Am J Clin Dermatol DOI 10.1007/s40257-014-0074-8
SHORT COMMUNICATION
Metabolic Syndrome Prevalence in Psoriasis A Cross-Sectional Study in the Italian Population Aurora Parodi • Nicola Aste • Camilla Calvieri • Franca Cantoresi • Marta Carlesimo • Paolo Fabbri • Giorgio Filosa • Antonia Galluccio • Paolo Lisi • Giuseppe Micali • Concetta Potenza Antonio Richetta • Marco Simonacci • Piergiusto Trevisan • Giancarlo Valenti • Stefano Calvieri
•
Ó Springer International Publishing Switzerland 2014
Abstract Background The pathogenesis of psoriasis is complex, with a significant role suggested for pro-inflammatory mediators. There is strong evidence of an association between psoriasis and the metabolic syndrome (MetS), a cluster of cardiovascular risk factors, which impose a substantial disease burden. Objective This study aimed to evaluate the prevalence of MetS and to examine the implications of disease severity, type 2 diabetes mellitus, and cardiovascular disease in a large cohort of Italian psoriatic patients representative of the whole population.
Methods This was a cross-sectional study involving 13 dermatological clinics in Italy. The primary study endpoint was a comparison of the prevalence of MetS between psoriatic patients and a non-psoriatic control group; secondary endpoints included the influence of psoriasis severity on the prevalence of MetS, and the relative prevalence and risk of type 2 diabetes mellitus and cardiovascular disorders. Results A total of 720 patients were enrolled (n = 360 per group). The prevalence of MetS was 26.84 % in the psoriatic population and 15.16 % in the control population
A. Parodi Section of Dermatology, Dipartimento di Scienze della Salute (DISSAL), University of Genoa and S. Martino University Hospital, Genoa, Italy
A. Galluccio Dermatological Unit, Sacro Cuore di Gesu` Fatebenefratelli Hospital, Benevento, Italy
N. Aste Dermatology Department, University of Cagliari, Cagliari, Italy C. Calvieri Cardiology, Department of Clinical and Molecular Medicine, School of Medicine and Psychology, ‘Sapienza’ University of Rome, AO Sant’Andrea, Rome, Italy F. Cantoresi A. Richetta S. Calvieri Dermatological Clinic, ‘Sapienza’ University of Rome, Rome, Italy M. Carlesimo NESMOS Department, ‘Sapienza’ University of Rome, AO Sant’Andrea, Rome, Italy P. Fabbri Section of Dermatology, Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy G. Filosa Dermatology Unit, A. Murri Hospital, Jesi, Italy
P. Lisi Dermatological Clinic, University of Perugia, Perugia, Italy G. Micali Dermatological Clinic, University of Catania, Catania, Italy C. Potenza Dermatological Unit, Polo Pontino, ‘Sapienza’ University of Rome, Rome, Italy M. Simonacci Dermatological Unit, Macerata Hospital, Macerata, Italy P. Trevisan Dermatological Clinic, University of Trieste, Trieste, Italy G. Valenti U.O. Dermatology of Catanzaro, Catanzaro, Italy S. Calvieri (&) U.O. di Dermatologia, Az. Policlinico Umberto I, viale del Policlinico 155, 00161 Rome, Italy e-mail: [email protected]
A. Parodi et al.
(p = 0.0001; adjusted odds ratio 1.96). MetS was associated with a greater degree of psoriasis severity, and the prevalence and risk of diabetes tended to be higher in psoriatic patients than in the control group. Conclusion In the Italian population, the prevalence of MetS and associated comorbidities is elevated in patients with psoriasis compared with non-psoriatic subjects, as has been demonstrated in other countries. Our findings reinforce the importance of considering the implications of metabolic comorbidities in treating patients with psoriasis.
influence the development of MetS, including diet and lifestyle. As data on the prevalence of MetS in Italian patients with psoriasis are limited, we undertook a crosssectional study to determine the prevalence of MetS and to examine the implications of disease severity, type 2 diabetes mellitus, and cardiovascular disease in a large cohort of Italian psoriatic patients representative of the whole population.
