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Abstract
Aim To investigate whether a higher burden of inflammation is associated with more severe atherosclerosis in patients with psoriatic arthritis (PsA).
Methods Patients from a large PsA cohort were analysed. The cumulative effect of inflammation was measured by a time-adjusted arithmetic mean of all measurements from the first visit to the clinic. The following variables were considered as predictors: Psoriasis Activity and Severity Index (PASI), erythrocyte sedimentation rate (ESR), white blood cell (WBC) count, tender and swollen joint counts, C-reactive protein, Psoriatic Arthritis Disease Activity Score (PASDAS) and Disease Activity for PsA (DAPSA). Vascular ultrasound of the carotid arteries was performed, and total plaque area was measured. This measure represented the extent of atherosclerosis and was considered the outcome of interest. The association between inflammation over time and atherosclerosis was assessed by regression models adjusted for age, sex and cardiovascular risk factors.
Results A total of 235 patients with PsA were analysed. Patients with more severe atherosclerosis were older (p<0.001), more likely to be obese (p=0.01), smokers (p=0.008) and have hypertension (p=0.001), diabetes (p<0.0001) and dyslipidaemia (p<0.0001). In a multivariate regression model adjusted for age and sex, higher ESR (p=0.009), WBC count (p=0.015) and DAPSA (p=0.04) were associated with more severe atherosclerosis. These associations were not significant after adjustment for traditional cardiovascular risk factors. No association was found between disease duration and atherosclerosis.
Conclusions Exposure to an increased burden of inflammation is associated with more severe atherosclerosis in patients with PsA. This association may be mediated by traditional cardiovascular risk factors.
- Psoriatic arthritis
- atherosclerosis
- inflammation
- ultrasound
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Recent literature has highlighted the increased cardiovascular risk in patients with psoriatic disease (PsD).1 Patients with psoriasis are up to twice as likely to develop myocardial infarction (MI) than unaffected individuals.2–4 The standardised prevalence ratio for coronary artery disease in patients with psoriatic arthritis (PsA) ranges from 1.3 to 2.57.5 ,6 Vascular imaging studies have shown increased atherosclerotic plaques and vascular inflammation in patients with PsD compared with unaffected individuals.7–9 Such abnormalities can be considered a preferred surrogate end point in prolonged disease processes such as atherosclerosis, as they predict the development of clinical events, and they also allow investigation of the underlying mechanisms related to the clinical event long before it occurs.
The increased cardiovascular morbidity in PsD may be partially attributed to the high prevalence of metabolic abnormalities, such as impaired glucose tolerance and atherogenic lipid profile, in these patients.10 ,11 However, the risk remains increased even after adjustment for these abnormalities, supporting the notion that PsD is an independent risk factor for cardiovascular events.12 PsD is associated with systemic inflammation that is not limited to the skin or the joints. It is now widely accepted that atherosclerosis, the main cause of cardiovascular diseases, is an inflammatory disorder in which immune mechanisms interact with metabolic risk factors to initiate and propagate lesions in the vascular walls.13 Psoriatic patients display abnormalities in the innate and adaptive immune system, which result in high serum levels of proinflammatory cytokines that upregulate cell-mediated immunity and promote inflammatory cell migration through the vascular endothelium resulting in endothelial dysfunction, which may lead to plaque formation.14 ,15 Endothelial dysfunction, an early phase of atherogenesis, was observed in a cohort of patients with PsA who did not have traditional cardiovascular risk factors.16
Recent evidence supports the link between the extent of inflammation and cardiovascular risk in patients with PsD. A dose–response association between the severity of psoriasis and the risk of MI has been reported.17–19 In addition, patients with PsA are at higher risk of developing cardiovascular events compared with those with psoriasis alone.20 There is limited information about the underlying mechanisms of such accelerated atherogenesis in patients with PsA. Most studies that investigated this topic were cross-sectional, which limited their ability to assess the effect of inflammation over time. In the present study, we aimed to investigate the association between the duration and extent of inflammation over time and the extent of atherosclerosis. We hypothesised that the severity of inflammation, as evidenced by clinical manifestations of PsA and laboratory biomarkers, is associated with more severe atherosclerosis.
Methods
Study population
Patients with PsA who satisfied the CASPAR criteria21 were recruited from the University of Toronto PsA clinic. Patients attending the clinic are part of an ongoing prospective cohort that was established in 1978 to study prognostic factors in PsA. The patients are followed in the clinic according to a standard protocol every 6–12 months.22 For the purpose of this study, consecutive patients who attended the clinic were recruited for an ultrasound assessment of the carotid arteries from 2010 to 2013. The study was approved by the University Health Network Research Ethics Board, and all patients gave their informed consent.
