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Subclinical cardiovascular disease in plaque psoriasis: Association or causal link?

      Abstract

      Background

      Psoriasis patients have a high prevalence of cardiovascular events and are thought to have a relative risk increase of 25% as compared to the general population. However, a causal relationship between psoriasis and cardiovascular disease has not been established. We sought to perform a systematic review of existing data regarding the presence of endothelial dysfunction and subclinical atherosclerosis in patients with plaque psoriasis.

      Methods

      A systematic literature search was performed, using Medline database and Ovid SP for relevant literature up to November 2012. Twelve studies met inclusion criteria from an initial search result of 529 articles.

      Results

      Among the twelve studies meeting inclusion criteria, two (17%) reported increased mean coronary artery calcification (CAC) in psoriatic patients. Six studies (50%) showed carotid intima–media thickness [CIMT] increase in psoriasis. Five studies (42%) examined flow mediated dilation [FMD], of which three showed decreased FMD in psoriasis patients. One study (8%) each demonstrated a decreased coronary flow reserve and increased arterial stiffness as assessed by pulse wave velocity.

      Conclusions

      Patients with psoriasis have an increased burden of subclinical atherosclerosis and endothelial dysfunction. Patients with greater severity and/or disease duration should be targeted for primary screening for cardiovascular disease risk reduction

      Keywords

      1. Background

      Psoriasis is a chronic inflammatory skin disease that affects 2–3% of the US population and an estimated 125 million people worldwide [
      • National Psoriasis Foundation
      About psoriasis: statistics.
      ]. Plaque psoriasis, which is characterized by recurring erythematous patches covered with silvery plaques, accounts for 80% of these patients. Psoriasis patients are known to have a high presence of traditional CVD risk factors [
      • Abuabara K.
      • Azfar R.S.
      • Shin D.B.
      • Neimann A.L.
      • Troxel A.B.
      • Gelfand J.M.
      Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the U.K..
      ,
      • Driessen R.J.
      • Boezeman J.B.
      • Van De Kerkhof P.C.
      • De Jong E.M.
      Cardiovascular risk factors in high-need psoriasis patients and its implications for biological therapies.
      ,
      • Kaye J.A.
      • Li L.
      • Jick S.S.
      Incidence of risk factors for myocardial infarction and other vascular diseases in patients with psoriasis.
      ,
      • Mehta N.N.
      • Yu Y.
      • Pinnelas R.
      • et al.
      Attributable risk estimate of severe psoriasis on major cardiovascular events.
      ,
      • Yang Y.W.
      • Keller J.J.
      • Lin H.C.
      Medical comorbidity associated with psoriasis in adults: a population-based study.
      ,
      • Mehta N.N.
      • Krishnamoorthy P.
      • Yu Y.
      • et al.
      The impact of psoriasis on 10-year Framingham risk.
      ]. The association of psoriasis with cardiovascular disease (CVD) has come under considerable scrutiny in recent years, with recent data suggesting that it is linked to increased cardiovascular outcomes independent of the clustering of traditional CVD risk factors [
      • Mehta N.N.
      • Yu Y.
      • Pinnelas R.
      • et al.
      Attributable risk estimate of severe psoriasis on major cardiovascular events.
      ,
      • Mehta N.N.
      • Azfar R.S.
      • Shin D.B.
      • Neimann A.L.
      • Troxel A.B.
      • Gelfand J.M.
      Patients with severe psoriasis are at increased risk of cardiovascular mortality: cohort study using the general practice research database.
      ]. A recent met-analysis concluded that patients with psoriasis carry an about 25% increased relative risk of cardiovascular disease, independent of smoking, obesity and hyperlipidemia [
      • Gaeta M.
      • Castelvecchio S.
      • Ricci C.
      • Pigatto P.
      • Pellissero G.
      • Cappato R.
      Role of psoriasis as independent predictor of cardiovascular disease: a meta-regression analysis.
      ]. However, whether the relationship between clinical CVD and psoriasis extends to early atherosclerosis or preclinical disease is not well known. Such an association could provide potential insight regarding the role of psoriasis in the development of CVD and can potentially guide the discussion about whether detection and treatment of early subclinical CVD should be considered for this high risk group. The advent of non-invasive means to assess subclinical atherosclerosis has brought about a paradigm shift in CVD risk assessment. In spite of these advances, assessment of subclinical atherosclerosis and endothelial dysfunction in psoriatic patients using coronary artery calcium (CAC) screening, carotid intima–media thickness (CIMT) measurement and brachial artery flow mediated dilatation (FMD) has not been extensively studied. Therefore, in this systematic review, we sought to collect and summarize existing data regarding the presence of endothelial dysfunction and subclinical atherosclerosis as measured by non-invasive imaging techniques in patients with plaque psoriasis.

      2. Methods

      Systematic literature search was performed, using Medline database (National Library of Medicine, Bethesda, MD) and Ovid SP (Ovid, New York, NY). We used both MeSH terms and relevant free-text terms. The following search terms (synonyms and combinations) were used: ‘psoriasis’ AND ‘coronary artery calci*’ OR ‘coronary angiography’ OR ‘ankle brachial index’ OR ‘brachial artery’ OR ‘brachial artery reactivity’ OR ‘flow mediated dilation’ OR ‘intima media thickness’ OR ‘IMT’ OR ‘endothelial function’ OR ‘subclinical atherosclerosis’ OR ‘arteriolosclerosis’ (Fig. 1). The results obtained were then manually scanned for relevant articles by two independent reviewers. Discordances were discussed and a consensus was reached for each article in question. The search was conducted from 1996 to November 2012. References of obtained articles were manually scanned for other relevant studies.
      Studies were included if they were in English, original research publications and contained data on subclinical atherosclerosis and psoriasis. The following data was extracted from the studies examined: number of patients and controls, age, inclusion/exclusion criteria, main findings (limited to techniques of interest) and statistical analyses. Review articles, case reports, studies on psoriatic arthritis alone and studies focusing on inflammatory markers alone were excluded from the analysis. Studies that analyzed heterogeneous groups of patients with both plaque psoriasis and psoriatic arthritis were also excluded. Using these methods, a total of 12 studies were included for review.
      All studies included for review defined psoriasis as a chronic inflammatory skin disorder characterized by erythrosquamous plaques. All studies assessed psoriasis severity with the Psoriasis Area Severity Index (PASI), a subjective assessment of psoriasis severity subject to observer variation. However it remains the most validated approach to documenting psoriasis severity [
      • Puzenat E.
      • Bronsard V.
      • Prey S.
      • et al.
      What are the best outcome measures for assessing plaque psoriasis severity? A systematic review of the literature.
      ].