2 Material and Methods 1 Introduction
2.1 Study Protocol
Psoriasis is a common, chronic, inflammatory skin disease, which affects about 2–3 % of the population worldwide [1–3]. While the risk of mortality for patients with mild psoriasis is similar to that for the general population, there is an increased overall mortality risk for patients with severe psoriasis [4]. Even though psoriasis was considered to be confined to the skin until recently, it is now accepted as a chronic inflammatory disease with systemic manifestations mirroring those of other autoimmune diseases, such as rheumatoid arthritis and Crohn’s disease [5]. The pathogenesis of psoriasis includes both genetic predisposition and precipitating factors, which lead to activation of the immune system [6–8]. Recent evidence suggests that the psoriatic autoimmune process might start as a local inflammatory mechanism leading to permanent activation of T cells, thus producing inflammatory mediators. Consequently, lesions might evolve in an interplay between cells and mediators of the immune system with innate and adaptive functions, and skin epithelium and connective tissue cells [8]. The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors, including glucose intolerance or insulin resistance, dyslipidemia, hypertension, and central obesity [9]. MetS is associated with greater cardiovascular risk and is a predictor of cardiovascular disease, diabetes, and stroke [10]. There is strong evidence showing an association between MetS and psoriasis. A diagnosis of MetS is more frequent in psoriatic patients than in the nonpsoriatic population and, furthermore, it is directly correlated with disease duration [11]. As MetS confers a substantial disease burden, including an increased risk of stroke, type 2 diabetes mellitus, coronary artery disease, and fatty liver disease [10], an understanding of its association with psoriasis is important. The majority of the reported studies examining the relationship between psoriasis and MetS were performed in American and European countries, and relate to specific populations, which may be differentiated by factors that
We planned a cross-sectional study involving 13 dermatological clinics in Italy (two in the north, seven in the central regions, two in the south, and two on the two main Italian islands), which were required to enroll a total of 720 subjects (360 psoriatic patients and 360 control subjects). The primary endpoint was comparison of the prevalence of MetS in the two groups, as defined by National Cholesterol Education Program–Adult Treatment Panel (NCEP– ATP III) criteria (a diagnosis of MetS is made if at least three of the following items are present: waist circumference [120 cm in males and [88 cm in females; level of blood triglycerides C150 mg/dL; high-density lipoprotein [HDL] cholesterol level B40 mg/dL in males and B50 mg/ dL in females; fasting glucose level C110 mg/dL; blood pressure C130/85 mm Hg [12]). Secondary endpoints included evaluation of the association between the Psoriasis Area and Severity Index (PASI) value and the prevalence of MetS, and between the PASI value and each MetS diagnostic factor. Furthermore, the prevalence of type 2 diabetes mellitus, diabetes risk, and cardiovascular risk was assessed in both groups, according to an algorithm proposed by Kahn et al. [13] and Reynolds’s risk calculation, respectively [14, 15]. To be formally enrolled, a patient had to be over 18 years old, with a diagnosis of chronic plaque psoriasis at least 6 months previously, without signs and symptoms of pustular psoriasis, and with discontinuation of any systemic anti-psoriatic treatment for at least the previous month. Female patients could not be pregnant. Patients with demographic characteristics similar to those of the psoriasis group, who had visited the hospital for treatment or prevention of benign dermatological tumors, for androgenetic alopecia treatment or for aesthetic treatment, but were not affected by inflammatory dermatological diseases, were enrolled in the control group. The study protocol was approved by the appropriate university or hospital ethics committees. After agreeing to study participation and signing their informed consent,
Metabolic Syndrome Prevalence in Italian Psoriasis Patients
every subject underwent a visit in which they were questioned on demography, family history of cardiovascular and metabolic diseases, smoking status, alcohol consumption, concomitant diseases and treatments, and their dermatological medical history and anti-psoriatic treatment history (for the psoriasis group only). In addition, PASI and Physician’s Global Assessment (PGA) values and body surface area (BSA) were determined and registered for the psoriasis group. Enrolled patients were requested to have the following laboratory tests, in the fasting condition: white blood cell count; red blood cell count; hemoglobin level; total platelet count; erythrocyte sedimentation rate; glucose and triglyceride levels; total cholesterol, low-density lipoprotein cholesterol (LDL), and HDL cholesterol levels; albumin level; glycated hemoglobin level; homocysteine level; high-sensitivity C-reactive protein (hsCRP) level; apolipoprotein A1 and B levels; fibrinogen level; and rheumatoid factor level. The physicians encouraged the patients to have all of the requested tests, but the tests for glucose, triglyceride, and HDL cholesterol levels were considered mandatory. The patients attended a second visit after having the blood tests (1–7 days after visit 1), when the physician checked the laboratory reports and measured vital signs (arterial blood pressure, heart rate), height, weight, waist circumference, and hip circumference. Data were collected on electronic case report forms. 2.2 Statistical Analysis The analysis of the prevalence of MetS and the analysis of diabetes prevalence were performed using a logistic mixed-effects model: the second-level variable was the study center, and the covariates were the patient group (psoriatic cases versus control subjects), gender, smoking status (smoker, ex-smoker, or non-smoker), alcohol consumption (yes or no), age (years), and body mass index (BMI). Differences in percentages and means were calculated using v2 tests and t tests, respectively. The association between diagnosis of MetS (or diabetes) and severity of psoriasis (the PASI value) in psoriatic patients was assessed using the same logistic mixed-effects model, adding PASI to all other included covariates (with the exception of the patient group). The analysis of diabetes risk and the analysis of cardiovascular risk were carried out through a hierarchical linear regression model, with the same covariates and second-level variable (the study center) as those in the logistic mixed-effects model. Expecting a prevalence of metabolic syndrome in the control group close to 20 %, we assumed a difference in
patients with psoriasis of about 10 %. According to this hypothesis, we planned 294 patients per group (360 to account for drop-outs) in order to ensure a 0.05 significance level and power equal to 80 %. The statistical analysis was performed using SAS (Statistical Analysis System) version 8.2 (SAS Institute Inc., Cary, NC, USA; STATA version 11).