Data collection
Assessment of inflammatory activity
As part of their follow-up in the clinic, patients underwent an assessment by a rheumatologist which included a complete history, physical examination and laboratory evaluation. The number of tender and swollen joints was assessed as 68/66 joints, respectively. Current psoriasis activity was scored by the Psoriasis Area and Severity Index (PASI).23 Additional laboratory tests included erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and white blood cell (WBC) count. Two novel PsA-specific composite measures, Disease Activity index for PsA (DAPSA) and Psoriatic Arthritis Disease Activity Score (PASDAS), were used. DAPSA includes the following items: patient and physician global assessments, pain score, tender and swollen joint counts, and CRP.24 PASDAS is derived by a mathematical formula that includes the following items: patient and physician global assessment, the physical component score derived from the SF-36, tender and swollen joint count, Leeds Enthesitis Index, number of dactylitic digits, and CRP.25 Of note, CRP has only been routinely performed in our clinic since 2006; therefore DAPSA and PASDAS could be calculated only as of this year. The remaining variables were collected from the first visit to the clinic on each patient.
Assessment of cardiovascular risk factors
Blood pressure was measured at each visit, and subjects were considered to have hypertension if they were taking antihypertensive agents or they had a systolic blood pressure of >140 mm Hg or a diastolic pressure of >90 mm Hg on at least two separate occasions. Body mass index (BMI) was calculated at each visit. Diabetes mellitus was considered to be present if a diagnosis of diabetes was reported by the patients or if antidiabetic medications were used. Patients were defined as smokers if they had ever smoked daily for more than 1 year. Dyslipidaemia was defined as the use of lipid-lowering agents or non-high-density lipoprotein cholesterol of >4.3 mmol/L.
Carotid ultrasound assessment
A single physician (LE) who is a rheumatologist trained in vascular ultrasound and has 4 years of experience using this technique (over 800 carotid ultrasound exams) performed all measurements following the study protocol, which has previously been described in detail.20 Scans were performed with MyLab 30 and MyLab 70 XVision (Esaote, Genoa, Italy) scanners with a linear LA523 7–13 MHz transducer (Esaote). The scan included detailed B-mode images of both right and left carotid arteries. An atherosclerotic plaque was defined as a localised intimal thickening exceeding 1 mm. The plaque area was measured by tracing the perimeter of each plaque.26 Total plaque area (TPA) was recorded as the sum of areas of all plaques in the right and left carotid arteries. Reading of the ultrasound scans was performed independently from the scanning by a single reader who was blinded to the clinical data. The intraobserver intraclass correlation coefficient for TPA was 0.94. Since the distribution of TPA was heavily skewed, it was classified into four ordered categories: (1) TPA=0 (no atherosclerosis); (2) 0<TPA≤10 mm2 (mild atherosclerosis); (3) 10<TPA≤40 mm2 (moderate atherosclerosis); (4) TPA >40 mm2 (severe atherosclerosis). The cut-off points were based on quartiles of TPA in patients with plaques. A TPA of more than 11.7 mm2 for men and more than 9.5 mm2 for women was associated with a relative risk of 2.3 and 2.9, respectively, for developing MI in a large population-based study.27
Statistical analysis
Baseline descriptive statistics were computed with continuous variables summarised by their means and SDs and categorical variables summarised by proportions. Comparisons between the TPA categories were made using the Cochran–Armitage trend test for categorical variables and linear trend test for continuous variables. A time-adjusted arithmetic mean of all available measurements from the first visit to the clinic to the time of ultrasound assessment was calculated for selected disease-related variables. These adjusted mean (AM) variables represented the cumulative inflammatory burden in PsA-related domains. The following AM variables were considered as predictors of atherosclerosis: PASI, tender and swollen joint counts, ESR, CRP, WBC count, PASDAS and DAPSA. The outcome of the study was the extent of atherosclerosis as measured by TPA categories. The association between each of the predictors and atherosclerosis was assessed in an ordinal logistic regression analysis. The initial model included each of the predictors as a single covariate in a regression model. Age and sex were then added to the model, and finally traditional cardiovascular risk factors were added as covariates. The full model included an AM PsA-related variable, age, sex, diabetes, smoking, hypertension, dyslipidaemia, BMI, race, and duration of PsA. For AM variables that were found to be associated with atherosclerosis in the age- and sex-adjusted models, further assessment was carried out using a multinomial regression model, with TPA categories as the outcome and age, sex and AM variables as covariates in the model, in order to assess the ORs associated with each TPA category. Finally, the effect of duration of PsA and PsD on atherosclerosis was studied by comparing TPA across three categories of disease duration: up to 5 years, 6–10 years, and more than 10 years. The duration of PsD was considered to be the time from the diagnosis of PsA or psoriasis, whichever came first. The comparison was made by Wilcoxon signed-rank test. The statistical computation was performed using SAS V.9.3.
