Research ArticleCardiovascular Risk in Psoriasis: A Population-Based Analysis with Assessment
of the Framingham Risk ScoreElena Myasoedova,1,2 Bharath Manu Akkara Veetil,1 Eric L.
Matteson,1,2 Hilal Maradit Kremers,2 Marian T. McEvoy,3 and Cynthia S. Crowson1,21Division
of Rheumatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905,
USA
2Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street
SW, Rochester, MN 55905, USA
3Department of Dermatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester,
MN 55905, USAReceived 18 December 2012; Accepted 7 January 2013Academic Editors: B. Z.
Simkhovich and U. TursenCopyright © 2013 Elena Myasoedova et al. This is an open access
article distributed under the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.AbstractObjective. To examine the utility of the Framingham risk score (FRS) in
estimating cardiovascular risk in psoriasis. Methods. We compared the predicted 10-year risk
of cardiovascular events, namely, cardiovascular death, myocardial infarction, heart failure,
percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting using the
FRS, to the observed risk of cardiovascular events in a population-based cohort of patients
with psoriasis. Patients with incident or prevalent adult-onset psoriasis aged 30–79 years
without prior history of cardiovascular disease were included. Results. Among the 1197
patients with predicted risk scores, the median FRS was 6.0%, while the observed 10-year
cardiovascular risk was 6.9% (standardized incidence ratio (SIR): 1.14; 95% confidence interval
(CI): 0.92–1.42). The SIR was not elevated for women nor for men. The differences between
observed and predicted cardiovascular risks in patients <60 years (SIR: 1.01; 95% CI: 0.73–1.41)
or ≥60 years (SIR: 1.26; 95% CI: 0.95–1.68) were not statistically significant. Conclusion. There
was no apparent difference between observed and predicted cardiovascular risks in patients
with psoriasis in our study. FRS reasonably estimated cardiovascular risk in both men and
women as well as in younger and older psoriasis patients, suggesting that FRS can be used in
risk stratification in psoriasis without further adjustment.1. IntroductionThere is increasing
interest in cardiovascular implications of chronic inflammatory conditions such as psoriasis [1].
Epidemiologic observations have demonstrated increased rates of cardiovascular events in
patients with psoriasis [2, 3]. Some studies suggested that psoriasis itself may be an
independent cardiovascular risk factor [4, 5], while others did not support this finding [6]. It is
unclear whether cardiovascular risk in psoriasis is increased beyond that conferred by
traditional cardiovascular risk factors and whether traditional risk assessment tools such as the
Framingham risk score (FRS) are useful for cardiovascular risk stratification in psoriasis. We
aimed to examine the utility of the FRS in estimating cardiovascular risk in psoriasis.2.
Materials and MethodsThis retrospective population-based study was conducted using the
Rochester epidemiology project (REP), a medical records linkage system containing complete
inpatient and outpatient records from all healthcare providers in Olmsted County, Minnesota.
The unique features of the REP were described previously [7]. The study protocol was
approved by the Institutional Review Boards of Mayo Clinic and Olmsted Medical Center.Using
the REP resources, we identified all Olmsted County, Minnesota, residents aged 30–79 years
with diagnostic codes consistent with psoriasis (International Classification of Diseases, Ninth
Revision (ICD-9) codes 696.1, 696.2, 696.8, 696.5, and 696.3) between 01-01-1998 and 01-01-
2008 [8]. Psoriasis was validated by a confirmatory diagnosis of dermatologist or a physician’s
description of the lesions in the medical record or a skin biopsy. Doubtful diagnoses were
resolved by the dermatologist coinvestigator. The study included patients with incident or
prevalent adult-onset psoriasis in 1998–2007. The psoriasis incidence date of incident subjects
and the prevalence date for prevalent subjects (i.e., first mention of psoriasis during the study
period) are further referred to as the baseline.The entire inpatient and outpatient medical
records of each patient were reviewed by trained nurse abstractors, beginning with the
subjects’ records at age 18 years or date of migration to Olmsted County until the death,
migration, or end of the study (12-31-2010). Data were collected on cardiovascular events,
namely, all hospitalized myocardial infarctions, revascularization procedures (i.e., coronary
artery bypass grafting and percutaneous interventions), heart failure, and cardiovascular
deaths throughout the followup. All subjects (irrespective of residency status) were tracked
nationally for vital status; death certificates were obtained from the respective states for
subjects who died outside Minnesota. The underlying cause of death was coded from national
mortality statistics, and cardiovascular death was defined as ICD-9 codes 390–459 and ICD-10
codes I00–I99 [9]. Systemic medication use included methotrexate, oral retinoids, cyclosporin,
sulfasalazine, hydroxyurea, hydroxychloroquine, azathioprine, cyclophosphamide, leflunomide,
etanercept, infliximab, adalimumab. Any use of these medications prior to baseline and during
followup was considered.Data on cardiovascular risk factors at baseline, namely, smoking,
blood pressure measures, use of antihypertensive and/or lipid-lowering medications, body
mass index (BMI), and diabetes mellitus, were collected as were the results of all fasting
clinically performed serum lipid measures. For blood pressure, the recorded value closest to
baseline ±1 year was used to calculate the risk of cardiovascular disease (CVD). For lipids, the
recorded value closest to baseline ±2 years was used, since guidelines recommend
measurement of lipids every 5 years.The 10-year FRS for general CVD, which includes
cardiovascular events of myocardial infarction, cardiovascular death, angina, stroke,
intermittent claudication, and heart failure, was calculated [10]. For those without lipid values,
we instead applied the office-based 10-year FRS which does not require laboratory values for
calculation of the FRS. Since information on stroke and intermittent claudication was not
collected in our study, the FRS was recalibrated to the subset of cardiovascular events
collected in our population using calibration coefficients provided with the published algorithm
[10].To facilitate comparison of the predicted 10-year FRS with the observed CVD risk, the
observed followup was truncated at 10 years after baseline. For patients with <10 years of
followup, the predicted CVD risk was adjusted proportionately. Poisson regression models
were used to obtain the standardized incidence ratio (SIR), that is, the ratio of the observed
CVD in psoriasis to the FRS-predicted CVD rates. Subgroup analyses were performed by sex,
age group, and exposure to systemic therapy. For the analysis of systemic therapy, patients
contributed person-years of followup to the unexposed analysis until they were exposed to
systemic therapy when they were moved to the systemic therapy group. An additional analysis
where patients were censored at diagnosis of psoriatic arthritis was also performed.3.
ResultsThe study population included 1421 patients with incident (
) or prevalent (
) adult-onset psoriasis without prior CVD. Of these, 1197 (84%) patients had complete risk
factor data to compute FRS, and 82 patients developed CVD during a mean followup of 8.1
years. Of the remaining 224 patients without FRS, 8 patients developed CVD during a mean
followup of 7.1 years. Patients with complete information for FRS were compared to those
without enough information (Table 1). For those with FRS, the predicted median 10-year FRS
was 6.0% (min: 0.0%, max: 72.1%). The observed 10-year CVD risk was 6.9% (95% confidence
interval (CI): 7.8%, 12%). The CVD rate was marginally lower in those without FRS (observed
10-year risk: 3.6%; 95% CI: 1.4%, 6.0%, log rank
).tab1Table 1: Characteristics and cardiovascular risk factors of patients with psoriasis and no
prior cardiovascular disease. Comparison of patients with enough information to compute the
Framingham risk score (FRS) to those without enough information for the FRS.In 82 patients
who developed CVD, 71.7 CVD events were predicted by the FRS (SIR 1.14, 95% CI: 0.92, 1.42;
Table 2). The SIR was not significantly elevated for women or men. The SIR was similar in both
age groups, as well as among patients using systemic therapy (Table 2). The results regarding
systemic therapy remained unchanged when patients who were diagnosed with psoriatic
arthritis (35 patients, 18%) were censored at diagnosis (SIR: 1.12; 95% CI: 0.62, 2.02).tab2Table
2: Comparison of observed and FRS-predicted CVD risk in patients with psoriasis.4.
DiscussionGiven the mounting evidence of increased CVD risk in psoriasis, it is all more
important to assess whether cardiovascular risk assessment tools such as the FRS are useful for
evaluating CVD risk in these patients. This study is among the first to assess the FRS in a
population-based cohort of patients with psoriasis. We found no apparent difference in the
observed versus FRS-predicted 10-year CVD risk. The SIR was not significantly elevated for men
or women and was similar across the age groups. This finding is in agreement with some prior
studies [6, 11] and in contrast to other reports that show an excess of CVD in psoriasis [2, 12].
Some studies emphasize that the risk is greatest in younger patients (<60 years) and in patients
with early-onset and longstanding psoriasis, presumably due to the fairly chronic course of the
inflammatory process and cumulative disease burden perpetuating atherosclerotic disease [2,
3]. We found no apparent differences between the observed and predicted CVD risks for
patients aged <60 years, which supports the findings of some investigators [13].It has been
suggested that increased cardiovascular risk in psoriasis is confined to patients with severe
disease [14, 15]. Shared genetic mechanisms for the risk of psoriasis, in particular severe
psoriasis, and increased cardiovascular risk have been described, including apolipoprotein E
gene polymorphism [16–18]. However, severe psoriasis was found to be a risk factor for CVD in
some studies [19] but not in others [11]. Using systemic therapy as a proxy for severity, we did
not find apparent difference in the observed versus predicted CVD rate. This is in line with our
earlier findings where systemic treatment was not significantly associated with CVD
occurrence in psoriasis after adjusting for traditional cardiovascular risk factors [20]. Of note,
the prevalence of severe psoriasis in population-based studies is very low [21]. Patients with
severe psoriasis with increased CVD risk beyond that accounted for by the FRS likely constitute
a very small percentage of patients (16% in our cohort), and this could account for the lack of
difference between observed and predicted CVD risks in our study.Strengths of this study
include the longitudinal population-based design and the use of the unique REP resources.