      3. Results

      3.1 Psoriasis and coronary artery calcification

      Two studies analyzed CAC in patients with plaque psoriasis, with both demonstrating an increased mean CAC score in subjects vs controls [
      • Ludwig R.J.
      • Herzog C.
      • Rostock A.
      • et al.
      Psoriasis: a possible risk factor for development of coronary artery calcification.
      ,
      • Yiu K.H.
      • Yeung C.K.
      • Zhao C.T.
      • et al.
      Prevalence and extent of subclinical atherosclerosis in patients with psoriasis.
      ] (see Table 1). Both were conducted in middle aged patient groups with plaque type psoriasis. One study recruited patients from outpatient discharge lists [
      • Yiu K.H.
      • Yeung C.K.
      • Zhao C.T.
      • et al.
      Prevalence and extent of subclinical atherosclerosis in patients with psoriasis.
      ], while the second study recruited in patients whose diagnosis had been verified by a dermatologist [
      • Ludwig R.J.
      • Herzog C.
      • Rostock A.
      • et al.
      Psoriasis: a possible risk factor for development of coronary artery calcification.
      ]. Both studies did not exclude patients with cardiovascular risk factors. Control populations were selected from different sources in both studies.
      Table 1Psoriasis and coronary artery calcification.
      Author, journal, yearStudy population

      N (age ± SD; %male)
      Main findingsComments
      Yiu et al.

      Journal of Internal Medicine

      2012
      N = 121

      Patients = 70 (46 ± 9; 71%)

      Controls = 51 (45 ± 7; 71%)
      Patients vs controlsChinese study population.

      After excluding subjects with traditional cardiovascular risk factors, no significant differences in CAC between patients (n = 34) and controls (n = 40)
      CAC > 0: 29% vs 4%; p < 0.01.
      CAC scores:
       67.4 ± 349.2 vs 0.5 ± 3.0; p < 0.05.
      Association of psoriasis & CAC > 0 (p < 0.01):
       Unadjusted OR – 9.80 (95% CI 2.17–44.19)
       Adjusted OR – 10.54 (95% CI 1.89–58.67)
      Adjusted for male sex, diabetes mellitus, triglycerides, total cholesterol, fasting glucose and high sensitivity C-reactive protein.
      Ludwig et al.

      British Journal of Dermatology

      2007
      N = 64

      Patients = 32 (49 ± 10; 81%)

      Controls = 32 (49 ± 10; 81%)
      Patients vs controlsPatients had >10 years duration of psoriasis and had undergone >2 episodes of systemic/inpatient treatment.
      CAC > 0: 59% vs 28%; p = 0.015.
      CAC scores: Patients vs controls
       78 ± 140 vs 22 ± 66; p = 0.019.
      Association of psoriasis and CAC > 0 (p < 0.01)
       Unadjusted OR – 2.11 (95% CI not given)
       Adjusted OR – not given (p = 0.001)
      Adjusted for age, sex, presence/absence of hypertension, hypercholesterolemia or hypertriglyceridemia, family history of CVD, diabetes, smoking, obesity, elevated CRP.
      CAC – coronary artery calcification; UOR – unadjusted odds ratio; AOR – adjusted odds ratio; CI – confidence interval; hs-CRP – high-sensitivity C-reactive protein.
      Yiu et al. [
      • Yiu K.H.
      • Yeung C.K.
      • Zhao C.T.
      • et al.
      Prevalence and extent of subclinical atherosclerosis in patients with psoriasis.
      ], which enrolled patients with >10% of body surface area involved, demonstrated that patients with psoriasis had a higher prevalence of coronary artery calcification (p < 0.01), and a higher degree of coronary artery calcification estimated by the mean CAC score compared with controls, (p < 0.05). C-Reactive protein levels were significantly higher in patients vs controls (5.6 ± 6.4 vs 1.9 ± 1.7, p < 0.01). Multiple logistic regression revealed that psoriasis was more strongly associated with the presence of CAC (OR: 10.54, p < 0.01) than serum total cholesterol level (OR 2.10). Severity of psoriasis as assessed by the Psoriasis Area Severity Index (PASI) score correlated with the presence of CAC (18.3 ± 10.8 vs 12.6 ± 8.6, p = 0.04). However, psoriasis duration was not seen to correlate with CAC > 0 (17.5 ± 9.1 vs 15.0 ± 6.1, p = 0.28).
      Ludwig et al. [
      • Ludwig R.J.
      • Herzog C.
      • Rostock A.
      • et al.
      Psoriasis: a possible risk factor for development of coronary artery calcification.
      ], which enrolled patients with psoriasis for >10 years, also demonstrated an increased prevalence of CAC in patients vs controls with an unadjusted odds ratio of 2.11 (59.4% vs 28.1%, p = 0.015) as well as a shift of distribution of CAC scores towards higher values in patients (78 ± 140 vs 22 ± 66, p = 0.019). C-Reactive protein levels were found to be significantly higher in patients vs controls (0.9 ± 1.0 vs 0.5 ± 0.6, p = 0.001). Regression analyses identified psoriasis as an independent risk factor for CAC score in two different analyses (p = 0.001 and p = 0.01).