Results
A total of 235 patients with PsA were included in the analysis. Four patients were excluded because of poor-quality images. The median amount of time since enrolment in the Toronto PsA cohort to the time of ultrasound assessment was 7 years (range 0–33 years). About half (144; 44.3%) of the patients were followed in the clinic from the early stages of their disease (within 2 years of the diagnosis), and the remaining 55.7% had established disease at their initial visit.
Association between traditional cardiovascular risk factors and atherosclerosis
The characteristics of the study population at the time of ultrasound assessment were compared across TPA categories (table 1). As expected, patients in the more severe atherosclerosis categories were older, had higher BMI, and were more likely to be male, ever smokers and to have diabetes, hypertension or dyslipidaemia. There was no difference in the duration of psoriasis and PsA or the use of non-steroidal anti-inflammatory drugs (NSAIDs), diease-modifying antirheumatic drugs (DMARDs) or biological agents across the TPA categories at the time of the ultrasound assessment.
Characteristics of the study population at the time of ultrasound assessment by TPA category
Association between disease activity at baseline and atherosclerosis
The levels of disease-related variables at the first visit were compared across the TPA groups (table 2). Patients with more severe atherosclerosis had higher levels of ESR and WBCs and more active disease as measured by PASDAS.
Disease activity at the first visit to the clinic by TPA category
Association between cumulative inflammation and atherosclerosis
The association between the extent of inflammation over time and atherosclerosis was assessed by regression analysis (table 3 and figure 1). In the age- and sex-adjusted models, increased AM-ESR (OR 1.41, 95% CI 1.09 to 1.82), AM-WBC (OR 1.21, 95% CI 1.04 to 1.41) and AM-DAPSA (OR 1.40 95% CI 1.01 to 1.93) were associated with a higher likelihood of being in a more severe atherosclerosis category. After adjustment for traditional cardiovascular risk factors, none of these associations remained statistically significant. Of the traditional cardiovascular risk factors, dyslipidaemia was the risk factor that was consistently associated with atherosclerosis in these models (full models are shown in online supplementary table 1). The inclusion of ever use of NSAIDs, DMARDs or tumour necrosis factor α blockers in the regression models did not affect the results (data not shown).
Association between level of inflammation over time and atherosclerosis by multivariate ordinal logistic regression
Association between disease-related variables and total plaque area (TPA) category by multinomial regression model adjusted for age and sex presented as ORs. Reference category: no plaques. (A) Adjusted mean erythrocyte sedimentation rate (ESR); (B) adjusted mean white blood cell (WBC) count; (C) adjusted mean Disease Activity for Psoriatic Arthritis (DAPSA).
Association between disease duration and atherosclerosis
To test the hypothesis that prolonged exposure to inflammation is associated with more severe atherosclerosis, we compared TPA across disease duration categories. No significant differences were found in TPA across the PsA or PsD disease duration groups (table 4).
TPA by disease duration (N=235)
Discussion
Atherosclerosis is a chronic vascular inflammation that can result in cardiovascular events. In this study, we assessed the association between the duration and extent of inflammation over time and the severity of atherosclerosis in patients with PsA. Elevated levels of inflammatory biomarkers and active clinical manifestations were associated with a higher burden of atherosclerosis. This association was attenuated after adjustment for traditional cardiovascular risk factors, suggesting that the effect of inflammation on atherogenesis may be partially mediated by adverse modification of these risk factors. Disease duration was not associated with the extent of atherosclerosis.