3 Results 3.1 Study Population This cross-sectional study enrolled a total of 734 subjects from July 2010 to September 2011, 390 in the psoriatic patient group and 344 in the non-psoriatic control group. The main demographic characteristics of the enrolled psoriatic patients and control subjects are listed in Table 1. The psoriatic cohort had a higher percentage of male subjects and a lower mean age. The mean BMI, proportions of smokers and consumers of alcohol, and levels of plasma glucose, triglycerides, total cholesterol, and hsCRP were all significantly higher in the psoriasis cohort than in the control group. Conversely, patients in the psoriasis group had significantly lower levels of HDL cholesterol than the control group. The distributions of the PASI and PGA psoriasis indices are listed in Table 2. Most of the patients in the psoriasis cohort had PASI values consistent with moderate (38.2 %) or severe (36.7 %) psoriasis, and 41.8 % showed a PGA value of 2. At baseline, the affected BSA in the psoriasis patients varied from 0 to 89 %. 3.2 Prevalence of Metabolic Syndrome A total of 723 subjects were evaluated for the presence of MetS (380 psoriatic patients, 343 control subjects). The prevalence of MetS was 26.84 % in the psoriatic population and 15.16 % in the control population (Table 3; p = 0.0001). An adjusted odds ratio (OR) of 1.96 (95 % confidence interval [CI] 1.22–3.14; p \ 0.006; Table 4) was calculated, using a logistic model adjusted for the well-accepted confounding factors of gender, age, BMI, smoking status, and alcohol consumption, and with the same logistic model inserted into a hierarchic system (mixed-effects model) where the study center was a second-level variable (to eliminate study center selection bias)—that is, the psoriasis group had double the risk of being diagnosed with MetS, when compared with the control group.
A. Parodi et al. Table 1 Demographic and clinical population characteristicsa Characteristic
Psoriatic group (n = 390)
Control group (n = 344)
p value
Male sex, n (%)
234 (60)
169 (49.1)
Age, years
52.9 ± 16.0
54.8 ± 18.1
BMI, kg/m2
27.3 ± 4.8
25.5 ± 4.2
Smoking habit, n (%)
143 (36.7)
78 (22.7)
\0.05
Alcohol consumption, n (%)
150 (38.5)
75 (21.8)
\0.05
\0.05
Systolic blood pressure, mmHg
128.6 ± 14.0
126.3 ± 12.7
\0.021
Diastolic blood pressure, mmHg
79.4 ± 9.6
77.3 ± 8.6
\0.002
Waist circumference, cm
95.4 ± 17.7
88.6 ± 15.3
\0.0001
Fasting plasma glucose level, mg/dL
98.3 ± 25.0 (n = 375)
92.8 ± 24.0 (n = 343)
\0.01
Fasting plasma triglyceride level, mg/dL
126.4 ± 69.8 (n = 380)
108.7 ± 61.3 (n = 343)
\0.01
Fasting plasma total cholesterol level, mg/dL Fasting plasma HDL cholesterol level, mg/dL
201.3 ± 40.0 (n = 382) 49.4 ± 13.8 (n = 378)
193.1 ± 40.1 (n = 343) 53.8 ± 14.5 (n = 332)
\0.01 \0.01
HsCRP level, mg/dL
5.1 ± 8.9 (n = 136)
2.3 ± 5.5 (n = 35)
\0.01
BMI body mass index, HDL high-density lipoprotein, hsCRP high-sensitivity C-reactive protein a
Reported as mean ± standard deviation unless otherwise indicated Table 4 Factors associated with the metabolic syndrome, according to a logistic mixed-effects model
Table 2 Distribution of psoriasis indices Psoriatic index
Psoriatic group, n (%) Psoriatic patient vs. control
PASI
Odds ratio
p [ |z|
95 % CI
1.96
0.006
1.22–3.14
Female vs. male
1.76
0.023
1.08–2.86
10–19.9, moderate
149 (38.2)
Ex-smoker vs. non-smoker
1.51
0.151
0.86–2.66
C20, severe
143 (36.7)
Smoker vs. non-smoker
1.43
0.233
0.79–2.60
390 (100)
Alcohol consumption: yes vs. no BMI, for unit increase
1.58 1.26
0.084 0.000
0.94–2.65 1.20–1.33
Age (years), for unit increase
1.04
0.000
1.03–1.06
\10, mild
98 (25.1)
Total PGA 0
4 (1.5)
1
72 (18.5)
2
163 (41.8)
3
79 (20.3)
4 5
56 (14.4) 14 (3.6)
Total
BMI body mass index, CI confidence interval
3.3 Influence of Psoriasis Severity on Metabolic Syndrome
390 (100)
PASI Psoriasis Area and Severity Index, PGA Physician’s Global Assessment
Table 3 Prevalence of the metabolic syndrome by patient group Group
Total
Psoriatic n
Control %
n
%
n
%
Metabolic syndrome Yes
102
26.84
52
15.16
154
21.3
No Total
278 380
73.16 100
291 343
84.84 100
569 723
78.7 100
Psoriatic patients with MetS had more severe psoriasis (mean PASI value 20.5 and median PASI value 18) than psoriatic subjects without MetS (mean and median PASI values 15.8 and 12.5, respectively). It was apparent that MetS prevalence increased according to PASI severity, with a prevalence of 20.4, 24, and 34 % in the mild, moderate, and severe classes, respectively. The estimated risk of being affected by MetS increased by 2.7 % (p = 0.043) for every unit increase in the PASI value, as shown by the results of the mixed-effects logistic regression model. 3.4 Diabetes Prevalence The prevalence of type 2 diabetes mellitus was 8.5 % overall in our cohort, ranging from 0 to 17.6 %, with high
Metabolic Syndrome Prevalence in Italian Psoriasis Patients