      3.2 Psoriasis and CIMT

      Studies linking psoriasis and increased CIMT are listed in Table 2 [
      • Yiu K.H.
      • Yeung C.K.
      • Zhao C.T.
      • et al.
      Prevalence and extent of subclinical atherosclerosis in patients with psoriasis.
      ,
      • Arias-Santiago S.
      • Orgaz-Molina J.
      • Castellote-Caballero L.
      • et al.
      Atheroma plaque, metabolic syndrome and inflammation in patients with psoriasis.
      ,
      • Balci D.D.
      • Balci A.
      • Karazincir S.
      • et al.
      Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis.
      ,
      • El-Mongy S.
      • Fathy H.
      • Abdelaziz A.
      • et al.
      Subclinical atherosclerosis in patients with chronic psoriasis: a potential association.
      ,
      • Enany B.
      • El Zohiery A.K.
      • Elhilaly R.
      • Badr T.
      Carotid intima-media thickness and serum leptin in psoriasis.
      ,
      • Troitzsch P.
      • Paulista Markus M.R.
      • Dorr M.
      • et al.
      Psoriasis is associated with increased intima-media thickness – the study of health in Pomerania (SHIP).
      ]. Five studies recruited patients from outpatient departments [
      • Yiu K.H.
      • Yeung C.K.
      • Zhao C.T.
      • et al.
      Prevalence and extent of subclinical atherosclerosis in patients with psoriasis.
      ,
      • Arias-Santiago S.
      • Orgaz-Molina J.
      • Castellote-Caballero L.
      • et al.
      Atheroma plaque, metabolic syndrome and inflammation in patients with psoriasis.
      ,
      • Balci D.D.
      • Balci A.
      • Karazincir S.
      • et al.
      Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis.
      ,
      • El-Mongy S.
      • Fathy H.
      • Abdelaziz A.
      • et al.
      Subclinical atherosclerosis in patients with chronic psoriasis: a potential association.
      ,
      • Enany B.
      • El Zohiery A.K.
      • Elhilaly R.
      • Badr T.
      Carotid intima-media thickness and serum leptin in psoriasis.
      ] while one study recruited patients from a population-based database [
      • Troitzsch P.
      • Paulista Markus M.R.
      • Dorr M.
      • et al.
      Psoriasis is associated with increased intima-media thickness – the study of health in Pomerania (SHIP).
      ]. Three studies excluded patients with traditional cardiovascular risk factors [
      • Arias-Santiago S.
      • Orgaz-Molina J.
      • Castellote-Caballero L.
      • et al.
      Atheroma plaque, metabolic syndrome and inflammation in patients with psoriasis.
      ,
      • Balci D.D.
      • Balci A.
      • Karazincir S.
      • et al.
      Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis.
      ,
      • Enany B.
      • El Zohiery A.K.
      • Elhilaly R.
      • Badr T.
      Carotid intima-media thickness and serum leptin in psoriasis.
      ]. All six studies demonstrated an increased CIMT in psoriasis patients vs controls.
      Table 2Psoriasis and carotid IMT.
      Author, journal, yearStudy population

      N (Age ± SD; %male)
      Main findingsComments
      Enany et al.

      Herz 2012

      (Online publication)
      N = 60

      Patients = 50 (44 ± 9; 70%)

      Controls = 10 (40 ± 7; 80%)
      Patients vs controls:Mean IMT correlated with psoriasis severity (r = 0.78, p < 0.001) and disease duration (r = 0.33, p < 0.05)
      Mean carotid IMT (mm):
       LCCA: 0.97 ± 0.26 vs 0.75 ± 0.14; p < 0.05.
       RCCA: 0.96 ± 0.26 vs 0.76 ± 0.149; p < 0.05.
       RICA: 1.02 ± 0.29 vs 0.77 ± 0.17; p < 0.05.
      Troitzsch et al.

      Atherosclerosis

      2012
      N = 2027

      Data expressed as median (25th percentile,75th percentile).
      Patients = 72 (57(45,67); 57%)

      Data expressed as median (25th percentile,75th percentile).
      Controls = 1955 (52(40,64); 47%)
      Patients vs controls:Large population based cross-sectional study.

      Lacks data on duration/severity of psoriasis.
      Mean CCA–IMT (mm): 0.73 mm vs 0.69 mm; p = 0.001.
      Association of psoriasis with CIMT:
      Data expressed as median (25th percentile,75th percentile).
      Adjusted – β = 0.0016 (0.0004; 0.028) (p < 0.01)
      Odds ratio for plaque prevalence:
      Data expressed as median (25th percentile,75th percentile).
      Adjusted OR – 1.12 (0.85; 1.47).
      Adjusted for age, sex, waist circumference, alcohol consumption, physical activity, systolic blood pressure, total/HDL cholesterol ratio, HbA1c, anti-hypertensive medication, anti-diabetic medication, lipid lowering medication and acetylsalicylic acid.
      Yiu et al.

      Journal of Internal Medicine

      2012
      N = 121

      Patients = 70

      (46 ± 9; 71%)

      Controls = 51 (45 ± 7; 71%)
      Patients vs controls:Non-significant trend towards early atherosclerosis in patients without cardiovascular risk factors.
      CIMT (mm): 0.73 ± 0.11 mm vs 0.67 ± 0.08 mm; p < 0.01.
      CIMT in participants with no CVD risk factors:
       0.71 ± 0.11 vs 0.67 ± 0.08; p = 0.08.
      Association of psoriasis with CIMT (regression coefficients):
      Unadjusted – β = 0.27, p < 0.01
      Adjusted – β = 0.02, p = 0.87
      Adjusted for age, systolic blood pressure, diastolic blood pressure, body mass index and total cholesterol.
      Arias-Santiago et al.

      Eur J Dermatol

      2012
      N = 133

      Patients = 72

      Males–(46.87 ± 13.68)

      Females–

      (45.42 ± 12.92)

      Controls = Other dermatologic diseases = 61

      Male–(43.54 ± 12.03)

      Female–(48.43 ± 8.47)
      Patients vs controls:Study stratified patients and controls by gender.