Limitations include insufficient statistical power in some subgroup analyses, in particular,
analyses examining the risk among patients who received systemic treatment. These results
should be interpreted with caution. Data on stroke and intermittent claudication were not
available. However, calibration coefficients were applied to recalibrate the FRS to the subset of
CVD events in our population which we believe minimizes this weakness. Information
regarding disease severity was not available. However, we used systemic therapy as a
surrogate in order to, at least in part, account for this limitation. There was no comparison
cohort without psoriasis to validate the FRS accuracy in our population. However, we have
previously shown that FRS accurately predicted CVD events in Olmsted County residents
without rheumatoid arthritis [22]. Considering a low prevalence (<1%) of rheumatoid arthritis,
we believe this analysis validates the FRS in our community. Also, other investigators using
cross-sectional data have demonstrated the utility of the FRS in psoriasis [12, 23]. Finally, the
population of Olmsted County, Minnesota, is predominantly White; thus, results may not be
generalizable to non-White subjects.In conclusion, the FRS reasonably estimates CVD risk in
both men and women as well as in younger (<60 years) and older (≥60 years) patients with
psoriasis and can be used in risk stratification in psoriasis without any further adjustment.
Psoriasis did not appear to be an independent risk factor for CVD in our study. More studies
are needed to better understand the nature of CVD in psoriasis and to develop effective
strategies for CVD prevention in patients with psoriasis.AcknowledgmentThis work was
partially funded by a grant from Pfizer and was made possible by a grant from Amgen/Wyeth
and by the Rochester Epidemiology Project (R01 AG034676 from the National Institute on
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Research ArticlePrevalence of Metabolic Syndrome in Patients with PsoriasisIlkin Zindancı,
Ozlem Albayrak, Mukaddes Kavala, Emek Kocaturk, Burce Can, Sibel Sudogan, and Melek
KoçDepartment of Dermatology, Goztepe Training and Research Hospital, Istanbul,
TurkeyReceived 22 November 2011; Accepted 21 December 2011Academic Editors: A. Cuocolo
and L. KullerCopyright © 2012 Ilkin Zindancı et al. This is an open access article distributed
under the Creative Commons Attribution License, which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is properly
cited.AbstractBackground. Psoriasis is a chronic inflammatory skin disorder in which
proinflammatory cytokines including IL-6 and TNF-α increase both locally and systematically. It
is thought that chronic inflammation results in metabolic diseases and proinflammatory
cytokines give rise to the development of atherogenesis, peripheral insulin resistance,
hypertension, and type 2 diabetes. Our aim was to investigate the prevalence of metabolic
syndrome in patients with psoriasis vulgaris. Methods. Study consisted of 115 plaque-type
psoriasis patients and 140 healthy individuals. Data including body weight, height, waist
circumference, body-mass index, and arterial blood pressure were collected. Fasting blood
glucose, triglyceride, and HDL levels were determined. International Diabetes Federation
Criteria for Metabolic Syndrome and Insulin Resistance were used for evaluating patients with
metabolic syndrome and diabetes. Results. Compared to the control group, metabolic
syndrome, diabetes mellitus, and hypertension were found to be higher in psoriasis patients.
Metabolic syndrome was increased by 3-folds in psoriasis patients and was more prevalent in
women than in men. It was determined that the prevalence of metabolic syndrome was higher
in psoriasis patients after the age of 40. Metabolic syndrome was not related to smoking,
severity of psoriasis, and duration of disease. Conclusions. Our findings suggest that psoriasis
preconditions occurrence of a group of diseases such as diabetes mellitus, hypertension, and
metabolic syndrome. For this reason, patients with psoriasis should be treated early and they
should be followed with respect to metabolic diseases.1. IntroductionPsoriasis is a chronic
inflammatory skin disorder which is characterized by local and systemic escalation of
proinflammatory cytokines such as IL-6 and TNF-α [1, 2]. Proinflammatory cytokines which
take place in chronic inflammation are accused of augmentation of atherogenesis and
peripheric insulin resistance and thus leading to hypertension and type II Diabetes Mellitus
(DM) [2, 3]. Recent research reported an association between psoriasis and metabolic
disorders such as obesity, dyslipidemia, and type II DM and it is shown that severe psoriasis
might be associated with increased mortality rate due to cardiovascular disorders [2, 4–6].
Since psoriasis is characterized by a systemic inflammation which involves numerous cytokines
and inflammatory markers in particular TNF-α, it may predispose the patients to metabolic
disorders. We aimed to investigate the prevalence of metabolic syndrome in patients with
psoriasis vulgaris.2. Patients and MethodsThe study included 115 psoriasis vulgaris patients
and 140 healthy, sex, and age-matched control subjects who do not have psoriasis and any
systemic disease. Inclusion criteria for cases were age more than 18 years, clinical diagnosis of
chronic plaque psoriasis (lasting at least 6 months), and not receiving any systemic or local
antipsoriatic treatment for the last 4 weeks. Informed consent was given by all the patients
who enrolled in the study. Information sheets for the patients included age, gender, weight,
height, body mass index (BMI), waist circumference, smoking habits, blood pressure, age of
onset, and duration of the disease. Exclusion criteria were pregnancy and psoriatic arthritis.
Severity of psoriasis was assessed by psoriasis area severity index (PASI) and accepted as
severe in patients with PASI > 10 and mild/moderate in patients with PASI ≤ 10 [7]. BMI was
calculated as weight/height (kg/m2) and metabolic syndrome was diagnosed in the presence
of central obesity in addition to two or more criteria of the International Diabetes Foundation:
waist circumference ≥94 cm in men or ≥80 cm in women; hypertriglyceridemia ≥150 mg/dL;
HDL <40 mg/dL in men or <50 mg/dL in women; blood pressure ≥130/85 mmHg; fasting blood
glucose ≥100 mg/dL [8]. Triglyceride and HDL levels were calculated by enzymatic assay,
glucose was calculated by glucose oxidase assay. Student’s t-test, Mann-Whitney U, chisquare, and Fisher’s exact chi-square tests were used for statistical analysis of the data. Enter
logistical regression analysis was used for multivariate determination of parameters affecting
metabolic syndrome. P values <0.05 were accepted as statistically significant and confidence
interval (CI) was 95%.3. ResultsThe study group included 64 (55.7%) females and 51 (44.3%)
males with a mean age of 45.4 (range 19–79) years. The control group consisted of 70 (50%)
females and 70 (50%) males with a mean age of 43.4 (range 19–70) years. Duration of the
disease was
1
1
.
4
±
9
.
2
years, and mean age of onset were
3
4
.
2
4
±
1
7
.
3
years. Severity of psoriasis was mild to moderate in 76 (66.1%) of the patients and severe in
39 (33.9%) of the patients with a mean PASI of
9
.
9
8
±
8
.
6
. There was a significant difference between the smoking rates of the groups which were
35.7% and 24.3% in psoriasis and control groups, respectively (
𝑃
<
0
.
0
5
). Waist circumference ≥94 cm in men and ≥80 cm in women was observed in 73% and 83.6%
of psoriasis and control subjects, respectively; waist circumference was significantly slimmer in
psoriasis patients (
𝑃
<
0
.
0
5
). Mean BMI was
2
8
.
7
3
±
6
.
1
2
kg/m2 and
2
8
.
2
2
±
4
,
9
kg/m2 in psoriasis and control groups, respectively. No significant differences were found
between groups with respect to BMI (
𝑃
>
0
.
0
5
). There were also no significant differences between groups with respect to high triglyceride
levels and low HDL levels (
𝑃
>
0
.
0
5
). In contrast, we found a significant correlation between psoriasis and hypertension, diabetes
mellitus and metabolic syndrome. Hypertension and diabetes mellitus were significantly more
common in psoriasis patients as compared to controls. We found a higher prevalence of MS in
psoriasis patients than in controls (53% versus 39%) (
𝑃
<
0
.
0
1
). The prevalence of various components of MS in cases and controls along with
𝑃
values is given in Table 1.tab1Table 1: Metabolic syndrome criteria in psoriasis patients and
controls.Although all patients with MS had waist circumference ≥80 cm in females and ≥94 cm
in males, there was no significant difference with respect to mean BMI between psoriasis
patients and control cases with MS (
𝑃
>
0
.
0
5
). But we observed that female psoriasis patients with MS had a higher BMI (
3
0
.
6
0
±
7
.
1
8
in females versus
2
6
.
3
7
±
3
.
3
7
in males) (
𝑃
<
0
.
0
1
).Considering the data for diabetes mellitus, hypertension, and MS in psoriasis patients, it
appeared that deviations from normal were most prevalent at the fifth decade of life (Table 2).
No apparent differences were noted regarding the prevalence of DM and hypertension
between the genders (
𝑃
>
0
.
0
5
). In contrast, we found a significant correlation between MS and female gender. MS was more
common in female patients than male patients (
𝑃
<
0
.
0
5
). The mean age of psoriasis onset in patients with MS was significantly higher than patients
without MS (
𝑃
<
0
.
0
1
). Prevalence of MS was not correlated to smoking, severity of psoriasis, and duration of
disease (
𝑃
>
0
.
0
5
) (Table 3).tab2Table 2: Association of MS, DM, and HT with age in psoriasis patients.tab3Table
3: The associations of MS with patient characteristics in psoriasis patients.Multiple logistic
regression analysis revealed that MS is increased by 2.94-fold in psoriasis patients (95%
CI : 1.40–6.19). When the parameters that might influence MS in psoriasis patients such as age,
gender, age of onset, and smoking were evaluated, the model was found highly significant (
𝑃
<
0
.
0
0
1
) with a Negelkerke (
𝑅
2
) value of 0.293 and determination coefficient of 72.2%. The influence of female gender and
age on the occurrence of MS in psoriasis patients was found significant (
𝑃
<
0
.
