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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 29, No 3, May/June 2018
190
AFRICA
A complex cross-talk between keratinocytes and dendritic cells
(DCs) in the skin, and T lymphocytes, mediated by a variety of
cytokines, results in keratinocyte hyperplasia, the characteristic
histological feature of PsO.
25
Initially, keratinocytes recruit DCs
to produce IL-23 and IL-12, which in turn activate mostly T
helper (Th) 1 and Th17 cells, resulting in further up-regulation
of cytokine secretion, especially IL-17, interferon-
γ
(IFN
γ
),
tumour necrosis factor (TNF) and IL-22.
12
These cytokines
amplify psoriatic inflammation and keratinocyte hyperplasia.
4
Moreover, pro-angiogenic factors produced by keratinocytes
such as vascular endothelial growth factor drive abnormal
vascular proliferation within the psoriatic plaque.
4,25
Psoriasis and cardiometabolic disorders
Recent interest has focused on the wide spectrum of
cardiometabolic co-morbidities observed in subjects with PsO.
These include obesity,
15
the metabolic syndrome (MetS) and its
components,
13,16
non-alcoholic fatty liver disease (NAFLD)
22
and
CVD
10,19,20,26-28
(Table 1). The dual burden of PsO and associated
co-morbidities impacts negatively on health-related quality of
life and is associated with an increased risk of premature death.
8,29
There is now a large body of evidence linking chronic
inflammation to accelerated atherosclerosis.
30,31
Rheumatoid
arthritis (RA) was the first chronic inflammatory condition to
be associated with an increased risk of premature cardiovascular
death, by as much as 50%.
32
The traditional Framingham risk
factors such as type 2 diabetes mellitus (T2DM), hypertension
and smoking have been shown to only partly account for the
increased cardiometabolic risk in RA.
33
Mechanistically, the pro-inflammatory state of RA leads
to cytokine-mediated accelerated atherosclerosis.
34,35
The
epidemiological evidence supporting the notion that PsO is
associated with a similar increased CMD risk is less well-
established and the precise pathobiology driving atherosclerosis
in PsO is complex and not fully elucidated. One hypothesis is
that the chronic inflammatory state of PsO triggers a ‘psoriatic
march’ where the pro-inflammatory milieu leads to insulin
resistance and endothelial cell dysfunction, predisposing to
accelerated atherosclerosis, finally manifesting as clinical CMD.
36
Epidemiology of cardiometabolic disease in
psoriasis
The association of PsO with cardiovascular disease (CVD)
was first proposed by McDonald and Calabresi in 1973 in a
letter published in the
New England Journal of Medicine
.
37
In
a subsequent retrospective record review comparing 323 PsO
and 325 non-psoriatic dermatology patients, they reported
an increased prevalence of ‘occlusive vascular disease’, which
included myocardial infarction (MI), stroke, thrombophlebitis
and pulmonary embolism in PsO patients.
38
Several recent registry-based studies, mainly from the United
Kingdom (UK) and Denmark have supported these initial
observations (Tables 2, 3). In a prospective study of 130 000
PsO patients and more than 500 000 control subjects in the
UK General Practice Research Database (UKGPRD), PsO was
found to be a risk factor for MI, with hazard ratios (HR) of 1.54
(95% CI: 1.24–1.91) and 7.08 (95% CI: 3.06–16.36) in mild and
severe cutaneous PsO, respectively.
10
The increased risk remained
even after controlling for major cardiovascular risk factors
such as age, gender, smoking, T2DM, hypertension, prior MI,
dyslipidaemia and body mass index (BMI).
In the Danish studies of more than 36 000 PsO patients, PsO
was associated with an increased risk of adverse CV events and
all-cause mortality.
26
Younger patients and those with severe
cutaneous disease appeared to have the greatest risk, a finding
that was similar to that for the UKGPRD cohort.
24
Two meta-
analyses, comprising 14 cohorts of patients from Europe and the
United States have shown that the risk for CVD is greatest in
patients with severe PsO.
27,28
A major limitation of many studies
included in the meta-analyses was the lack of adjustment for
traditional cardiovascular (CV) risk factors.
Some smaller studies have failed to show the association
between PsO and CVD. A prospective study of 1 380 PsO
patients, followed up for 10 years, showed no increase in
Table 2. Longitudinal studies arising from the UK General Practice Research database
Reference
Sample
size
Control
group size
Variables in multivariate models
Main outcomes
HR mild
PsO
HR severe
PsO
Gelfand
et al
.
10
Mild: 127 139
Severe: 3 837
556 995
Age. gender, HT, DM, BMI, previous MI,
cholesterol, smoking
PsO may confer an independent risk of MI
1.54
(1.24–1.91)
7.08
(3.06–16.36)
Gelfand
et al
.
20
Mild: 129 143
Severe: 3 603
Mild: 496 666
Severe: 14 330
Age, gender, HT, DM, cholesterol, smoking,
cerebrovascular disease
Both mild and severe PsO were independent
risk factors for stroke
1.06
(1.0–1.1)
1.43
(1.1–1.9)
Mehta
et al
.
51
Severe: 3 603
14 330
Age, gender, smoking, DM, HT,
hyperlipidaemia
Severe PsO was an independent risk factor
for cardiovascular mortality
–
1.57
(1.26–1.96)
Abubara
et al
.
52
Severe: 3 603
14 330
Age, gender
Patients with severe PsO were at increased
risk for death from CVD
–
1.57
(1.26–1.96)
HT, hypertension; DM, diabetes mellitus; BMI, body mass index; MI, myocardial infarction.
Table 3. Longitudinal studies arising from the Danish Nationwide cohort
Reference
Sample
size
Control
group size
Variables in multivariate models
Main outcomes
RR
mild PsO
RR
severe PsO
Ahlehoff
et al
.
26
Mild: 34 371
Severe: 2 621
4 003 625 Age, gender, co-morbidities, medication Cardiovascular mortality was increased in patients
with PsO
1.14
(1.06–1.22)
1.57
(1.27–1.94)
Ahlehoff
et al
.
26
Mild: 34 371
Severe: 2 621
4 003 625 Age, gender, co-morbidities, medication
MI was increased in patients with PsO
1.22
(1.12–1.33)
1.45
(1.10–1.90)
Ahlehoff
et al
.
19
Mild: 36 765
Severe: 2 793
4 478 926 Age, gender, co-morbidities, medication PsO was associated with an increased risk of
ischaemic stroke
1.25
(1.17–-1.64)
1.65
(1.33–2.05)
MI, myocardial infarction.