      Psoriasis severity, disease duration and age correlated with IMT.
      CIMT (mm):
      RCCA = 0.72 vs 0.64; p = 0.013.
      LCCA = 0.72 vs 0.65; p = 0.042.
      Carotid plaque prevalence: 34.7% vs 8.2%; p = 0.001.
      Association of psoriasis with any carotid plaques:
      Unadjusted OR = 4.46, 95% CI: 1.85–10.72 (p = 0.001)
      Adjusted OR = 7.32, 95% CI: 2.00–26.84 (p < 0.03)
      Adjusted for age, sex, weight, height, metabolic syndrome, tobacco, sedentarism and alcohol consumption.
      El-Mongy et al.

      European Academy of Dermatology and Venereology

      2009
      N = 130

      Patients = 80 (51 ± 14; 60%)

      Controls = 50 (49 ± 7; 62%)
      Patients vs controls:IMT correlated with psoriasis severity (r = 0.5, p < 0.001) and duration (r = 0.4, p = 0.001).

      Higher plaque prevalence in patients, however, difference not statistically significant.
      IMT (mm): 0.9 ± 0.2 vs 0.7 ± 0.1; p < 0.001.
      Association of psoriasis severity with IMT (regression coefficient):
       Adjusted: β = 0.24, p ≤ 0.005
      Adjusted for age, PASI score and duration of psoriasis.
      Balci et al.

      European Academy of Dermatology and Venereology

      2008
      N = 86

      Patients = 43 (38 ± 14; 53%)

      Controls = 43(38 ± 14; 53%)
      Patients vs controls:

      IMT (mm):

       RCCA – 0.607 ± 0.144 vs 0.532 ± 0.101; p = 0.006.

       LCCA – 0.611 ± 0.157 vs 0.521 ± 0.117; p = 0.003.

       Averaged CCA – 0.609 ± 0.146 vs 0.526 ± 0.104; p = 0.003

      Association of psoriasis and IMT (regression coefficient):

       Adjusted β = 0.310 (p < 0.001)

      Adjusted for age, BMI, waist-hip ratio, LDL cholesterol, total cholesterol and presence of psoriasis.
      Younger study population (mean age 38.5 years)

      No significant association between carotid-IMT and disease duration.
      OR – odds ratio; IMT – intima media thickness; LCCA – left common carotid artery; RCCA – right common carotid artery; LICA – left internal carotid artery; CVD – cardiovascular disease; BSA – body surface area; PASI – psoriasis area and severity index.
      a Data expressed as median (25th percentile,75th percentile).
      Enany et al. [
      • Enany B.
      • El Zohiery A.K.
      • Elhilaly R.
      • Badr T.
      Carotid intima-media thickness and serum leptin in psoriasis.
      ] found an increased mean CIMT in the left common carotid artery (CCA), right common carotid artery and right internal carotid artery (p < 0.05, p < 0.05, p < 0.05 respectively). Mean CIMT showed the strongest positive correlation with psoriasis severity (r = 0.78, p < 0.001) compared to other factors such as age (r = 0.57, p < 0.001), disease duration (r = 0.33, p < 0.05) and body mass index (r = 0.43, p < 0.05) amongst others.
      Troitzsch et al. [
      • Troitzsch P.
      • Paulista Markus M.R.
      • Dorr M.
      • et al.
      Psoriasis is associated with increased intima-media thickness – the study of health in Pomerania (SHIP).
      ] conducted a large population based study with 2027 participants (1029 women and 926 men, aged 25–88 years) of which 3.6% had the diagnosis of psoriasis. Patients with psoriasis had higher mean CRP and CIMT values (p < 0.01) than those without psoriasis. Patients also had a significantly greater presence of traditional cardiovascular risk factors. After adjustments for confounders, psoriasis was still significantly associated with CCA–CIMT (β = 0.016, p < 0.008). Carotid plaque prevalence was slightly higher in subjects with psoriasis (OR 1.12) but did not reach statistical significance. This study did not provide information regarding the severity and duration of psoriasis.
      Yiu et al. [
      • Yiu K.H.
      • Yeung C.K.
      • Zhao C.T.
      • et al.
      Prevalence and extent of subclinical atherosclerosis in patients with psoriasis.
      ] documented an increased CIMT in psoriasis patients (p = 0.001). After excluding patients with traditional cardiovascular risk factors, they found a non-significant (p = 0.08) trend towards early carotid atherosclerosis in patients. Although, they found psoriasis to significantly predict CIMT (p < 0.01), this association became non-significant after adjusting for confounders (p = 0.87).
      Arias-Santiago et al. [
      • Arias-Santiago S.
      • Orgaz-Molina J.
      • Castellote-Caballero L.
      • et al.
      Atheroma plaque, metabolic syndrome and inflammation in patients with psoriasis.
      ] demonstrated an increased carotid plaque prevalence (p = 0.001) in addition to documenting significantly increased CIMT in patients with severe psoriasis. They also demonstrated a significant increase in CIMT in male patients vs females (p = 0.049). The PASI score was noted to correlate well with CIMT changes.
      El-Mongy et al. [
      • El-Mongy S.
      • Fathy H.
      • Abdelaziz A.
      • et al.
      Subclinical atherosclerosis in patients with chronic psoriasis: a potential association.
      ] demonstrated increased CIMT in patients vs controls (p < 0.001). Although no significant increase in prevalence of carotid plaques was noted (22 ± 27.8 vs 7 ± 14, p = 0.07), they documented a strong positive correlation between CIMT in psoriatic patients and their ages at the time of the study, duration of the disease and PASI Score (r = 0.6, p < 0.001; r = 0.4, p = 0.001; r = 0.5, p < 0.001 respectively). Furthermore, they found that CRP levels were higher in patients vs controls (11.8 ± 4.1 vs 7.8 ± 1.3, p ≤ 0.001).
      Balci et al. [
      • Balci D.D.
      • Balci A.
      • Karazincir S.
      • et al.
      Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis.
      ] found that the mean CIMT values of the right, left and averaged common carotid arteries were significantly higher in patients compared to controls (p = 0.006, p = 0.003 and p = 0.003, respectively). There was no significant association between CIMT and PASI score and disease duration.