0
1
). Female gender increased the risk of MS by 3.195-fold (95% CI : 1.12–9.04) compared to
males; patients aged between 40–49 had an increased risk of MS by 5.141-fold (95% CI : 1.75–
24.47), patients aged over 60 had an increased risk of MS by 6.531-fold (95% CI : 1.55–3.37). It
was found that MS was independent from smoking habit (Table 4).tab4Table 4: Multiple
regression analysis.4. DiscussionThis study reveals that hypertension, diabetes mellitus, and
MS are significantly more common in psoriasis patients than controls. Therefore, all
dermatologists should be aware of MS or individual components of MS might be associated
with psoriasis during the course of this disease. Recent studies showed that psoriasis is
associated with metabolic disorders such as hypertension, type II DM, dyslipidemia, abdominal
obesity, insulin resistance, and cardiac disorders and the risk of metabolic syndrome is
increased in patients with psoriasis [2–6, 9–12]. Sommer et al. reported that there is a
significant association between psoriasis and type II DM, hypertension, hyperlipidemia, and
coronary artery disease and MS is increased by twofolds in a study they conducted in 581
patients [3]. Other studies showed an increased frequency of ischemic heart disease, DM,
hypertension, and dyslipidemia in patients with psoriasis when compared to controls [13, 14].
Gisondi et al. found increased prevalence of hypertrygliceridemia and MS in psoriasis patients
compared to controls, but they did not find any difference between psoriasis patients and
controls with respect to low levels of HDL, DM, and hypertension [15]. Farshchian et al. failed
to demonstrate any difference between psoriasis patients and controls with regard to fasting
blood glucose, triglyceride, cholesterol, HDL, LDL, and VLDL levels [16]. In our study we
observed that psoriasis is associated with smoking, DM, hypertension, and MS. DM and
hypertension was accompanying our psoriasis patients along with MS. These findings
confirmed the literature [3, 11, 13, 14]. It is reported that smoking is more prevalent in
psoriasis patients [13–15]. We found the rates of smoking higher than controls. Levels of
triglyceride and cholesterol were reported to be high in psoriasis patients [3, 13, 14]. We did
not detect any dyslipidemia in our patients. This was consistent with previous findings which
found normal lipid levels in psoriasis patients and concluded that hyperlipidemia did not have
a clinical significance in psoriasis patients [15, 16]. It has been reported that hypertension and
DM were common in psoriasis patients regardless of gender and hypertension had an
increased frequency by advanced age while DM might be seen in any age [3, 13, 14]. In our
study, we found both hypertension and DM in advanced age, regardless of gender.Although
obesity is reported more frequent among psoriasis patients, we have not found BMI and waist
circumference significantly higher in psoriasis patients [3, 13, 14]. However we observed a
higher prevalence of MS among psoriasis patients than controls. This may be explained by the
literature which concluded that the association between psoriasis and MS is independent from
the tendency of psoriatic patients to be obese [15].In our study we observed that MS was
increased by 3-fold in psoriasis patients. The association of psoriasis with MS was independent
from smoking. These findings confirmed those in the literature [11, 13, 14, 17]. We found the
prevalence of MS increased by 5-fold in patients aged between 40 and 59 years. This was
consistent with previous studies by Sommer et al. and Gisondi et al. who reported that MS was
significantly higher in psoriasis patients after the age of 40 [3, 15]. Cohen et al. also
demonstrated that the association between psoriasis and MS was pronounced after the age of
50 [13]. However Nisa and Qazi observed the higher prevalence of MS in psoriasis patients in
the age group 18–30 [17].In contrast to the reports that MS was regardless of gender, we
observed a significant relationship between MS and gender [3, 11, 15, 17]. MS was more
prevalent in women and female gender increased the prevalence of MS by 3-fold.High BMI
levels were frequent in our female patients with MS and this finding was confirming the
previous findings [3]. We believe that high frequency of MS in female patients is the result of
increased waist circumference due to high BMI.It was reported that MS is related to the
duration of the disease, psoriasis starts in young ages in patients with MS and duration of the
disease is longer in patients with MS [3, 15]. But we observed that psoriasis started at
advanced age in our patients with MS and MS was not related to the duration of the disease.
There are controversies in the literature about the association of MS with severity of the
disease. Sommer et al. reported a positive relation with severity, while Gisondi et al. and Nisa
and Qazi declared an independent relation [3, 15, 17]. Like Gisondi et al. and Nisa and Qazi, we
did not observe an association between severity of the disease and MS.Our results showed
that psoriasis predisposes to the development of DM, hypertension, and MS and psoriasis
increased the prevalence of MS by 3-fold. Therefore, we recommend evaluating psoriasis
patients for the presence of metabolic diseases which may interfere with the patients’ health
for the rest of their living.References
M. P. Schon and W. H. Boehncke, “Psoriasis,” New England Journal of Medicine, vol. 352, no.
18, pp. 1899–1912, 2005. View at Publisher · View at Google Scholar · View at ScopusT.
Henseler and E. Christophers, “Disease concomitance in psoriasis,” Journal of the American
Academy of Dermatology, vol. 32, no. 6, pp. 982–986, 1995. View at Publisher · View at Google
Scholar · View at ScopusD. M. Sommer, S. Jenisch, M. Suchan, E. Christophers, and M.
Weichenthal, “Increased prevalence of the metabolic syndrome in patients with moderate to
severe psoriasis,” Archives of Dermatological Research, vol. 298, no. 7, pp. 321–328, 2006.
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Mallbris, O. Akre, F. Granath et al., “Increased risk for cardiovascular mortality in psoriasis
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Neimann, D. B. Shin, X. Wang, D. J. Margolis, and A. B. Troxel, “Risk of myocardial infarction in
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“Prevalence of metabolic syndrome in patients with psoriasis,” Indian Journal of Dermatology,
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Google Scholar
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Journal of Nutrition and Metabolism
Volume 2012 (2012), Article ID 965385, 4 pages
doi:10.1155/2012/965385Review ArticleA Review of Psoriasis, a Known Risk Factor for
Cardiovascular Disease and Its Impact on Folate and Homocysteine MetabolismIan McDonald,
Maureen Connolly, and Anne-Marie TobinDepartment of Dermatology, The Adelaide and
Meath Hospital Incorporating the National Children’s Hospital, Tallaght, Dublin 24,
IrelandReceived 16 January 2012; Accepted 18 March 2012Academic Editor: Vieno Piironen
Copyright © 2012 Ian McDonald et al. This is an open access article distributed under the
Creative Commons Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.AbstractPsoriasis is a
chronic inflammatory skin condition with an increased risk of cardiovascular disease. This risk
has been attributed to an association with many independent risk factors including obesity,
hypertension, smoking, and dyslipidemia. Psoriasis patients also have lower levels of folate
and conversely higher levels of homocysteine, which in itself is a risk factor for cardiovascular
disease. It has been postulated that low folate levels in this group may be a direct cause of
hyperhomocysteinemia and therefore a treatable risk factor by folate supplementation. This
paper looks at the literature published to date on the relationship between psoriasis,
homocysteine, and folate levels.1. IntroductionPsoriasis is a chronic recurrent inflammatory
skin condition. Its prevalence varies among ethnic groups, but it affects approximately 1–3%
[1] of the population in industrialised countries. Its clinical course can vary greatly in terms of
morphology, distribution, and severity of the disease. In its commonest subtype it is
characterised by the formation of discrete, pink, scaly plaques occurring at various sites on the
body. It affects men and women equally and is seen in all races [2]. Although it can present at
any age, it occurs most frequently between the ages of 15 and 20 and again between 50 and
60 years of age.Psoriasis has very significant psychosocial morbidity which appears
independent of objective disease severity [3, 4]. It is also associated with an increased risk of
cardiovascular disease and mortality [5–8]. Indeed patients with psoriasis have almost twice
the risk of cardiovascular disease when compared with normal controls [9, 10]. The exact
reason for this increased risk is unknown. A number of studies have shown significantly
increased rates of hypertension, dyslipidemia, diabetes mellitus, smoking, and excessive
alcohol consumption in patients with psoriasis [11]. Neimann et al. found that patients with
severe psoriasis had an increased risk of diabetes (odds ratio (OR), 1.62; 95% confidence
interval (CI), 1.3–2.01), obesity (OR, 1.79; 95% CI, 1.55–2.05), and smoking (OR, 1.31; 95% CI,
1.17–1.47) compared with controls [12]. Prodanovich et al. also found a higher prevalence of
these risk factors in patients with psoriasis. However, even after controlling for these variables,
they found a higher prevalence of ischemic heart disease (OR 1.78; 95% CI, 1.51–2.11),
cerebrovascular disease (OR, 1.70; 95% CI, 1.33–2.17), and peripheral vascular disease (OR,
1.98; 95% CI, 1.32–2.82) when compared with controls. Indeed they also found psoriasis to be
an independent risk factor for mortality (OR, 1.86; 95% CI, 1.56–2.21) as a result of the
association with atherosclerosis [13]. These risk factors in combination with the chronic
inflammatory process are thought to be significant components in the development of
vascular disease [9, 14]. Links with alterations in levels of folate and homocysteine in patients
with psoriasis have also been implicated in contributing to the propagation of atherosclerosis
and atherothrombotic events [9, 15, 16].2. Pathogenesis of Low Folate and High Homocysteine
Levels in Patients with Psoriasis Recent case control studies have demonstrated that patients
with psoriasis have lower levels of folate in comparison to normal controls [9, 15, 17, 18]. The
exact aetiology of this association remains unclear. Postulated mechanisms include alterations