The association between PsA and increased cardiovascular diseases is well established4 ,5; however, only a few studies investigated the underlying mechanisms of this link. Furthermore, most studies that investigated this topic were cross-sectional, which precluded an accurate assessment of the inflammatory burden over time. We found that elevated levels of ESR and WBCs over time, both biomarkers of systemic inflammation, were associated with more severe atherosclerosis. Leucocytes play a key role in the inflammatory responses involved in atherogenesis. Blood monocytes and T cells cross the endothelial layer into the intima, where they produce proinflammatory cytokines that upregulate cell-mediated immunity and promote vascular endothelial dysfunction, which results in plaque formation.13 Activated neutrophils and their products have been linked with vulnerable plaques.28 ,29 Extensive data from large observational studies have shown that an increased WBC count predicts cardiovascular events in the general population.30–32 PsD is associated with vascular inflammation, as demonstrated by sensitive imaging studies in humans and animal models.7 ,33 Furthermore, the products of activated neutrophils are elevated in the serum and in the affected skin of psoriatic patients.34 Overall, these data and our findings indicate that the extent of inflammation over time can explain part of the atherosclerotic process in patients with PsA. These biomarkers may serve to identify patients who are at higher risk of worse disease outcome and cardiovascular events.
CRP, which has been found to be associated with increased cardiovascular risk, was not associated with atherosclerosis in our study. This seemingly surprising finding may be explained by the relatively low levels of chronic inflammation that are commonly found in PsA compared with other rheumatic conditions, which requires the use of high-sensitivity assays, which were not used in this study. On the other hand, the combined effect of joint inflammation, CRP and patient-reported outcomes, as measured by DAPSA, was associated with more severe atherosclerosis. The clinical assessment of disease activity in PsA is complex, as the disease can manifest in a variety of clinical features. Currently, there is no accepted outcome measure for the assessment of disease activity in PsA. None of the items comprising DAPSA was associated with atherosclerosis when assessed separately, possibly because of a weak effect of each one of them. Only a few studies in the past assessed the association between clinical manifestation of PsA and cardiovascular disease. None of the previous cross-sectional studies found an association between disease activity and atherosclerosis on imaging studies.8 ,12 ,35–37 Gonzalez-Juanatey et al16 reported an association between elevated levels of inflammatory markers and endothelial dysfunction, which is an early phase of atherogenesis, in a cohort of patients with PsA without traditional cardiovascular risk factors. In addition, Gladman et al5 reported that severe psoriasis predicted clinical cardiovascular events in a cohort of patients with PsA. Additional studies are required to investigate the effect of inflammatory burden on atherogenesis in PsA.
Traditional cardiovascular risk factors are prevalent in patients with PsA.38 We found an association between all of the assessed traditional cardiovascular risk factors and atherosclerosis. Recent data suggest that these abnormalities correlate with disease activity and severity. Labitigan et al39 reported that high disease activity in PsA is associated with an atherogenic lipid profile in the CORRONA database. We have shown that the metabolic syndrome and related adipokines correlate with disease activity in PsA.40 In our study, the association between inflammation and atherosclerosis was attenuated by adjusting for traditional cardiovascular risk factors, suggesting that the latter may partially mediate the effect of inflammation on atherogenesis.
The lack of association between disease duration and atherosclerosis is surprising, as studies in patients with rheumatoid arthritis and/or lupus showed an association between longer disease duration and higher cardiovascular risk.41 ,42 Our results may be explained by the insidious onset of the disease in many patients with PsA, which makes it difficult to determine the exact date of onset. An alternative explanation may be that the increase in cardiovascular risk is related, partially, to the high prevalence of traditional cardiovascular risk factors that may be present before the onset of PsA.
Our study has several limitations. First, it should be noted that the outcome of this study is a surrogate of clinical cardiovascular events. Although TPA is a strong and independent predictor of cardiovascular events, other aspects of atherosclerosis, such as plaque vulnerability, were not assessed. Second, not all potential causes of atherogenesis, such as physical activity or family history of cardiovascular events, were assessed; however, part of the effect of these factors is probably reflected by other traditional risk factors that were measured. Last, we could not account for disease activity before the first visit to the clinic; however, 44.3% of the patients were seen in the clinic within the first 2 years after the diagnosis. The strength of the study is the comprehensive and accurate phenotyping of the patients, which allowed estimation of the inflammatory burden of the disease over a long period of time. To the best of our knowledge, this is the largest study to date to investigate the association between the inflammatory burden of the disease and atherosclerosis in patients with PsA.
In summary, elevated inflammatory burden is associated with more severe atherosclerosis in patients with PsA. Traditional cardiovascular risk factors also play an important role in atherogenesis in these patients. Future studies are needed to determine whether control of inflammation by systemic therapies can prevent the progression of atherosclerotic plaques, thereby reducing the risk of cardiovascular events.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online table 1
Footnotes
Handling editor Tore K Kvien
Contributors All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. DDG 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.
Competing interests None.
Ethics approval University Health Network—Research Ethics Board.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All authors were involved in the study conception and design, acquisition of data (except RC), and analysis and interpretation of data.