      3.3 Psoriasis and FMD

      Table 3 lists the studies examining FMD in psoriasis patients [
      • Balci D.D.
      • Balci A.
      • Karazincir S.
      • et al.
      Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis.
      ,
      • De Simone C.
      • Di Giorgio A.
      • Sisto T.
      • et al.
      Endothelial dysfunction in psoriasis patients: cross-sectional case-control study.
      ,
      • Karadag A.S.
      • Yavuz B.
      • Ertugrul D.T.
      • et al.
      Is psoriasis a pre-atherosclerotic disease? Increased insulin resistance and impaired endothelial function in patients with psoriasis.
      ,
      • Martyn-Simmons C.L.
      • Ranawaka R.R.
      • Chowienczyk P.
      • et al.
      A prospective case-controlled cohort study of endothelial function in patients with moderate to severe psoriasis.
      ,
      • Ulusoy R.E.
      • Karabudak O.
      • Yokusoglu M.
      • Kilicaslan F.
      • Kirilmaz A.
      • Cebeci B.S.
      Noninvasive assessment of impaired endothelial function in psoriasis.
      ,
      • Usta M.
      • Yurdakul S.
      • Aral H.
      • et al.
      Vascular endothelial function assessed by a noninvasive ultrasound method and serum asymmetric dimethylarginine concentrations in mild-to-moderate plaque-type psoriatic patients.
      ]. Three studies excluded patients with traditional cardiovascular risk factors [
      • Balci D.D.
      • Balci A.
      • Karazincir S.
      • et al.
      Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis.
      ,
      • Martyn-Simmons C.L.
      • Ranawaka R.R.
      • Chowienczyk P.
      • et al.
      A prospective case-controlled cohort study of endothelial function in patients with moderate to severe psoriasis.
      ,
      • Usta M.
      • Yurdakul S.
      • Aral H.
      • et al.
      Vascular endothelial function assessed by a noninvasive ultrasound method and serum asymmetric dimethylarginine concentrations in mild-to-moderate plaque-type psoriatic patients.
      ]. Two studies found no statistically significant differences in FMD in patients with psoriasis [
      • Martyn-Simmons C.L.
      • Ranawaka R.R.
      • Chowienczyk P.
      • et al.
      A prospective case-controlled cohort study of endothelial function in patients with moderate to severe psoriasis.
      ,
      • Usta M.
      • Yurdakul S.
      • Aral H.
      • et al.
      Vascular endothelial function assessed by a noninvasive ultrasound method and serum asymmetric dimethylarginine concentrations in mild-to-moderate plaque-type psoriatic patients.
      ]. Usta et al. [
      • Usta M.
      • Yurdakul S.
      • Aral H.
      • et al.
      Vascular endothelial function assessed by a noninvasive ultrasound method and serum asymmetric dimethylarginine concentrations in mild-to-moderate plaque-type psoriatic patients.
      ] found no significant differences in baseline brachial artery dilation (BBAD), FMD, or nitroglycerin-induced dilation (NID) (p = 0.597, p = 0.441, and p = 0.557, respectively) in patients with mild-moderate plaque type psoriasis vs controls. However, they found CRP levels to be significantly higher in patients vs controls (2.52 vs 1.62, p = 0.008). Martyn-Simmons et al. [
      • Martyn-Simmons C.L.
      • Ranawaka R.R.
      • Chowienczyk P.
      • et al.
      A prospective case-controlled cohort study of endothelial function in patients with moderate to severe psoriasis.
      ] found no significant differences in FMD in patients with moderate-severe psoriasis (p > 0.5). They did however document a highly significant increase in high-sensitivity C-reactive protein (p < 0.0001) and HDL cholesterol levels (p = 0.003) in patients with psoriasis vs controls.
      Table 3Psoriasis and flow mediated dilatation.
      Author/journal/yearStudy population

      N (Age ± SD; %male)
      Main findingsComments
      De Simone et al.

      Eur J Dermatol

      2011
      N = 63

      Patients = 32 (36 ± 10; 66%)

      Controls = 31 (41 ± 11; 68%)
      Patients vs controls:

      FMD (%): 6 ± 6 vs 11 ± 6; p = 0.012.
      Subgroup analysis of patients, %FMD not significantly different across genders, smokers and non-smokers, with or without a hypercholesterolemia or hypertension, or family history of CVD. No correlation between disease duration/severity and FMD impairment. PASI = 17.9 ± 10.9.
      Usta et al.

      Clinical Biochemistry

      2011
      N = 54

      Cases = 29 (34 ± 9; 44%)

      Controls = 25 (35 ± 9; 34%)
      Patients vs controls:

      FMD (%): 3.6 ± 0.63 vs 3.7 ± 0.57; p = 0.441):
      Only included patients with mild-moderate plaque type psoriasis.

      Only 6.9% of patients had PASI values ≥ 10.
      Martyn-Simmons et al.

      British Journal of Dermatology

      2011
      N = 177

      Patients = 60 (51; 77%)

      Controls = 117 (49; 42%)
      Patients vs controls:

      FMD (%): 6.644, (95% CI 5.99–7.30) vs 6.370%, (95% CI 5.93–6.81); p = 0.508.
      Included patients with severe psoriasis without CVD risk factors.

      High prevalence of traditional risk factors (56%) as well as clinical CVD (6%) in patients with severe psoriasis who were assessed for eligibility.
      Ulusoy et al.

      Rheumatol Int

      2010
      N = 56

      Patients = 28 (23 ± 6; 100%) Controls = 28 (21 ± 7; 100%)
      Patients vs controls:

      FMD (%): 13.9 ± 0.5 vs 32.6 ± 6.3; p < 0.001.
      Young study population.

      Intraobserver reproducibility of FMD was 75%.
      Balci et al.

      European Academy of Dermatology and Venereology

      2008
      N = 86

      Patients = 43

      (38 ± 14; 53%)

      Controls = 43

      (38 ± 14; 53%)
      Patients vs controls:

      Mean FMD (mm): 13.36 ± 6.39 vs 9.60 ± 11.23; p = 0.002.