in gut absorption of folate due to microscopic inflammatory changes seen in the bowel mucosa
of patients with active psoriasis and psoriatic arthritis [15]. A more likely explanation however
probably relates to the accelerated keratinocyte turnover seen in patients with psoriasis. This
action results in excessive consumption of folate used to methylate DNA in these actively
dividing cells thus lowering folate levels [9].Conversely homocysteine levels are elevated in
psoriasis patients [9, 15, 17]. In one case-controlled study this was found to directly correlate
with disease severity and to be inversely related to plasma folate levels [15]. Plasma
homocysteine is an independent risk factor for cardiovascular disease [19, 20], peripheral
vascular disease, cerebrovascular disease and possibly Alzheimer’s diseases. The magnitude of
this risk is equivalent to the risk of smoking or dyslipidemia [9]. Hyperhomocysteinemia
(>15 umol/L) is thought to favour atherosclerosis and vascular thrombosis by a number of
mechanisms. These include damaging endothelial cells, promoting clot formation, decreasing
flexibility of blood vessels leading to aortic stiffness, and reducing blood flow velocity [20]. The
endothelial dysfunction is thought to result from the accumulation of asymmetrical
dimethylarginine (ADMA) which is a natural inhibitor of nitric oxide synthase. As a result there
is a reduction in the production of the vasodilator nitric oxide which protects the vessel wall
against the pathogenesis of atherosclerosis and thrombosis (Figure 1).965385.fig.001Figure 1:
Proposed mechanism of homocysteine-induced endothelial dysfunction and atherogenesis
[21].It has been suggested that hyperhomocysteinemia in addition to other factors may be
caused by reduced levels of folate in these patients [9, 15]. Coenzymes methylene tetrahydrofolate, methylcobalamin, and pyridoxal phosphate are essential for three of the enzymes
involved in the metabolism of homocysteine and are dependent on folate, vitamin B12 and B6,
respectively. Hence in patients with severe psoriasis who have large areas of rapid skin
turnover and increased keratinocyte activity, there is excessive consumption of folate. This in
turn results in reduced breakdown and elevated serum levels of homocysteine with all of its
adverse effects.3. Discussion It appears from this paper that patients with psoriasis have lower
levels of folate and higher levels of homocysteine than normal controls. As psoriasis is
associated with an increased risk of cardiovascular morbidity and mortality and homocysteine
is an independent risk factor for cardiovascular disease, it may seem intuitive that managing
this risk factor would have beneficial effects in terms of cardiovascular mortality and
morbidity. The possible benefit of folate supplementation seems logical [22]. Folate has long
been used in combination with methotrexate in the management of psoriasis, psoriatic
arthritis, and rheumatoid arthritis. Here it is effective in reducing gastrointestinal side effects
and liver function test abnormalities [23]. In a retrospective cohort study looking at over seven
thousand patients with psoriasis, methotrexate was found to reduce the incidence of vascular
disease and this reduction was further enhanced when folic acid was added (Figure 2)
[24].965385.fig.002Figure 2: Proposed action of combination therapy, in addition to risk
factors such as age, sex, hypertension, and dyslipidemia, homocysteine and inflammation lead
to increased incidence of vascular disease. Consequently reducing inflammation with
methotrexate and hyperhomocysteinemia by folic acid may lead to a decreased incidence of
vascular disease for patients with psoriasis [24].However, homocysteine levels can be elevated
for other reasons including obesity, hypertension, smoking, and excessive alcohol consumption
all of which have significant prevalence in the psoriatic patient population [11]. Armitage et al.
in a double-blinded randomised control trial assessed the beneficial effects of lowering
homocysteine levels in over 12,000 post-MI patients. They failed to demonstrate any benefit in
vascular outcomes from long-term reductions in homocysteine with folate and vitamin B12
supplementation [25]. It is possible that hyperhomocysteinemia in psoriasis is independent of
folate deficiency and instead is linked with other risk factors such as hypertension and obesity
[9]. “The psoriatic march”, a concept of how severe psoriasis may drive cardiovascular
morbidity, suggests a process of genetic susceptibility triggered by environmental factors and
immune responses. This leads to disease expression and co-morbidity resulting from chronic
inflammation. It is this chronic inflammatory burden and state of insulin resistance which can
result in endothelial dysfunction and ultimately atherosclerosis [26].4. Conclusion It is well
established that folic acid supplementation has a role in the treatment of psoriasis in
conjunction with methotrexate treatment. However, the evidence to support its use in
reducing the risk of cardiovascular disease by directly impacting on plasma homocysteine
levels is lacking. Certainly further work within this group is necessary. For now management of
associated risk factors such as obesity, dyslipidemia, and hypertension as well as encouraging
smoking cessation are paramount for these patients as is, of course, the management of their
skin.References
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Troxel, “Risk of myocardial infarction in patients with psoriasis,” Journal of the American
Medical Association, vol. 296, no. 14, pp. 1735–1741, 2006. View at Publisher · View at Google
Scholar · View at ScopusT. Henseler and E. Christophers, “Disease concomitance in psoriasis,”
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International Journal of Endocrinology
Volume 2012 (2012), Article ID 561018, 16 pages
doi:10.1155/2012/561018Review ArticleMechanisms of Action of Topical Corticosteroids in
PsoriasisLuís Uva, Diana Miguel, Catarina Pinheiro, Joana Antunes, Diogo Cruz, João Ferreira,
and Paulo FilipeClínica Universitária de Dermatologia, Faculdade de Medicina de Lisboa, Av.
Professor Egas Moniz, 1649-035 Lisbon, PortugalReceived 31 August 2012; Revised 14 October
2012; Accepted 20 October 2012Academic Editor: Egle Solito Copyright © 2012 Luís Uva et al.
This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.AbstractPsoriasis is a lifelong, chronic, and immune-mediated
systemic disease, which affects approximately 1–3% of the Caucasian population. The different
presentations of psoriasis require different approaches to treatment and appropriate
prescriptions according to disease severity. The use of topical therapy remains a key
component of the management of almost all psoriasis patients, and while mild disease is
commonly treated only with topical agents, the use of topical therapy as adjuvant therapy in
moderate-to-severe disease may also be helpful. This paper focuses on the cutaneous
mechanisms of action of corticosteroids and on the currently available topical treatments,
taking into account adverse effects, bioavailability, new combination treatments, and
strategies to improve the safety of corticosteroids. It is established that the treatment choice
should be tailored to match the individual patient’s needs and his/her expectations,
prescribing to each patient the most suitable vehicle.1. IntroductionPsoriasis is a lifelong,
chronic, and immune-mediated systemic disease with preferential skin involvement, which
affects approximately 1–3% of the Caucasian population [1, 2]. Psoriasis may appear at any
age; however, over 75% of patients belong to a clear subgroup, that develops the disease
before the age of 40 (type 1 or early-onset psoriasis) [3, 4]. The most common clinical variant is
plaque-type psoriasis, characterized by erythematous scaly plaques, round or oval, variable in
size, frequently located in scalp, lower back, umbilical region, intergluteal cleft, knees, and
elbows [1, 5, 6]. As a clinically heterogeneous disease, psoriasis presents several degrees of
severity and a wide array of presentations in different patients [7]. Approximately 80% of
psoriasis patients have mild disease, with skin plaques usually covering less than 10% of the
body surface area (BSA). However, some patients have moderate to/or severe disease, with
greater than 10% of the BSA involvement [3, 6].The different presentations of psoriasis require
a variable approach to treatment and the current treatment concept advocates that the type
of therapy prescribed should be appropriated to disease severity. Although there is a wide
range of therapies available for the treatment of psoriasis, either systemic or topical agents,
the use of topical therapy (Figure 1) remains a key component of the management of almost
all psoriasis patients. While mild disease is commonly treated only with topical agents, the use
of topical therapy as adjuvant therapy in moderate-to-severe disease may also be helpful and
can potentially reduce the amount of phototherapy or systemic agent required to achieve
satisfactory disease control.561018.fig.001Figure 1: Topical therapy for management of
psoriasis.Topical therapies available for mild-to-moderate psoriasis involve a great number of
different agents, including [3, 7, 8](i)emollients;(ii)tars;(iii)dithranol;(iv)topical retinoids
(Tazarotene);(v)calcineurin inhibitors (pimecrolimus and tacrolimus);(vi)keratolytics (salicylic
acid, urea);(vii)topical vitamin D analogues (calcitriol, tacalcitol, and calcipotriol);(viii)topical
corticosteroids.Since their introduction to dermatology, more than 50 years ago, topical
corticosteroids have become the mainstay of treatment of various dermatoses including
psoriasis, mainly due to their immunosuppressive, anti-inflammatory and antiproliferative
properties, which makes this class of drugs an useful therapy for this immune-mediated
disease [9, 10].Although topical corticosteroids are an integral part of the psoriasis therapeutic
armamentarium, limitations due to the occurrence of well-known cutaneous adverse effects
such as atrophy, striae and/or telangiectases, and also potential systemic adverse events
prevent their optimal long-term and extensive utilization. Therefore, strategies such as the
weekend-only/pulse therapy regimen or combining topical corticosteroids with other topical
agents may improve their efficacy and safety profile over longer periods [11, 12].The purpose
of the therapy is to reduce the extent and severity of psoriasis to the point at which it is no
longer detrimental to a patient’s quality of life. Treatment choice should always be tailored to