variability among the different study centers. It was slightly higher in men than in women (9.2 vs. 7.6 %, respectively) and in the psoriatic group (9.1 vs. 7.8 %), but the difference reached statistical significance only between age classes (\55 vs. C55 years: 1.7 vs. 15.6 %; p \ 0.0001). Only BMI and age were detected as significant risk factors for diabetes in the logistic mixed-effects model. 3.5 Diabetes Risk The risk of diabetes, as assessed in 236 patients, was affected by smoking, age, and BMI, but no significant difference between psoriatic patients and control subjects was detected. The diabetes risk in the psoriasis patients (138 assessable patients) showed a slight trend toward being greater in patients with higher PASI values, although the result in the hierarchical linear regression model was not statistically significant. 3.6 Cardiovascular Risk No significant difference in cardiovascular risk was detected between psoriatic patients and control subjects, but the analysis was affected by the small number of assessable observations: only 113 patients over 45 years of age (90 in the group with psoriasis and 23 in the control group).
4 Discussion We found that patients with psoriasis in our cohort of 734 Italian subjects had a higher prevalence of MetS than nonpsoriatic control subjects. Our psoriatic population displayed a doubled risk of MetS, when compared with the control subjects. In addition, psoriatic patients with MetS showed higher PASI values than psoriatic patients without MetS. Our findings are broadly in agreement with those of a hospital outpatient-based cross-sectional study published in 2007 and conducted in a smaller sample that was less representative of the entire Italian population [16]. That study found a prevalence of MetS of 30.1 % in psoriatic patients and 20.6 % in control subjects (OR 1.65) after controlling for age and sex, which compares with our findings of 26.84 versus 15.16 % (OR 1.96) for psoriatic patients versus control subjects. Perhaps of more relevance, a recent meta-analysis of 12 observational studies, which included nearly 42,000 psoriatic subjects in Europe, the USA, Japan, India, the Middle East, and North Africa found a pooled OR for MetS of 2.26 (95 % CI 1.70–3.01) compared with the general population [17]. As in our study, there was a correlation between psoriasis severity
and the prevalence of MetS. Results from the most recently published US National Health and Nutrition Examination Survey (2003–2006) found a multivariate OR of 2.16 (95 % CI 1.01–3.77) [18]. It is therefore clear that an increased risk of MetS in psoriatic patients is of worldwide concern, suggesting the importance of correcting modifiable cardiovascular risk factors in these patients. Emerging data suggest that MetS occurs early in the course of psoriasis, and that it is associated with obesity and elevated serum lipid levels [19]. In this study, it was demonstrated that increased psoriasis severity was frequently associated with a higher incidence of MetS. In addition, obesity, hypertriglyceridemia, and hyperglycemia demonstrate a ‘‘dose–response’’-like association with psoriasis severity, which is independent of other components [20]. These results suggest that psoriasis severity is a driving factor behind the metabolic disorders that are frequently observed in these patients or, alternatively, that metabolic disorders might lead to worsening in the severity of psoriasis. In agreement with a previous study in Italian psoriasis patients [21], our results confirmed that a smoking habit and alcohol consumption were more predominantly distributed among the psoriatic cohort. Although no difference in cardiovascular risk between the psoriasis group and the control group was detected in our study, this secondary outcome may have been subject to enrollment bias, which did not permit statistical significance to be reached for this outcome. In our study, we found an increased BMI and a greater waist circumference in patients with psoriasis than in the control group. This finding confirms epidemiological studies suggesting that obesity is a risk factor for development of psoriasis and is associated with a poorer longterm clinical outcome [22–24]. Indeed, adipose tissue is the main extrahepatic source of angiotensinogen, which is implicated in enhanced inflammation and development of atherosclerosis and hypertension [25]. In agreement with this evidence, we found higher systolic and diastolic blood pressure values in our patients with psoriasis. Some studies have shown that psoriatic patients exhibit clinically significant levels of insulin resistance [26]. Moreover, there is evidence to suggest that insulin resistance in psoriasis might be related to higher PASI values [26, 27]. In this regard, our results showed that fasting plasma glucose levels were higher in patients with psoriasis than in the control group. This might reflect the condition of insulin resistance accompanying this disease. In our cohort, we found that the prevalence of type 2 diabetes mellitus was 8.5 % overall and 9.1 % in patients with psoriasis. This result is in agreement with several reports showing an association between psoriasis and type 2 diabetes mellitus [28–30], and a recent systematic review and metaanalysis of 27 observational studies, which showed an increased prevalence and incidence of diabetes in psoriatic