       Odds ratios: not given

      Association of psoriasis with FMD (regression coefficient):

       Adjusted β = −0.320 (p < 0.01)

      Included age, sex, waist-hip ratio, LDL, HDL cholesterol and presence of psoriasis
      FMD in psoriasis patients associated with disease duration.
      BBAD – Baseline Brachial Artery Diameter; FMD – Flow mediated Dilatation; NID – Nitroglycerin induced Dilatation; PASI – Psoriasis Area and Severity Index; CVD – Cardiovascular disease; OR – Odds Ratio.
      In contrast to the two studies described above, three studies demonstrated a decrease in FMD in patients with psoriasis [
      • Balci D.D.
      • Balci A.
      • Karazincir S.
      • et al.
      Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis.
      ,
      • De Simone C.
      • Di Giorgio A.
      • Sisto T.
      • et al.
      Endothelial dysfunction in psoriasis patients: cross-sectional case-control study.
      ,
      • Karadag A.S.
      • Yavuz B.
      • Ertugrul D.T.
      • et al.
      Is psoriasis a pre-atherosclerotic disease? Increased insulin resistance and impaired endothelial function in patients with psoriasis.
      ,
      • Ulusoy R.E.
      • Karabudak O.
      • Yokusoglu M.
      • Kilicaslan F.
      • Kirilmaz A.
      • Cebeci B.S.
      Noninvasive assessment of impaired endothelial function in psoriasis.
      ]. De Simone et al. [
      • De Simone C.
      • Di Giorgio A.
      • Sisto T.
      • et al.
      Endothelial dysfunction in psoriasis patients: cross-sectional case-control study.
      ] found that FMD was significantly lower in patients vs controls (p = 0.012). They did not however find a correlation between FMD impairment and psoriasis duration and severity. Ulusoy et al. [
      • Ulusoy R.E.
      • Karabudak O.
      • Yokusoglu M.
      • Kilicaslan F.
      • Kirilmaz A.
      • Cebeci B.S.
      Noninvasive assessment of impaired endothelial function in psoriasis.
      ] studied a younger patient population with mild-moderate psoriasis and reported a 37% decrease in FMD in patients vs controls (13.9 ± 0.5 vs 32.6 ± 6.3, p < 0.001). Correlation with PASI score and disease duration was not calculated.
      Balci et al. [
      • Balci D.D.
      • Balci A.
      • Karazincir S.
      • et al.
      Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis.
      ,
      • Osto E.
      • Piaserico S.
      • Maddalozzo A.
      • et al.
      Impaired coronary flow reserve in young patients affected by severe psoriasis.
      ] found that the mean FMD and NID values of the psoriasis patients were significantly lower than controls (p = 0.002 and p = 0.013, respectively). The differences in the FMD measurements were still statistically significant between the two groups after controlling for HDL levels (p = 0.01). Duration of disease weakly correlated with FMD (β 0.259, p < 0.05).

      3.4 Psoriasis with markers of coronary flow and arterial stiffness

      Studies demonstrating the relationship between psoriasis and other markers of subclinical atherosclerosis are listed in Table 4. Osto et al. [
      • Osto E.
      • Piaserico S.
      • Maddalozzo A.
      • et al.
      Impaired coronary flow reserve in young patients affected by severe psoriasis.
      ] showed that patients with severe psoriasis had lower coronary flow reserve (CFR) than controls (p = 0.02). In patients with CFR ≤ 2.5, PASI was higher (p = 0.006) compared to patients with CFR > 2.5. After multivariable analysis, PASI remained the only determinant of CFR ≤ 2.5 (p = 0.02). Gisondi et al. [
      • Gisondi P.
      • Fantin F.
      • Del Giglio M.
      • et al.
      Chronic plaque psoriasis is associated with increased arterial stiffness.
      ] found that carotid-femoral pulse wave velocity (PWVcf) after adjustment for age, gender, smoking status, hypertension and body mass index was significantly higher in patients with moderate-severe psoriasis than in controls (p = 0.03) and was directly correlated with psoriasis duration in years (r = 0.58; p = 0.0001) but not with severity of psoriasis. No significant differences were found in CRP levels between patients and controls (p = 0.78). Carotid-radial pulse wave velocity (PWVcr) was not significantly different between patients and controls. They also demonstrated that psoriasis was independently associated with increased arterial stiffness by age, gender, smoking status, hypertension and body mass index.
      Table 4Psoriasis and arterial stiffness.
      Author/journal/yearStudy population

      N (Age ± SD; %male)
      Method of assessing endothelial functionMain findingsComments
      Osto et al.

      Atherosclerosis

      2012
      N = 112

      Patents = 56 (37 ± 3; 75%)

      Controls = 56 (Age; gender information not given)
      Coronary flow reserve (CFR) defined as ratio of hyperemic to baseline peak diastolic coronary flow velocities.Patients vs controls

      CFR:

       3.2 ± 0.9 vs 3.7 ± 0.7; p = 0.02.

      Association of psoriasis severity and CFR ≤ 2.5 (p = 0.02):

       Adjusted OR = 1.70, CI = 1.05–2.6

      Adjusted for age, gender, hsCRP, BMI, smoking status, hypertension, time from diagnosis, heart rate, systolic blood pressure and Framingham risk score
      Patients with CFR < 2.5 had more severe disease vs controls (PASI: 11 ± 6 vs 7 ± 3, p = 0.006)
      Gisondi et al.

      Dermatology

      2009
      N = 77

      Psoriasis patients = 39 (51 ± 13; 50%)

      Patients with other skin diseases = 38 (52 ± 13; 50%)
      Pulse wave velocityPatients vs controls:

      Unadjusted PWVcf (m/s):

       8.88 ± 1.96 vs 7.57 ± 1.34; p = 0.001.

      Adjusted PWVcf (m/s): Patients vs controls:

       8.78 ± 1.98 vs 7.78 ± 2.0; p = 0.03.