match the individual patient’s needs and his expectations. When employed under these
circumstances, a topical treatment regimen is more likely to produce a satisfactory clinical
outcome [3, 8].2. Currently Available Topical Corticosteroids for Treatment of
PsoriasisCorticosteroids remain first-line treatment in the management of all grades of
psoriasis, both as monotherapy or as a complement to systemic therapy. They are available in
a wide range of preparations including gel, cream, ointment, foam, lotion, oil and spray, and a
new and innovative vehicle (Table 1) [3, 16]. tab1Table 1: Corticosteroid classification system,
adapted from [12].According to Cornell and Stoughton, we know that the vehicle can directly
modify a preparation’s therapeutic and adverse effects by changing the pharmacokinetics of
the topical corticoid molecule. Therefore, the development of an improved vehicle for
corticosteroids is at the forefront of dermatologic research [16, 17].Although the decision of
the agent depends on patient’s choice, distribution of disease and local availability, bioassays
comparing vehicles and corticoid molecules have demonstrated that ointments are the most
effective, followed by creams and lotions. A recent study with clobetasol has suggested spray
vehicle to be slightly more efficacious than other vehicles. Besides the important role of
specific factors involved in the formulation of the spray, this greater efficacy may be due to
increased patient compliance with an odorless, easy to apply, low residue, and elegant vehicle
[3, 16, 18].In 1985, Stoughton and Cornell classified corticosteroids potency according to their
vasoconstrictive properties [3, 11, 17]. While in the USA there are seven potency groups, the
UK considers four classes: mild (class IV), moderately potent (class III), potent (class II), and
very potent (class I) [3, 11, 19, 20].Lower-potency corticosteroids are particularly
recommended to apply on the face, groin, axillary areas, and in infants and children, whereas
mid- and higher-potency corticosteroids are commonly used as initial therapy on all other
areas in adults. Superpotent corticosteroids are mainly used for stubborn, cutaneous plaques
or lesions on the palms, soles, and/or scalp [11, 21, 22]. Regardless of the inexistence of
studies to prove the assurance of topical corticosteroid use on the scalp beyond 4 weeks, in
general, high-potency topical corticosteroids can be successfully and safely used. The reason
for that safety is possibly due to the presence of dense vascularization and abundance of
adnexal structures on the scalp that minimize the possibility of tachyphylaxis and side effects
such as skin atrophy [23, 24].As an initial therapy to achieve a faster improvement of lesions, in
clinical practice, potent and superpotent corticosteroids are often used; however, they should
not be used for more than 2 weeks and the patient should be under close surveillance [3, 11,
20, 25].Psoriasis is a clinically heterogeneous disease, and its individual presentation can make
the selection of the most appropriated treatment difficult. To overcome the variable nature of
the disease and also the several options of treatment, there are currently two sets of
guidelines from Germany [22] and USA [6] available for the different forms of topical
treatment, which allow = a more effective therapy decision and to decide when patients move
from topical to systemic treatment [7]. However, there are huge differences between
recommendations from different countries [7, 9]. While German guidelines [22] recommend a
combination of topical steroids with salicylic acid (broad combination is possible; care must be
taken regarding steroid side effects), USA guidelines [6] suggest the use of topical steroids as
monotherapy in mild-to-moderate psoriasis or in combination with other topical agents, UV
light or systemic agents in moderate-to-severe disease [7].3. Cutaneous Mechanisms of Action
of Topical CorticosteroidsPsoriasis is an autoinflammatory and in some aspects an
autoimmune disease of the skin. Both keratinocytes and leukocytes are actively involved in the
immunopathology of the disease. Neutrophils, plasmacytoid dendritic cells (DCs), and CD11c+
(myeloid) DCs are present in psoriatic lesions as part of the innate immunity. Acquired
immunity is diverted towards a T helper 1 (
) CD4+ cells-mediated response producing IFN-γ, TNF-α, and interleukin-2 (IL-2), along with T
cytotoxic (TC) CD8+ cells [2]. Recently,
cells have been suggested to be involved in the pathogenesis of psoriasis synthesizing IL-17A,
IL-17F, and IL-22.
cells’ differentiation, proliferation, and survival are dependent on IL-6, TGF, IL-1β, IL-23, and
IL-21. Particularly, IL23 is important for the pathogenicity at later stages of
development. IL-23 and IL-12 share a common p40 subunit, which is covalently linked to
either a p35 or p19 subunit forming IL-12 or IL-23, respectively. IL-23, secreted by activated
myeloid dendritic cells, will drive T-cell differentiation toward Th17 subset and also release IL12, inducing
differentiation [26]. IL-17A leads to joint pathology due to its potential activity of inducing
RANKL and its synergistic effect with IL-1β and TNF-α. Th17 cells produce IL-22, which have
potent keratinocyte proliferative ability. IL-22, along with IL-17, induces STAT3 activation and
cytokine/chemokine production, showing that way, an important role in the physiopathology
of psoriasis. Anti-IL-17 monoclonal antibodies (AIN457 and LY2439821) may be useful in
patients with psoriasis and autoimmune arthritis, as showed by successful experiments in
animal models. Further clinical trials with these anti-IL-17 monoclonal antibody preparations in
psoriasis and psoriatic arthritis are necessary [27].Corticosteroids act in two different ways at
the cellular level, divided into genomic and nongenomic pathways. The genomic pathway
refers to the glucocorticoid receptor (GR) and to its activation by cortisol, subsequent receptor
homodimerization, and binding to glucocorticoid-responsive elements (GREs). When the ligand
is absent, the glucocorticoid receptor accumulates in the cytoplasm complexing with proteins,
including the large heat shock proteins HSP90 and HSP70. But when the ligand binds to the
receptor, this complex is disrupted and the GR migrates to the nucleus. Upon dimerisation of
GR and binding to a palindromic promoter sequence, the glucocorticoid response elements,
the transcription of genes with anti-inflammatory functions such as tyrosine amino transferase
(TAT), phosphoenolpyruvate carboxykinase (PEPCK), IL-10, β-adrenergic receptor, IL-1-receptor
antagonist, and dual-specificity protein phosphatase 1 (DUSP-1) are promoted. GC negatively
regulates the expression of proinflammatory genes by transrepression, for example, cytokines,
growth factors, adhesion molecules, nitric oxide, prostanoids, and other autacoids [28].
Further, coactivators or corepressors help modifying the structure of chromatin, enabling the
DNA transcription [29]. The cortisol-glucocorticoid receptor complex may interact with nuclear
factor-κB leading to its transrepression (NF-κB) [30, 31]. The latter mechanism apparently
requires lower cortisol levels than the mechanism involving the GRE [32].The nongenomic
pathway takes membrane-bound receptors and second messengers into account, and it is
responsible for the rapid effects of glucocorticoids that occur in a few minutes. This pathway
does not require de novo protein synthesis and acts by modulating the level of activation and
responsiveness of target cells, such as monocytes, T cells, and platelets [33, 34].The
glucocorticoid receptor is encoded by the GR gene, localized to chromosome 5q31-32 locus
[32]. Posttranscriptional processing includes splicing of exon 9, yielding either GRα mRNA or
GRβ mRNA [35]. Glucocorticoid receptor α isoform is responsible for the known actions of
cortisol, whereas glucocorticoid receptor β isoform appears to play a regulatory role. An
increase of the β/α isoforms ratio in a cell generates glucocorticoid resistance [36].
Glucocorticoids possess numerous functions such as anti-inflammatory, antimitotic, apoptotic,
vasoconstrictive and immunomodulatory functions. These properties are closely associated
with their efficacy in the skin disease treatment (Figure 2) [37]. 561018.fig.002Figure 2: Antiinflammatory, immunosuppressive, and vasoconstrictive effects of topical corticosteroids [13,
14].Anti-Inflammatory Properties
The inflammatory process is controlled by the glucocorticoids’ activity, enhancing the
transcription of anti-inflammatory genes and decreasing the transcription of inflammatory
genes (Figure 3) [15].
Glucocorticoids induce the expression of annexin A1 (also known as lipocortin 1; encoded by
ANXA 1) and ALXR (the annexin A1 receptor) by mechanisms still not known. Annexin A1 is a
protein mainly located on basal keratinocytes of the basement membrane. Although in normal
skin annexin A1 has been identified within cytoplasm, in diseased skin the intracellular
localization of annexin A1 is apparently modified. In lesional psoriatic skin, annexin A1 appears
only in the cell membrane, suggesting a translocation of the protein. This transition may occur
to promote the binding of annexin A1 to phospholipids, therefore reducing the production of
inflammatory prostanoids [37].
Annexin A1 inhibits phospholipase A2 (PLA2), thus blocking the synthesis of arachidonatederived eicosanoids (prostaglandins, prostacyclins, leukotrienes, and thromboxanes) [32]. This
blocking is furthered by the repression of glucocorticoid-mediated cyclooxygenase 2
transcription [38–41]. It remains unclear if the reduction of these substances levels come first
and then plaque resolution, or if the normalization of prostanoid levels follows plaque
clearance [37].
Exogenous and endogenous annexin A1 may regulate the innate immune cells activities
controlling its levels of activation. Annexin A1 signals throw a formyl peptide receptor 2 (FPR2,
ALXR in humans). Despite the activation of ALXR singnalling can occur by the annexin A1
autocrine, paracrine, and juxtacrine functions, the juxtacrine interaction seems to be the
mechanism by which the anti-inflammatory process occurs. Concerning the innate response, it
seems that the upregulation of the annexin A1 expression by leukocytes induced by
glucocorticoids may be responsible for the inhibition of leukocytes response. Glucocorticoids
also increase the secretion of annexin A1 by macrophages and the annexin A1 secreted by
mast cells and monocytes, promotes the clearance of apoptotic neutrophils by macrophages.
