisone dose†||0.030||0.87|
Patients with PsA with carotid plaques were older (mean ± SD age 59.4 ± 9.3 years versus 46.9 ± 12.0 years; P = 0.004), had marginally increased disease duration at the time of the study (12.4 ± 9.5 years versus 7.0 ± 5.5 years; P = 0.07), and had greater carotid IMT (0.876 ± 0.129 mm versus 0.667 ± 0.151 mm; P < 0.001) compared with patients with PsA without carotid plaques.
Differences between patients with PsA with polyarticular pattern and the remaining patients with PsA.
The carotid IMT in patients with polyarticular pattern was nonsignificantly less than those with other articular patterns (mean ± SD 0.689 ± 0.170 mm versus 0.718 ± 0.157 mm). This difference may be explained by a greater proportion of women fulfilling definitions for the polyarticular pattern (21 [55%] of 38) compared with the remaining patients (7 [33%] of 21) (Table 3). Other differences between the 38 patients with polyarticular pattern and the remaining 21 patients with PsA are shown in Table 3 (P > 0.05 in all cases).
|Polyarticular (n = 38)||Other (n = 21)||P|
|At the time of study||49.8 ± 12.9||47.1 ± 11.4||0.43|
|At the onset of psoriasis||28.2 ± 12.4||31.4 ± 12.4||0.35|
|At the diagnosis of PsA||41.9 ± 12.6||39.5 ± 13.1||0.50|
|Disease duration, years at the time of the study||7.9 ± 6.6||7.6 ± 6.3||0.84|
|CRP level, mg/liter|
|At the time of the study||8.8 ± 5.8||7.6 ± 6.3||0.46|
|At disease diagnosis||23.4 ± 34.0||14.3 ± 14.8||0.25|
|At the time of the study||19.6 ± 14.4||10.2 ± 8.6||0.06|
|At disease diagnosis||31.7 ± 25.5||24.9 ± 19.3||0.29|
|Lipid profile, mg/dl at the time of the study|
|Total cholesterol||192.8 ± 34.1||198.3 ± 26.5||0.52|
|HDL cholesterol||53.4 ± 12.1||54.5 ± 11.6||0.75|
|LDL cholesterol||116.4 ± 25.2||117.5 ± 24.4||0.87|
|Triglycerides||95.2 ± 32.0||80.6 ± 27.1||0.08|
|Carotid IMT, mm||0.689 ± 0.170||0.718 ± 0.157||0.53|
|Carotid plaques, no. (%)||6 (16)||3 (14)||0.60|
The present study demonstrates that patients with PsA without clinically evident cardiovascular disease have a high prevalence of macrovascular disease in the form of increased carotid artery IMT compared with ethnically matched controls. These observations are in keeping with a previous report from our group that disclosed the presence of endothelial dysfunction in patients with PsA without clinically evident cardiovascular or classic atherosclerosis risk factors (9).
A potential limitation of this study was the lack of skin evaluation. Although, as mentioned in the Patients and Methods section, the relatively small number of patients might be another limitation, in view of the exclusion and inclusion criteria and matching of controls, we believe that our results do indeed confirm the presence of increased atherosclerosis in patients with PsA. We also recognize that the lack of a significant association between the presence of plaque and PsA in our series may be due to a Type II error.
RA, another rheumatic disease considered as the prototype of chronic inflammatory disease involving the joints, has been associated with accelerated atherogenesis and increased cardiovascular mortality (31). In this regard, patients with RA from the Lugo region of northwestern Spain without clinically evident cardiovascular disease also exhibited increased prevalence of subclinical atherosclerosis (28, 32). In patients with RA, accelerated atherosclerosis could not only be explained by the presence of traditional cardiovascular risk factors (33, 34). Chronic inflammation has also been proposed as being responsible for the development of accelerated atherosclerosis in these patients (35). Studies from our group supported this hypothesis (36). As pointed out by Sattar et al, even during quiescent phases of RA, systemic levels of cytokines or their regulatory components often remain dysregulated compared with non-RA individuals and as such will continue to promote vascular disease (35). This may also be the case for individuals with PsA. Therefore, as observed in RA, prolonged disease duration in patients with this chronic inflammatory disease may promote the development of accelerated atherogenesis.
Serum lipids are strong predictors of cardiovascular risk. Interestingly, although we intended to exclude patients with dyslipidemia from our study, the carotid artery IMT showed a direct correlation with total and LDL cholesterol. This finding raises our concern about the definition of normality in terms of total and LDL cholesterol in patients with chronic inflammatory diseases.
Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have antiinflammatory and immunomodulatory actions that may be useful in the management of chronic inflammatory rheumatic diseases (37). McCarey et al observed a beneficial effect of atorvastatin in a randomized, double-blind, placebo-controlled study of 116 patients with active RA (38). At 6 months DAS28 scores and acute-phase reactants were reduced in patients who received atorvastatin (40 mg/day) compared with those who received placebo (38). Statins also improve endothelial function and increase endothelium-dependent vasodilation independent of changes in lipids (39). Hermann et al demonstrated a dramatic improvement of endothelial function in patients with RA following simvastatin therapy (40 mg/day) (40). These observations may support a potential role for statins in the treatment of patients with chronic inflammatory rheumatic diseases.
Finally, in our series no association between cumulative prednisone dose and carotid artery IMT was found. This is in accordance with recent studies that challenge the classic assumption that glucocorticoids are responsible for a proatherogenic effect in patients with rheumatic diseases (41). In conclusion, our observations support the evidence of increased prevalence of subclinical atherosclerotic macrovascular disease in patients with PsA.
Dr. Gonzalez-Gay had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Gonzalez-Juanatey, Llorca, Martin, Gonzalez-Gay.
Acquisition of data. Gonzalez-Juanatey, Amigo-Diaz, Gonzalez-Gay.
Analysis and interpretation of data. Gonzalez-Juanatey, Llorca, Dierssen, Gonzalez-Gay.
Manuscript preparation. Gonzalez-Juanatey, Llorca, Martin, Gonzalez-Gay.
Statistical analysis. Llorca, Dierssen, Gonzalez-Gay.
- 7Endothelial function and dysfunction. Part II. Association with cardiovascular risk factors and diseases: a statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens 2005; 23: 233–46., , , , , , et al.
- 8Endothelial function and dysfunction. Part I. Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens 2005; 23: 7–17., , , , , , et al.
- 24Ischemic heart disease in patients from Northwest Spain with biopsy proven giant cell arteritis: a population based study. J Rheumatol 2005; 32: 502–6., , , , , , et al.
- 34Traditional and nontraditional cardiovascular risk factors are associated with atherosclerosis in rheumatoid arthritis. J Rheumatol 2005; 32: 435–42., , , , , , et al.