      Adjusted for age, gender, smoking status, hypertension and body mass index.
      Positive correlation between PWVcf and duration of psoriasis (r = 0.58; p = 0.0001), but not with disease severity.
      BSA – body surface area involved; PASI – psoriasis area and severity index; PWVcf – carotid-femoral pulse wave velocity; hsCRP – high sensitivity C-reactive protein.

      4. Discussion

      The present study systematically examines the presence and burden of measures of subclinical CVD in patients with plaque psoriasis. In summary, we observed that out of the twelve studies reviewed, individuals with psoriasis were consistently found to have a higher carotid IMT and had a higher burden of CAC, arterial stiffness and endothelial dysfunction. This association persisted after accounting for traditional risk factors, suggesting that psoriasis itself confers increased CVD risk. The largest population based study of the relationship between CVD events and psoriasis demonstrated that CVD events correlated to psoriasis severity [
      • Gelfand J.M.
      • Neimann A.L.
      • Shin D.B.
      • Wang X.
      • Margolis D.J.
      • Troxel A.B.
      Risk of myocardial infarction in patients with psoriasis.
      ]. Our review of the literature supports this observation. Of the five studies that used CAC and CIMT and calculated disease severity, four showed a statistically significant correlation between psoriasis severity and atherosclerotic burden [
      • Yiu K.H.
      • Yeung C.K.
      • Zhao C.T.
      • et al.
      Prevalence and extent of subclinical atherosclerosis in patients with psoriasis.
      ,
      • Arias-Santiago S.
      • Orgaz-Molina J.
      • Castellote-Caballero L.
      • et al.
      Atheroma plaque, metabolic syndrome and inflammation in patients with psoriasis.
      ,
      • El-Mongy S.
      • Fathy H.
      • Abdelaziz A.
      • et al.
      Subclinical atherosclerosis in patients with chronic psoriasis: a potential association.
      ,
      • Enany B.
      • El Zohiery A.K.
      • Elhilaly R.
      • Badr T.
      Carotid intima-media thickness and serum leptin in psoriasis.
      ]. Armstrong et al., in a retrospective cohort analysis showed that among patients referred for invasive coronary angiography, those with psoriasis were more likely to have coronary artery disease (CAD) (84.3% vs 75.7%, p = 0.005) and that this association persisted after taking into account established cardiovascular risk factors. The duration of psoriasis was independently associated with angiographically confirmed CAD [
      • Armstrong A.W.
      • Harskamp C.T.
      • Ledo L.
      • Rogers J.H.
      • Armstrong E.J.
      Coronary artery disease in patients with psoriasis referred for coronary angiography.
      ]. The data for disease duration in studies that used CAC or CIMT was equivocal with two studies showing an association [
      • El-Mongy S.
      • Fathy H.
      • Abdelaziz A.
      • et al.
      Subclinical atherosclerosis in patients with chronic psoriasis: a potential association.
      ,
      • Enany B.
      • El Zohiery A.K.
      • Elhilaly R.
      • Badr T.
      Carotid intima-media thickness and serum leptin in psoriasis.
      ] while two other showed no correlation [
      • Yiu K.H.
      • Yeung C.K.
      • Zhao C.T.
      • et al.
      Prevalence and extent of subclinical atherosclerosis in patients with psoriasis.
      ,
      • Balci D.D.
      • Balci A.
      • Karazincir S.
      • et al.
      Increased carotid artery intima-media thickness and impaired endothelial function in psoriasis.
      ]. This supports the findings of the study by Gelfand et al., which showed that the relative risk of myocardial infarction was highest in younger patients with severe disease compared to older patients – who did however have a higher absolute risk [
      • Gelfand J.M.
      • Neimann A.L.
      • Shin D.B.
      • Wang X.
      • Margolis D.J.
      • Troxel A.B.
      Risk of myocardial infarction in patients with psoriasis.
      ].
      The mechanisms through which individuals with psoriasis are likely affected with early subclinical CVD remain an active area of research. The association of psoriasis with CVD is likely multi-factorial. Large epidemiological studies have noted that patients with psoriasis have an increased prevalence of CVD risk factors such as obesity [
      • Ridker P.M.
      • Fonseca F.A.
      • Genest J.
      • et al.
      Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein.
      ], smoking [
      • Kronmal R.A.
      • McClelland R.L.
      • Detrano R.
      • et al.
      Risk factors for the progression of coronary artery calcification in asymptomatic subjects: results from the Multi-Ethnic Study of Atherosclerosis (MESA).
      ], elevated lipids [
      • Sarwar A.
      • Shaw L.J.
      • Shapiro M.D.
      • et al.
      Diagnostic and prognostic value of absence of coronary artery calcification.
      ,
      • Blacher J.
      • Asmar R.
      • Djane S.
      • London G.M.
      • Safar M.E.
      Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients.
      ], diabetes mellitus (independent of obesity) [
      • Gelfand J.M.
      • Neimann A.L.
      • Shin D.B.
      • Wang X.
      • Margolis D.J.
      • Troxel A.B.
      Risk of myocardial infarction in patients with psoriasis.
      ] and depression [
      • Blacher J.
      • Guerin A.P.
      • Pannier B.
      • Marchais S.J.
      • Safar M.E.
      • London G.M.
      Impact of aortic stiffness on survival in end-stage renal disease.
      ]. However, with the exception of Troitzsch et al. who found significantly different lipid profiles and a higher prevalence of diabetes in patients vs controls; most of the studies included for review either excluded subject with traditional risk factors or did not document the same difference between psoriasis patients and controls, presumably due to their small sample size. Furthermore, common treatments for psoriasis (e.g. cyclosporine, acitretin) worsen cardiovascular risk profiles by worsening blood pressure and lipid profiles [
      • Kremers H.M.
      • McEvoy M.T.
      • Dann F.J.
      • Gabriel S.E.
      Heart disease in psoriasis.
      ]. The common role of inflammation is being vigorously examined. The concept of a ‘psoriatic march’ has been forwarded, which proposes that systemic inflammation may cause insulin resistance, which in turn triggers endothelial cell dysfunction, leading to atherosclerosis and finally myocardial infarction or stroke [
      • Boehncke W.H.
      • Boehncke S.
      • Tobin A.M.
      • Kirby B.
      The ‘psoriatic march’: a concept of how severe psoriasis may drive cardiovascular comorbidity.