Endogenous annexin A1 is also released from apoptotic neutrophils and acts on macrophages
promoting phagocytosis and removal of the apoptotic cells. The ALXR may be one mediator of
this mechanism. Contrasting with the innate immunity, the adaptive immune system seems to
act in a different way. Activation of T cells results in the release of annexin A1 and in the
expression of ALXR. Although, glicocorticoids may reduce the annexin A1 expression within Tcell exposure as a consequence, there is an inhibition of T-cell activation and T cells
differentiate into T helper 2 [42, 43].561018.fig.003Figure 3: Action of glucocorticoids in gene
transcription (adapted from [15]).Glucocorticoids induce expression of the MAPK phosphatase
1 (MKP-1). MAPK phosphatase 1 owes its anti-inflammatory properties to the interference in
the MAPK pathway. MAPK phosphatase 1 dephosphorylates and hence further inactivates cJun (the terminal kinase in the MAPK pathway). The inactivation of MAPKs and also of MAPKinteracting kinase by MKP-1 is due to the inhibition of PLA2 activity mediated by
glucocorticoids [32]. If glucocorticoids induce MKP-1 to suppress the inflammation, it seems
that glucocorticoids resistance in some inflammatory diseases could be related to defects in
the expression, or function, of MKP-1. It has been described in some inflammatory diseases
that c-jun N terminal kinase and p38 activities are increased, becoming possible targets for
clinical intervention. Possible mechanisms for glucocorticoids resistance may be associated
with a failure in the inhibition of c-jun N terminal kinase and p38 because these kinases
negatively regulate GR function. For example, an initial defect in glucocorticoids-induced MKP1 expression/activity might increase MAPK activity, thus impairing the GR function. As a
consequence of this failure, an increase in transcription of proinflammatory genes, or in the
instability of the mRNAs, may occur. Alternative to the hyperactive MAPK pathway, a reduced
number of activated GR within the nucleus or a lack of interaction with the basal transcription
process may be a reason for steroid resistance. It can be relevant, concerning the
glucocorticoid tachyphylaxia, whether these mechanisms can be implicated [44, 45]. c-Jun is a
transcription factor recognized to form homodimers and heterodimers with c-Fos, the latter
combination resulting in the activator protein 1 (AP-1). Both c-Jun homodimer and AP-1
heterodimer are associated with transcription of inflammatory and immune genes. There is
also evidence of direct protein-protein interactions between the glucocorticoid receptor and cJun homodimers and AP-1 heterodimers, conferring to the nongenomic pathway of cortisol a
large share of the anti-inflammatory action of glucocorticoids [31]. Other genomic mechanisms
include the direct repression of the NF-κB transcription factor by the glucocorticoid receptor.
NF-κB binds to DNA and induces transcription of genes encoding cytokines, chemokines,
complement proteins, cell-adhesion, molecules and cyclooxygenase 2 [46], all associated with
inflammation.It is unquestionable that the expression and activity of several cytokines relevant
to inflammatory diseases may be inhibited by treatment with glucocorticoids. These cytokines
include IL-1, IL-2, IL-3, IL-6, IL-11, TNF-α, GM-CSF, and chemokines that “call” inflammatory
cells to the site of inflammation, namely, IL-8, RANTES, MCP-1, MCP-3, MCP-4, MIP-1α, and
eotaxin. Furthermore, the inflammatory process receptors, such as
and
-receptors, are involved in the transcription of genes coding for these mediated inflammatory
receptors by glucocorticoids activity. The glucocorticoids suppressive effects are related with
inhibition of cytokine gene expression by inhibiting the transcription factors that regulate their
expression, rather than binding to their promoter regions [15]. Regarding genomic and
nongenomic pathways, it seems that the nongenomic pathway stands out powerful enough to
mediate the anti-inflammation process by itself. In an experiment, the GR mouse gene was
mutated so that the glucocorticoid receptor lost the ability to dimerize, and thus bind DNA. In
these
mice, glucocorticoids were only allowed to act via the nongenomic pathway. A phorbol 12myristate 13-acetate- (PMA-) mediated ear edema was then induced in both wild-type and
mice. Surprisingly, the edema was reduced in both strands of mice after administration of
dexamethasone. Additionally, dexamethasone suppressed serum TNF-α and IL-6, and
lipopolysaccharide (LPS)-induced transcription of TNF-α, IL-6, IL-1β, and cyclooxygenase 2
genes in both wild-type and mutant mice [47]. Nitric oxide (NO) has a relevant function in
multiple systems modeling physiological and pathological processes in the skin, namely,
vasodilation, immunomodulation, inflammation, and oxidative damage to cells and tissues.
Thereby, NO represents another possible target for glucocorticoids. The synthesis of NO is
dependent of the nitric oxid synthases (NOS), a family of enzymes with three isoforms, the
constitutive endothelial eNOS, neuronal nNOS, and the inducible iNOS. While glucocorticoids
restrain the induction of iNOS, they do not produce any effect over eNOS and nNOS activity.It
is thought that inhibition of NO by glucocorticoids occurs only in the presence of high NO
levels, caused by inflammatory substances such as lipopolysaccharides or cytokines, in a
similar way to the COX system. The nitric oxide synthases’ inhibitors appear to be related with
the NO role in erythema and oedema formation in psoriasis. Moreover, iNOS was found in
lesional psoriatic skin [37, 48]. The modulation of mast cell numbers and activity has been
suggested as an additional mechanism for the anti-inflammatory properties. These cells have
numerous pro-inflammatory mediators, as histamine and prostaglandins, which are released,
in response to mast cell degranulation. Thereby, we may obtain an anti-inflammatory action by
inhibiting this mast cell reaction. The use of glucocorticosteroids diminishes the number of
mast cell in the skin, which is responsible for reducing histamine content in the treated skin
[37, 49]. Antiproliferative Properties
Another beneficial action of the topical glucocorticoids is their antimitotic activity, which has
been suggested as providing positive results in the treatment of psoriasis, where cell turnover
rate of the skin is substantially elevated. Studies on normal and psoriatic skin suggest that
topical glucocorticoids decrease the number of epidermal mitoses. Dexamethasone may have
an anti-proliferative effect over the A549 cell line, which is associated with an increase of
annexin A1 [37]. It would be of interest to find out whether the antimitotic power of
glucocorticoids is caused by these effects on annexin A1 in order to develop new therapeutic
tools and diminish the skin thinning.Apoptotic and Antiapoptotic Properties
Eosinophils and lymphocytes are also an aim of glucocorticoids therapy. These drugs decrease
the survival of both types of cells, leading to programmed cell death or apoptosis. The
apoptosis of eosinophils appears to be related with a blockade of the IL-5 and GM-CSF effects,
of which eosinophils are dependent. On the contrary, glucocorticoids reduce apoptosis and
enhance neutrophils survival [15].Vasoconstrictive Properties
Although associated with an unclear mechanism, the vascular action has been proposed to be
part of the anti-inflammatory effects of glucocorticoids, since there is a reduction in blood flow
to the inflamed site. Vasoconstriction, also termed “blanching,” when related to skin surface,
forms the basis of the standard assay for evaluation of the potency of topical glucocorticoids
[37]. Immunosuppressive Properties
The regulation of several aspects of immune-cell function is also pertinent to the cutaneous
function of glucocorticoids, conferring an additional benefit in treatment of dermal diseases. In
addition to inhibiting humoral factors involved in the inflammatory response and the leukocyte
migration to sites of inflammation, glucocorticoids interfere with the function of endothelial
cells, granulocytes, and fibroblasts. Therefore, glucocorticoids commonly repress maturation,
differentiation, and proliferation of all immune cells, including DCs and macrophages.
Suppressing dendritic cells and macrophages, and consequently the production of T helper 1cell-inducing cytokine interleukin-12 (IL-12), glucocorticoids generate a shift in adaptive
immune responses from a
type to a
type. Furthermore, these drugs may amplify delayed-type hypersensitivity [13]. 3.1. Systemic
Adverse Effects of Topical CorticosteroidsConsidering the broad array of interactions between
glucocorticoids and specific and nonspecific molecular targets within the cell (Figure 3), it is
expectable that prescribing corticosteroids may produce a wide range of undesirable adverse
effects. This has led, in fact, to a “steroid phobia” among patients [50]. The adverse effects of
glucocorticoids tend to be more severe with systemic rather than with topical treatment [51].
Nevertheless, glucocorticoid topical therapy for cutaneous and pulmonary (nasal
administration) diseases is known to be associated with systemic adverse reactions [52,
53].The impaired barrier function in psoriatic skin facilitates the cutaneous penetration of the
topical corticosteroid independently from its potency. The concomitant vasodilatation in
psoriatic vessels increases the possibility of topical corticosteroids to reach the systemic
vessels. A large extent of body surface and long-term use of topical corticosteroids may
conduct to a higher concentration of corticosteroids in the blood, leading to systemic side
effects. The risk of systemic side effects associated with chronic topical corticosteroid use
increases with high-potency formulations.As anti-inflammation is one of the main goals in the
treatment of psoriasis, it should be noted that the lack of immune function, a state of
immunosuppression, brings about opportunistic infections that the human organism would
otherwise efficiently deal with. Among these, there are infections caused by Candida spp., or
reinfections caused by previously latent virus, like Cytomegalovirus [51]. Endogenous
hypercortisolism may also account for these infections [54]. Overt cataract and glaucoma may
also develop [55, 56], due to the effects that glucocorticoids have on the endocrine and
cardiovascular systems. Glaucoma is a consequence of an increased intraocular pressure.
Exogenous corticosteroids are not inactivated by 11β-hydroxysteroid dehydrogenase, so they
actually activate the mineralocorticoid receptor allowing ENaCs to increase serum Na+ levels
and causing hypertension [57]. Other glucocorticoids cardiovascular adverse effects include a
hypercoagulability state and dyslipidemia [58, 59]. The correlation with the glucose
metabolism is notorious, since glucocorticoids may aggravate previous diabetes mellitus [51].
Indeed, the United States of America’s National Health and Wellness Survey (NHWS) identified
psoriasis to be associated with cardiovascular risk factors such as hypertension,
hypercholesterolemia, and diabetes [60]. Glucocorticoids promote hepatic gluconeogenesis
[51]. Glucose-6-phosphatase, a key enzyme in the gluconeogenesis pathway, is encoded by the
G6Pase gene. The G6Pase gene promoter includes a glucocorticoid-responsive element (GRE),
this way augmenting the gluconeogenesis rate after glucocorticoid receptor activation [61].