A. Parodi et al.
patients [31]. We calculated the risk of type 2 diabetes mellitus in both groups and found higher values in patients with psoriasis, although the difference did not reach statistical significance. However, the expected risk of type 2 diabetes mellitus in psoriasis patients was higher in patients showing higher PASI values. These data are consistent with the risk observed in the meta-analysis by Armstrong et al. [31]. Serum lipid levels have been studied in several groups of psoriatic patients. In general, these studies revealed significant differences between psoriatic patients and control subjects with respect to lipid levels [32–34], which is in agreement with our observation of statistically significantly increased levels of total cholesterol, LDL cholesterol, and triglycerides, together with decreased serum HDL cholesterol levels, in psoriatic patients. Although our study did not find any significant difference in cardiovascular risk between patients with and without psoriasis, there is evidence that the risk of cardiovascular events is higher in psoriasis patients with more serious disease [35, 36]. It has been shown that when psoriatic patients were matched for age, gender, and known risk factors with a non-psoriatic population, psoriasis was identified as a risk factor for coronary artery calcification [37]. Indeed, the results of an observational study comparing 3,236 psoriatic patients with 2,500 non-psoriatic control subjects showed higher frequencies of ischemic heart disease, cerebrovascular disease, and peripheral vascular disease in the psoriasis patients [38]. Further study is required to confirm if a similar pattern is seen in the Italian psoriasis population. Our study had several limitations. As a cross-sectional study, the directionality of the association between psoriasis and MetS could not be determined. In addition, the definition of MetS is not universally agreed, although the NCEP– ATP III definitions [12] we utilized are widely accepted and used. A major strength of our study was our enrollment of a large number of patients broadly representative of the Italian psoriasis population across the entire country and with varying degrees of psoriasis severity. However, at the same time, we have to underscore how the risk of clinical bias (with studies such as this) must always be taken into consideration. Further, although some factors that are associated with the development of MetS, such as diet or physical activity levels, were not evaluated in our study, we employed statistical models designed to compensate for a range of known confounding factors and study center selection bias.
5 Conclusion Our findings on the prevalence of MetS and the risk of type 2 diabetes mellitus and cardiovascular events in a cohort of Italian psoriatic patients support the concept of psoriasis as a pre-atherosclerotic disease in the Italian
population, as has been suggested for other populations. The increased prevalence of MetS identified in Italian psoriasis patients in our study should be viewed against the associated increased risk of cardiovascular events and allcause mortality associated with MetS, even in the absence of baseline cardiovascular disease and diabetes. Our results reinforce the importance of treating psoriatic patients beyond the care of skin lesions, and highlight the need for consideration of the implications of metabolic comorbidities. Acknowledgments The authors would like to thank Annalisa Arcese and Raffaella Ceschini for their contribution to the study; and Ray Hill, an independent medical writer, who provided copy editing and journal styling prior to submission on behalf of Springer Healthcare. Sheridan Henness, PhD, of Springer Healthcare Communications, provided post-submission medical writing assistance. All medical writing assistance was funded by Pfizer Italy. Nicola Aste received support for travel to meetings and honoraria for participation in review activities, such as data monitoring boards, from Pfizer. Aurora Parodi received grants, consulting fees, and payment for lectures from AbbVie, Galderma, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme, Novartis, Pfizer, and Shire; support for travel to meetings from AbbVie, Galderma, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme, Novartis, and Pfizer; and honoraria for participation in review activities, such as data monitoring boards, from AbbVie, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme, Novartis, and Pfizer. Concetta Potenza received grants from AbbVie and Janssen-Cilag and payment for lectures from AbbVie. All other authors declare that they have no competing interests.