      ]. While this model has not been formally proven, it has provided interesting guidelines for research. Emerging data also suggests that chronic inflammatory states such as psoriasis, through the production of proinflammatory lipoprotein particles and the impairment of reverse cholesterol transport, may adversely affect lipoprotein metabolism and resulting in a high preponderance of HDL dysfunction [
      • de la Llera Moya M.
      • McGillicuddy F.C.
      • Hinkle C.C.
      • et al.
      Inflammation modulates human HDL composition and function in vivo.
      ]. Mehta et al. [
      • Mehta N.N.
      • Li R.
      • Krishnamoorthy P.
      • et al.
      Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis.
      ] reported increased LDL particle concentrations and lower mean LDL particle size in psoriasis. They also reported a lower HDL efflux capacity in psoriasis compared to controls in fully adjusted models. These changes in lipid physiology may potentially play a role in the development of earlier subclinical disease in this vulnerable population. Shared genetics, if any, between CVD and psoriasis remain less well investigated [
      • Trembath R.C.
      • Clough R.L.
      • Rosbotham J.L.
      • et al.
      Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.
      ].
      Our extensive review of all studies assessing relationship of psoriasis with subclinical CVD identified some issues that need further discussion. Firstly, the role of systemic inflammation is worthy of note. As described above, the role of inflammation in the pathogenesis of early endothelial dysfunction and subsequent development of atherosclerosis has been established. In our review, only two studies [
      • Ludwig R.J.
      • Herzog C.
      • Rostock A.
      • et al.
      Psoriasis: a possible risk factor for development of coronary artery calcification.
      ,
      • Osto E.
      • Piaserico S.
      • Maddalozzo A.
      • et al.
      Impaired coronary flow reserve in young patients affected by severe psoriasis.
      ] demonstrated an independent association between hs-CRP (an established marker of generalized inflammation) and CAC in patients with psoriasis. Future studies should clarify whether this association noted in our systematic review can be explained by a heightened burden of inflammation. Secondly, to date all the studies have been cross-sectional and as a result causality cannot be determined. Evidence about whether patients with psoriasis are at increased risk of ‘development’ and progression of early changes in subclinical CVD remains unclear. Prospective studies are needed to elucidate this relationship. There is also a great need to understand whether the association between psoriasis and cardiac events can be explained by an increased subclinical CVD burden noted in these individuals.
      Finally, the implications of the associations demonstrated in our review are unclear. Should individuals with psoriasis be screened for measures of subclinical CVD or should all of these individuals be treated with preventive therapies? Since most current treatment focuses on reducing inflammatory processes, it is unknown whether these treatments will also be helpful in reducing risk for future CVD and atherosclerosis development. The role of statins in this group (standard of care in primary CVD strategies) also remains an unanswered question. There is a need for consensus in this specific area. Irrespective, patients with psoriasis should be carefully counseled regarding increased cardiovascular risk and assessed for at least traditional cardiovascular risk factors and treated accordingly. This recommendation has also been forwarded by a recent consensus statement [
      • Friedewald V.E.
      • Cather J.C.
      • Gelfand J.M.
      • et al.
      AJC editor's consensus: psoriasis and coronary artery disease.
      ].
      Our study findings should be interpreted in light of several limitations. Psoriasis affects only 2–3% of the population, thus most studies performed contained small patient cohorts. Only one study was based on a population-based cohort [
      • Troitzsch P.
      • Paulista Markus M.R.
      • Dorr M.
      • et al.
      Psoriasis is associated with increased intima-media thickness – the study of health in Pomerania (SHIP).
      ]. This may in part be responsible for the failure to detect significant associations i.e. increased carotid plaque prevalence in studies using IMT as a marker. The development of plaques is considered as a late phenomenon in the development of atherosclerosis and most studies may have been underpowered to detect a significant difference. These studies did however document increased absolute IMT values in psoriasis patients, suggesting an increased atherosclerotic burden in this population, despite the failure to detect significantly higher plaque prevalence. All studies were conducted among Caucasian populations, with the exception of Yiu et al. [
      • Yiu K.H.
      • Yeung C.K.
      • Zhao C.T.
      • et al.
      Prevalence and extent of subclinical atherosclerosis in patients with psoriasis.
      ], which demonstrated a ∼10-fold increased risk of subclinical coronary atherosclerosis in patients compared to controls. This may in part be explained by the lower overall prevalence of coronary atherosclerosis in Chinese patients and points to the lack of generalizability of studies performed on a single ethnic/racial group. Most of the studies reviewed/recruited patients and controls from different sources which may introduce bias in their results. The studies reviewed in this paper represented patients with plaque psoriasis, thus these findings might not be applicable to other subtypes of psoriasis e.g. psoriatic arthritis. Despite these limitations, the fact that most studies were in agreement lends credence to the validity of their results.

      5. Summary

      In conclusion, based on our systematic review, it is evident that individuals with plaque psoriasis have an increased burden of the atherosclerotic process in multiple vascular beds, impaired endothelial function and augmented arterial stiffness. These changes were independent of the effect of traditional risk factors, suggesting that psoriasis alone confers increased CVD risk, although the intricacies of this association have not been fully explored. This suggests strongly that psoriasis may have a causal link with CVD, identifying an urgent need for prospective studies to assess this claim. Important issues that need further exploration include identification of appropriate screening strategies for subclinical CVD, seeking consensus and evidence on whether non-pharmacological and pharmacological approaches result in slower progression of subclinical CVD and reduction in clinical events among patients with psoriasis. Large, well-planned comprehensive trials aimed at answering these key questions will help to solidify the role of early prevention efforts in this vulnerable population.

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