Glucocorticoids concomitantly generate iatrogenic Cushing’s syndrome and adrenal
insufficiency [62]. High levels of glucocorticoids in the bloodstream imbalance the
hypothalamus-pituitary-adrenal axis equilibrium and suppress the ACTH levels, as a result of a
negative regulatory effect on ACTH release. It leads to adrenal cortex atrophy and, thereafter,
to complications like hypogonadism, inhibition of growth, or osteoporosis [51]. Osteoporosis is
a serious complication of glucocorticoid treatment, particularly when affecting trabecular bone
[63]. The pathophysiology underlying osseous degradation is related to the upregulation of the
receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA by glucocorticoids, helping
osteoclasts to differentiate and therefore degrading bone. On the other hand, osteoprotegerin
(OPG) gene transcription is repressed [51].Myopathy and muscle atrophy are also possible
adverse effects of glucocorticoid treatment. It was found that proteolysis is augmented in
myocytes, due to a glucocorticoid-mediated increase in the transcription of genes-encoding
proteins linked to the ubiquitin-proteasome pathway [64].Glucocorticoids may also aggravate
previous psychiatric disorders [65]. Accordingly, the NHWS places depression as a comorbidity
significantly associated with psoriasis [60].3.2. Cutaneous Adverse Effects of Topical
CorticosteroidsThe very first contact that the patient has with topical corticosteroids is mostly
through skin. Although corticosteroids help mitigate psoriatic lesions, cutaneous side effects
are numerous and not rare. Skin atrophy, striae rubrae distensae and perturbed cicatrization
are the most common. Hypertrichosis, steroid acne, perioral dermatitis, erythema, and
telangiectasia may also occur. Erythema and telangiectasia together with skin atrophy may
lead to permanent rubeosis steroidica (Figure 4). Hyperpigmentation is rarer than the abovementioned adverse effects [51]. 561018.fig.004Figure 4: Purpura, milia and rubeosis steroidica
induced by superpotent topical corticosteroids.Glucocorticoids-mediated skin atrophy involves
thinning of the epidermis and dermis (and even hypodermis), resulting in increased water
permeability and, thus, in increased transepidermal water loss [66, 67]. The thinning is caused
by a decreased proliferative rate of keratinocytes and dermal fibroblasts [68]. The origin of the
decreased proliferation lies in collagen turnover. Transforming growth factor β (TGF-β) is a
signaling molecule that, among other actions, promotes production of collagen, using Smad
proteins as second messengers [69]. Activated GR negatively regulates Smad3 through a
protein-protein interaction, in this way, blocking expression of the COL1A2 gene, which
encodes a type I collagen chain [70]. Type I collagen represents roughly 80% of the total share
of skin collagen [51]. Therefore, glucocorticoids reduce collagen turnover through blocking of
TGF-β actions. Coincidentally, TGF-β plays a central role in the epithelial-to-mesenchymal
transition (EMT), an essential mechanism for cicatrization [71–73]. Glucocorticoids also
diminish synthesis of epidermal lipids [67]. Furthermore, glucocorticoids reduce collagenases,
which are part of the matrix metalloproteinases (MMPs) and tissue inhibitors of the
metalloproteinases TIMP-1 and TIMP-2. Striae formation, which occurs in hypercortisolism and
may occur after long-term topical treatment with glucocorticoids, may be explained by the skin
tensile strength determined by type I and type III collagens [74–77]. The thinning of epidermis
caused by glucocorticoids’ long-term topical treatment appears also to be related with the
repression of K5–K14 keratin genes, which are markers of the basal keratinocytes. Additionally,
these drugs inhibit K6–K16 keratin genes, markers of activated keratinocytes, therefore
promoting impaired wound healing. Special attention should be paid when applying topical
corticosteroids in the presence of an infection, as there is a risk of exacerbation. Topical
corticosteroids can inhibit the skin’s ability to fight against bacterial or fungal infections. A
common example of this inhibition is seen when a topical steroid is applied to an itchy groin
rash. If this is a fungal infection, the rash gets redder, itchier, and spreads more extensively
than a normal mycosis. The result is a tinea incognito, a rash with bizarre pattern of
widespread inflammation [78]. Glucocorticoids’ adverse effects are an obstacle to psoriasis
treatment. Abolishing these reactions and at the same time maintaining glucocorticoids
efficacy has been a challenge to researchers. Selective glucocorticoid receptor agonists
(SEGRAs or, alternatively, dissociating glucocorticoids), nitrosteroids, and liposomal
glucocorticoids are under development [79]. To this date, we still rely on conventional
glucocorticoids.4. Bioavailability of Topical CorticosteroidsThe type of psoriasis and drug
metabolism in the skin are the main factors that influence bioavailability of topical
corticosteroids.Alterations in the epidermal permeability barrier may contribute to psoriasis,
as evidenced by the enhanced transepidermal water loss. Recently, an association between
the gene of psoriasis and variations in the late cornified envelope gene loci has been
confirmed, establishing a relation between an alteration of the permeability in the epidermis
and the pathogenesis of the disease [80]. There is also the 500 Dalton rule for the skin
penetration of chemical compounds and drugs, which states that molecules above that weight
are not capable of crossing the stratum corneum [81]. For instance, topical tacrolimus (802 Da)
is not effective in chronic plaque-type psoriasis but it is useful in psoriasis in the face or
intertriginous areas, in pustular psoriasis [82], and when combined with descaling agents [83–
86].Skin acts as a barrier due to its physicochemical properties [87] and to the enzymes
present in the keratinocytes (cytochrome P450 enzymes), which inactivate some topical
corticosteroids and metabolize others in more active substances [88]. Corticosteroids are
lipophilic and readily migrate through the cell membrane to bind the corticoid receptor thus
forming dimers, which then migrate to the cell nucleus inducing the therapeutic effect by
regulating gene expression [89]. Fluticasone propionate and methylprednisolone aceponate
are very lipophilic, and due to that they have an increased bioavailability; but while the first
one is hydrolyzed in an inactive substance, the last one is hydrolyzed by cutaneous esterase’s
in a more active metabolite [10].One of the most important points to achieve the success in
treatment is to choose the best corticosteroid formulation according to each patient. There is
an array of manufactured vehicles including creams, ointments, lotions, foams, oils, gels,
solutions, drops, shampoos, sprays, and tape; the efficacy rates between them are roughly
comparable [90]. For example, scalp, foams, gels, or sprays may be more easy to apply, and so,
a better result is expected. The vehicle has a therapeutic effect; scalp lipogel without active
ingredients showed response rates of over 20% in scalp psoriasis [91]. Also a 15%–47%
response to placebo was described with emollients in psoriatic patients, but it is already
known that hydration improves signs and symptoms of psoriasis [6, 21]. Ointments are
composed by more than 70%, of lipids, lipid-rich creams by 70% and creams only 15% to 25%.
In contrast to what was assumed, a recent study with betamethasone with a low-lipid content
formulation showed a higher efficiency than high-lipid concentrated creams and ointments,
confirming the need of tailor therapies to individual patients and the impact of bioavailability
of specific components of the vehicles. We can add specific ingredients to increase
bioavailability; for instance, propylene glycol is a percutaneous absorption enhancer of
hydrocortisone [10].The volume of the prescription should be planned considering the
frequency and the effective dose; the fingertip unit is used as a pattern for the topical agent
required. Dressings are also used, enhancing the drug delivery, and this choice depends on
local availability and patient preference [92].When applied in a higher concentration, or
multiple times a day, the levels of a corticoid (triamcinolone acetonide) in the stratum
corneum of the skin, after 24 h, were the same as in a lower dose and a less frequent
application [10].Topical treatments in psoriasis should be specific to each topographic region,
and steroids are absorbed at different rates in different parts of the body as follows: (i)eyelids
and genitals absorb 30%;(ii)face absorbs 7%;(iii)armpit absorbs 4%;(iv)forearm absorbs
1%;(v)palm absorbs 0,1%;(vi)sole absorbs 0,05%.Vitamin D analogues and low-potency steroids
in a cream base are indicated for psoriasis of the face or flexures [93]. The scalp skin has very
specific properties, it is covered by hair and sebaceous glands are abundant; therefore, a large
proportion of the drug applied is wasted and adhered to the hair not having contact with the
scalp. New vehicles are proposed to improve the treatment of scalp psoriasis such as
calcipotriol-betamethasone dipropionate scalp lipogel [91], clobetasol propionate and
betamethasone valerate foam [94], clobetasol propionate shampoo [95], and clobetasol
propionate 0.05% spray [96].Combined treatments with different biological targets are already
accepted, usually having an additive or synergistic effect. These treatments act by adding the
effects on different targets (T-cell functions, innate immunity, epidermal differentiation, and
proliferation), reducing the side effects and managing recalcitrant lesions. Topical therapies
can be used during the phase that the systemic treatment is suboptimal [10].5. New
Combination Treatment of Topical CorticosteroidsCombination therapy has emerged with the
development of new noncorticosteroid preparations, but before the merge we have to make
sure that the two combinations are compatible, synergistic, and safe. As an example,
calcipotriol is just compatible with tar gel and halobetasol propionate preparations and it has a
superior effect when combined with halobetasol ointment. Halobetasol decreased the irritant
dermatitis caused by calcipotriol [97, 98]. Also ammonium lactate is compatible with
hydrocortisone valerate and halobetasol propionate, and it has been shown to protect against
skin atrophy [10, 99].Salicylic acid, vitamin D analogues and retinoids, with different
mechanisms of action, are usually combined with topical corticosteroids. Concerning
polytherapy versus fixed-dose combinations, the last one requires less frequent applications
and has a higher adherence from the patients.5.1. Topical Vitamin D Analogues and
CorticosteroidsThese agents were found in the sequence of the discovery that oral vitamin D
had a therapeutic effect on psoriatic plaques [100].While vitamin D has mainly antiproliferative
(epidermal) effects, corticosteroids have mainly anti-inflammatory (dermal) effects.The
vitamin D analogues correct epidermal hyperproliferation, abnormal angiogenesis, and
keratinization and induces apoptosis in inflammatory cells by acting through vitamin D