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24. Wolters M. Diet and psoriasis: experimental data and clinical evidence. Br J Dermatol. 2005;153(4):706–14. 25. Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, et al. Weight loss and the renin–angiotensin–aldosterone system. Hypertension. 2005;45(3):356–62. 26. Boehncke S, Thaci D, Beschmann H, Ludwig RJ, Ackermann H, Badenhoop K, et al. Psoriasis patients show signs of insulin resistance. Br J Dermatol. 2007;157(6):1249–51. 27. Davidovici BB, Sattar N, Prinz J, Puig L, Emery P, Barker JN, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol. 2010;130(7):1785–96. 28. Cohen AD, Dreiher J, Shapiro Y, Vidavsky L, Vardy DA, Davidovici B, et al. Psoriasis and diabetes: a population-based crosssectional study. J Eur Acad Dermatol Venereol. 2008; 22(5):585–9. 29. Binazzi M, Calandra P, Lisi P. Statistical association between psoriasis and diabetes: further results. Arch Dermatol Res. 1975;254(1):43–8. 30. Shapiro J, Cohen AD, David M, Hodak E, Chodik G, Viner A, et al. The association between psoriasis, diabetes mellitus, and atherosclerosis in Israel: a case–control study. J Am Acad Dermatol. 2007;56(4):629–34. 31. Armstrong AW, Harskamp CT, Armstrong EJ. Psoriasis and the risk of diabetes mellitus: a systematic review and meta-analysis. JAMA Dermatol. 2013;149(1):84–91. 32. Mallbris L, Ritchlin CT, Stahle M. Metabolic disorders in patients with psoriasis and psoriatic arthritis. Curr Rheumatol Rep. 2006;8(5):355–63. 33. Pietrzak A, Jastrzebska I, Krasowska D, et al. Serum pancreatic lipase activity, serumlipid profile and peripheral blood dendritic cell populations in normolipidemic males with psoriasis. J Mol Catal. 2006;40(3–4):144–54. 34. Akkara Veetil BM, Matteson EL, Maradit-Kremers H, McEvoy MT, Crowson CS. Trends in lipid profiles in patients with psoriasis: a population-based analysis. BMC Dermatol. 2012;12:20. 35. Mallbris L, Akre O, Granath F, Yin L, Lindelof B, Ekbom A, et al. Increased risk for cardiovascular mortality in psoriasis inpatients but not in outpatients. Eur J Epidemiol. 2004;19(3):225–30. 36. Reich K. The concept of psoriasis as a systemic inflammation: implications for disease management. J Eur Acad Dermatol Venereol. 2012;26(Suppl 2):3–11. 37. Ludwig RJ, Herzog C, Rostock A, Ochsendorf FR, Zollner TM, Thaci D, et al. Psoriasis: a possible risk factor for development of coronary artery calcification. Br J Dermatol. 2007;156(2):271–6. 38. Prodanovich S, Kirsner RS, Kravetz JD, Ma F, Martinez L, Federman DG. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch Dermatol. 2009;145(6):700–3.
SHORT COMMUNICATION
Metabolic Syndrome Prevalence in Psoriasis A Cross-Sectional Study in the Italian Population Aurora Parodi • Nicola Aste • Camilla Calvieri • Franca Cantoresi • Marta Carlesimo • Paolo Fabbri • Giorgio Filosa • Antonia Galluccio • Paolo Lisi • Giuseppe Micali • Concetta Potenza Antonio Richetta • Marco Simonacci • Piergiusto Trevisan • Giancarlo Valenti • Stefano Calvieri
•
Ó Springer International Publishing Switzerland 2014
Abstract Background The pathogenesis of psoriasis is complex, with a significant role suggested for pro-inflammatory mediators. There is strong evidence of an association between psoriasis and the metabolic syndrome (MetS), a cluster of cardiovascular risk factors, which impose a substantial disease burden. Objective This study aimed to evaluate the prevalence of MetS and to examine the implications of disease severity, type 2 diabetes mellitus, and cardiovascular disease in a large cohort of Italian psoriatic patients representative of the whole population.
Methods This was a cross-sectional study involving 13 dermatological clinics in Italy. The primary study endpoint was a comparison of the prevalence of MetS between psoriatic patients and a non-psoriatic control group; secondary endpoints included the influence of psoriasis severity on the prevalence of MetS, and the relative prevalence and risk of type 2 diabetes mellitus and cardiovascular disorders. Results A total of 720 patients were enrolled (n = 360 per group). The prevalence of MetS was 26.84 % in the psoriatic population and 15.16 % in the control population
A. Parodi Section of Dermatology, Dipartimento di Scienze della Salute (DISSAL), University of Genoa and S. Martino University Hospital, Genoa, Italy
A. Galluccio Dermatological Unit, Sacro Cuore di Gesu` Fatebenefratelli Hospital, Benevento, Italy
N. Aste Dermatology Department, University of Cagliari, Cagliari, Italy C. Calvieri Cardiology, Department of Clinical and Molecular Medicine, School of Medicine and Psychology, ‘Sapienza’ University of Rome, AO Sant’Andrea, Rome, Italy F. Cantoresi A. Richetta S. Calvieri Dermatological Clinic, ‘Sapienza’ University of Rome, Rome, Italy M. Carlesimo NESMOS Department, ‘Sapienza’ University of Rome, AO Sant’Andrea, Rome, Italy P. Fabbri Section of Dermatology, Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy G. Filosa Dermatology Unit, A. Murri Hospital, Jesi, Italy
P. Lisi Dermatological Clinic, University of Perugia, Perugia, Italy G. Micali Dermatological Clinic, University of Catania, Catania, Italy C. Potenza Dermatological Unit, Polo Pontino, ‘Sapienza’ University of Rome, Rome, Italy M. Simonacci Dermatological Unit, Macerata Hospital, Macerata, Italy P. Trevisan Dermatological Clinic, University of Trieste, Trieste, Italy G. Valenti U.O. Dermatology of Catanzaro, Catanzaro, Italy S. Calvieri (&) U.O. di Dermatologia, Az. Policlinico Umberto I, viale del Policlinico 155, 00161 Rome, Italy e-mail: [email protected]
A. Parodi et al.
(p = 0.0001; adjusted odds ratio 1.96). MetS was associated with a greater degree of psoriasis severity, and the prevalence and risk of diabetes tended to be higher in psoriatic patients than in the control group. Conclusion In the Italian population, the prevalence of MetS and associated comorbidities is elevated in patients with psoriasis compared with non-psoriatic subjects, as has been demonstrated in other countries. Our findings reinforce the importance of considering the implications of metabolic comorbidities in treating patients with psoriasis.
influence the development of MetS, including diet and lifestyle. As data on the prevalence of MetS in Italian patients with psoriasis are limited, we undertook a crosssectional study to determine the prevalence of MetS and to examine the implications of disease severity, type 2 diabetes mellitus, and cardiovascular disease in a large cohort of Italian psoriatic patients representative of the whole population.
2 Material and Methods 1 Introduction
2.1 Study Protocol
Psoriasis is a common, chronic, inflammatory skin disease, which affects about 2–3 % of the population worldwide [1–3]. While the risk of mortality for patients with mild psoriasis is similar to that for the general population, there is an increased overall mortality risk for patients with severe psoriasis [4]. Even though psoriasis was considered to be confined to the skin until recently, it is now accepted as a chronic inflammatory disease with systemic manifestations mirroring those of other autoimmune diseases, such as rheumatoid arthritis and Crohn’s disease [5]. The pathogenesis of psoriasis includes both genetic predisposition and precipitating factors, which lead to activation of the immune system [6–8]. Recent evidence suggests that the psoriatic autoimmune process might start as a local inflammatory mechanism leading to permanent activation of T cells, thus producing inflammatory mediators. Consequently, lesions might evolve in an interplay between cells and mediators of the immune system with innate and adaptive functions, and skin epithelium and connective tissue cells [8]. The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors, including glucose intolerance or insulin resistance, dyslipidemia, hypertension, and central obesity [9]. MetS is associated with greater cardiovascular risk and is a predictor of cardiovascular disease, diabetes, and stroke [10]. There is strong evidence showing an association between MetS and psoriasis. A diagnosis of MetS is more frequent in psoriatic patients than in the nonpsoriatic population and, furthermore, it is directly correlated with disease duration [11]. As MetS confers a substantial disease burden, including an increased risk of stroke, type 2 diabetes mellitus, coronary artery disease, and fatty liver disease [10], an understanding of its association with psoriasis is important. The majority of the reported studies examining the relationship between psoriasis and MetS were performed in American and European countries, and relate to specific populations, which may be differentiated by factors that
We planned a cross-sectional study involving 13 dermatological clinics in Italy (two in the north, seven in the central regions, two in the south, and two on the two main Italian islands), which were required to enroll a total of 720 subjects (360 psoriatic patients and 360 control subjects). The primary endpoint was comparison of the prevalence of MetS in the two groups, as defined by National Cholesterol Education Program–Adult Treatment Panel (NCEP– ATP III) criteria (a diagnosis of MetS is made if at least three of the following items are present: waist circumference [120 cm in males and [88 cm in females; level of blood triglycerides C150 mg/dL; high-density lipoprotein [HDL] cholesterol level B40 mg/dL in males and B50 mg/ dL in females; fasting glucose level C110 mg/dL; blood pressure C130/85 mm Hg [12]). Secondary endpoints included evaluation of the association between the Psoriasis Area and Severity Index (PASI) value and the prevalence of MetS, and between the PASI value and each MetS diagnostic factor. Furthermore, the prevalence of type 2 diabetes mellitus, diabetes risk, and cardiovascular risk was assessed in both groups, according to an algorithm proposed by Kahn et al. [13] and Reynolds’s risk calculation, respectively [14, 15]. To be formally enrolled, a patient had to be over 18 years old, with a diagnosis of chronic plaque psoriasis at least 6 months previously, without signs and symptoms of pustular psoriasis, and with discontinuation of any systemic anti-psoriatic treatment for at least the previous month. Female patients could not be pregnant. Patients with demographic characteristics similar to those of the psoriasis group, who had visited the hospital for treatment or prevention of benign dermatological tumors, for androgenetic alopecia treatment or for aesthetic treatment, but were not affected by inflammatory dermatological diseases, were enrolled in the control group. The study protocol was approved by the appropriate university or hospital ethics committees. After agreeing to study participation and signing their informed consent,
Metabolic Syndrome Prevalence in Italian Psoriasis Patients