receptors present on keratinocytes and lymphocytes. They also modulate the decrease of IL-1
and IL-6 levels, the reducing of CD45RO and C8+ T cells. They inhibit the epithelial cell growth
by increasing transforming growth factor-β1 and -β2 levels [101]. Many of these effects
protect skin from the cutaneous atrophy caused by corticosteroids [102].Vitamin D analogues
and corticosteroids are the combining topical agents of choice in psoriasis showing a superior
efficacy when compared with monotherapy [20].The most common side effects are skin
irritation, dryness, peeling, erythema, and edema, which can occur in up to 35% of the
patients. Adverse effects will diminish along the time.At the moment, three vitamin D
analogues are approved for the treatment of psoriasis: calcitriol, calcipotriol, and tacalcitol.The
corticosteroids effects can be diminished by administrating calcipotriol 0.03% once daily in the
morning plus betamethasone valerate once daily in the evening [103].Calcipotriol is the
vitamin D analogue most widely accepted for the combination therapy with corticosteroids,
although not all corticosteroids can be mixed with calcipotriol due to incompatibilities [97]. A
combined ointment with calcipotriol and betamethasone dipropionate is already being used
and showing good results, giving to the patient’s skin stability and optimal delivery of both
substances. Cutaneous atrophy caused by this ointment is similar to the corticosteroid alone
during a 4-week treatment period [104, 105]. Recent data says that the combination has
proved to be superior in efficacy than the individual components alone [106].This combination
of calcipotriol and betamethasone dipropionate is approved for use in trunk and extremities,
but it is not recommended for face, intertriginous areas, and scalp. Although this combination
has now been developed as an oily lipogel indicated for scalp psoriasis, showing the same
efficacy, safety, and tolerability as the ointment [91, 107].5.2. Topical Salicylic Acid and
CorticosteroidsSalicylic acid is a topical keratolytic used in the treatment of a variety of
papulosquamous lesions such as psoriasis. Its mechanism of action is still unclear, but it is
believed to act by inducing disruption of keratinocyte-keratinocyte binding and softening of
the stratum corneum by decreasing its pH [108].Salicylic acid has a filtering effect reducing the
efficacy of UVB therapy, so it should not be applied before treatment. Due to scarce data, it
should not be applied during pregnancy [3].Usually, salicylic acid is safe; however, with longterm use in large skin areas, systemic salicylic acid toxicity can occur [108].Studies with
tritiated triamcinolone acetonide, desoximetasone, and hydrocortisone 17-valerate showed
that salicylic acid enhance the efficacy of these corticosteroids by increasing their penetration
in skin. This faster penetration of corticosteroids in skin does not occur when mixed with other
ingredients such as camphor, menthol, phenol, or urea.Fixed-dose combinations such as
salicylic acid and betamethasone propionate or salicylic acid with diflucortolone are already
available in some countries and they show similar efficacy. They both appear to be efficacious
and well tolerated during short-term period treatment of plaque psoriasis and their use is
recommended for limited areas of skin: for thick, scaly, and psoriatic plaques [10]. 5.3. Topical
Tazarotene and CorticosteroidsTazarotene was the first topic retinoid found to be effective for
mild-to-moderate psoriasis and it is available in cream or gel form.Tazarotene is a retinoid
derivate which binds the retinoic acid receptor (RAR) in a class-specific manner, preferentially
binding RAR-γ and RAR-β than RAR-α [109]. This regulation of transcription result in reduced
keratinocyte proliferation, normalized keratinocyte differentiation, and decreased
inflammation. Its protective role against cutaneous atrophy from corticosteroid induction, may
be important already shown by the retinoid tretinoin [110]. This retinoid may cause skin
irritation in up to 30% of users [111], and this irritation was more pronounced in patients
receiving tazarotene plus corticosteroids than in those receiving calcipotriol [112].Retinoids
may reduce UVB tolerance, and tazarotene has proven to be more efficacious than UVB alone
[113].As the systemic retinoids, tazarotene is contraindicated in pregnancy.It is not indicated
to prescribe tazarotene mixed with corticosteroids. Although tazarotene showed to be
chemically compatible with a number of topical corticosteroids, no experiment testing over
two weeks of treatment has been performed [114]. 6. New Strategies to Improve Safety of
Topical CorticosteroidsTaking into account one of the most important features of psoriasis, its
chronic nature, the therapeutic approach should be prolonged, which makes it challenging to
use high-potency topical corticosteroids safely in long-term management of the disease [3,
11].Therefore, therapy should be monitored by a competent healthcare professional to limit
the risk of cutaneous or systemic side effects, and some general principles should be followed
to minimize these effects (Figure 5). The untoward effects of topical corticosteroids have been
well documented and can be widely categorized as local (atrophy, telangiectasia, striae
distensae, folliculitis, acne, and purpura) or systemic (hypertension, osteoporosis, Cushing’s
syndrome, cataracts, glaucoma, diabetes, and avascular necrosis of the femoral head or
humeral head) [3, 11].561018.fig.005Figure 5: Strategies to improve safety for long-term use
of topical corticosteroids in psoriasis.6.1. Using Treatment Regimens That Minimize Side
EffectsIn order to reduce side effects for long-term use of topical corticosteroids, a number of
new therapy regimens have been studied. One of them is weekend or pulse therapy where
three consecutive doses of corticosteroids at 12 h intervals are given on the weekends,
following a successful initial cleared or almost cleared therapeutic response to daily potent
topical corticosteroids application [115, 116].6.2. Combining Topical Corticosteroids with Other
Topical AgentsThe combination of topical corticosteroids with other topical anti-inflammatory
agents, as steroid-sparing therapies, can result in an improvement of efficacy with less side
effects. Sequential therapy with higher-potency corticosteroids in combination with a vitamin
D analogue such as calcipotriene can increase short-term efficacy and decrease side effects in
long-term treatment [117].Another successful combination is topical corticosteroids and
tazarotene, which has improved efficacy compared to tazarotene therapy alone [114, 118,
119]. Whilst corticosteroids maximize efficacy and minimize toxicity of tazarotene, this drug
reduces the development of corticosteroid-induced cutaneous atrophy [110].Salicylic acid can
also be applied in combination with mild-potency corticosteroids increasing the skin
penetration [118].Besides the combination with other topical agents, corticosteroids are often
used in combination with UVB phototherapy, traditional systemic agents (acitretin,
cyclosporine, and methotrexate), and biological agents [11].6.3. Following Recommendations
of UsageThe topical corticosteroid recommendations suggest, for the most corticosteroids,
60 g, as a maximum dosage per week, and for some superpotent corticosteroids 50 g per
week. However, there are particularly cases in which patients need to exceed what the
package insert recommends, and in those circumstances the possibility of systemic absorption
must be considered.For thick areas that are more resistant to steroid side effects such as the
palms and soles, limited occlusion may be necessary and would require close followup, but for
more prone areas such as the axillae, groin, and face, occlusion is more probable to result in
adverse effects [11].6.4. Considering Use in ChildrenChildren are more susceptible to systemic
side effects, like hypothalamic-pituitary-adrenal axis suppression, compared with adult
patients, owing to their greater body surface area-to-weight ratio. Accordingly, lower-potency
corticosteroids are frequently applied in infants and children [3, 11, 120].6.5. Considering Use
in Vulnerable AreasThe face and the intertriginous areas are particularly sensitive to untoward
effects. For that reason, the protracted use of corticosteroids, even with lower potency, can be
associated with telangiectasia on the face and formation of striae on intertriginous sites such
as the groin, axillae, or under the breasts [11].Even though safety of topical corticosteroids and
other topical treatments has been recently reviewed, additional studies of topical
corticosteroids are imperative. 7. CommentsMild-to-moderate psoriasis can be controlled with
topical therapy; however, topical therapy should be administrated with adjunctive therapy in
severe and extended psoriasis.Glucocorticoid research is an ongoing process with the
development of hyperselective therapeutic agents acting at different stages of the psoriasis
inflammatory response. One of the most desired targets of the new drugs is to induce selective
transrepression. The development of selectivity in a molecular level may bear less on
efficacy.Tachyphylaxis is the rapidly decreasing response to topical corticosteroids. After
corrected and sustained use of topical steroids, the capillaries in the dermis do not constrict as
well as before, requiring higher doses or more frequent applications of steroids to achieve the
former results. The ability of the blood vessels to constrict as before eventually returns to
normal after stopping therapy. The common and known clinical perception of tachyphylaxis
may also be significantly related to issues of compliance outside the study group, or to vessels
flare unrelated to therapy. Du Vivier and Stoughton, in 1975, were the first describing the
persistence and recurrence of psoriasis in patients who were previously treated with topical
corticosteroids with a successful result [121]. The question remains if this is a truly clinical
entity or if it is just due to a nonadherence to the topical regimen.Rebound caused by abruptly
withdrawal, or ending of steroid therapy by the individual him/herself, can result in sudden
worsening of psoriasis. Furthermore, the psoriasis may return more aggressively. A localized or
a mild form of psoriasis may become generalized, or a generalized form can be precipitated as
pustular or erythrodermic form, when patients do not wean gradually off of corticosteroids.
The treatment should be tailored in an individual manner, prescribing to each patient the most
suitable vehicle. Despite ointments being clinically more effective in psoriasis symptoms, what
really matters is the desire of the patient, and the way he/she adheres to the topical
treatment.Each patient will adhere “better” to a different vehicle, some will prefer ointments,
others gel or spray, and others will prefer occlusion therapy.Tight supervision during the
treatment with topical corticosteroids by giving support and answers to patient concerns must
be provided, and this can make the difference between a successful treatment and a
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