every subject underwent a visit in which they were questioned on demography, family history of cardiovascular and metabolic diseases, smoking status, alcohol consumption, concomitant diseases and treatments, and their dermatological medical history and anti-psoriatic treatment history (for the psoriasis group only). In addition, PASI and Physician’s Global Assessment (PGA) values and body surface area (BSA) were determined and registered for the psoriasis group. Enrolled patients were requested to have the following laboratory tests, in the fasting condition: white blood cell count; red blood cell count; hemoglobin level; total platelet count; erythrocyte sedimentation rate; glucose and triglyceride levels; total cholesterol, low-density lipoprotein cholesterol (LDL), and HDL cholesterol levels; albumin level; glycated hemoglobin level; homocysteine level; high-sensitivity C-reactive protein (hsCRP) level; apolipoprotein A1 and B levels; fibrinogen level; and rheumatoid factor level. The physicians encouraged the patients to have all of the requested tests, but the tests for glucose, triglyceride, and HDL cholesterol levels were considered mandatory. The patients attended a second visit after having the blood tests (1–7 days after visit 1), when the physician checked the laboratory reports and measured vital signs (arterial blood pressure, heart rate), height, weight, waist circumference, and hip circumference. Data were collected on electronic case report forms. 2.2 Statistical Analysis The analysis of the prevalence of MetS and the analysis of diabetes prevalence were performed using a logistic mixed-effects model: the second-level variable was the study center, and the covariates were the patient group (psoriatic cases versus control subjects), gender, smoking status (smoker, ex-smoker, or non-smoker), alcohol consumption (yes or no), age (years), and body mass index (BMI). Differences in percentages and means were calculated using v2 tests and t tests, respectively. The association between diagnosis of MetS (or diabetes) and severity of psoriasis (the PASI value) in psoriatic patients was assessed using the same logistic mixed-effects model, adding PASI to all other included covariates (with the exception of the patient group). The analysis of diabetes risk and the analysis of cardiovascular risk were carried out through a hierarchical linear regression model, with the same covariates and second-level variable (the study center) as those in the logistic mixed-effects model. Expecting a prevalence of metabolic syndrome in the control group close to 20 %, we assumed a difference in
patients with psoriasis of about 10 %. According to this hypothesis, we planned 294 patients per group (360 to account for drop-outs) in order to ensure a 0.05 significance level and power equal to 80 %. The statistical analysis was performed using SAS (Statistical Analysis System) version 8.2 (SAS Institute Inc., Cary, NC, USA; STATA version 11).
3 Results 3.1 Study Population This cross-sectional study enrolled a total of 734 subjects from July 2010 to September 2011, 390 in the psoriatic patient group and 344 in the non-psoriatic control group. The main demographic characteristics of the enrolled psoriatic patients and control subjects are listed in Table 1. The psoriatic cohort had a higher percentage of male subjects and a lower mean age. The mean BMI, proportions of smokers and consumers of alcohol, and levels of plasma glucose, triglycerides, total cholesterol, and hsCRP were all significantly higher in the psoriasis cohort than in the control group. Conversely, patients in the psoriasis group had significantly lower levels of HDL cholesterol than the control group. The distributions of the PASI and PGA psoriasis indices are listed in Table 2. Most of the patients in the psoriasis cohort had PASI values consistent with moderate (38.2 %) or severe (36.7 %) psoriasis, and 41.8 % showed a PGA value of 2. At baseline, the affected BSA in the psoriasis patients varied from 0 to 89 %. 3.2 Prevalence of Metabolic Syndrome A total of 723 subjects were evaluated for the presence of MetS (380 psoriatic patients, 343 control subjects). The prevalence of MetS was 26.84 % in the psoriatic population and 15.16 % in the control population (Table 3; p = 0.0001). An adjusted odds ratio (OR) of 1.96 (95 % confidence interval [CI] 1.22–3.14; p \ 0.006; Table 4) was calculated, using a logistic model adjusted for the well-accepted confounding factors of gender, age, BMI, smoking status, and alcohol consumption, and with the same logistic model inserted into a hierarchic system (mixed-effects model) where the study center was a second-level variable (to eliminate study center selection bias)—that is, the psoriasis group had double the risk of being diagnosed with MetS, when compared with the control group.
A. Parodi et al. Table 1 Demographic and clinical population characteristicsa Characteristic
Psoriatic group (n = 390)
Control group (n = 344)
p value
Male sex, n (%)
234 (60)
169 (49.1)
Age, years
52.9 ± 16.0
54.8 ± 18.1
BMI, kg/m2
27.3 ± 4.8
25.5 ± 4.2
Smoking habit, n (%)
143 (36.7)
78 (22.7)
\0.05
Alcohol consumption, n (%)
150 (38.5)
75 (21.8)
\0.05
\0.05
Systolic blood pressure, mmHg
128.6 ± 14.0
126.3 ± 12.7
\0.021
Diastolic blood pressure, mmHg
79.4 ± 9.6
77.3 ± 8.6
\0.002
Waist circumference, cm
95.4 ± 17.7
88.6 ± 15.3
\0.0001
Fasting plasma glucose level, mg/dL
98.3 ± 25.0 (n = 375)
92.8 ± 24.0 (n = 343)
\0.01
Fasting plasma triglyceride level, mg/dL
126.4 ± 69.8 (n = 380)
108.7 ± 61.3 (n = 343)
\0.01
Fasting plasma total cholesterol level, mg/dL Fasting plasma HDL cholesterol level, mg/dL
201.3 ± 40.0 (n = 382) 49.4 ± 13.8 (n = 378)
193.1 ± 40.1 (n = 343) 53.8 ± 14.5 (n = 332)
\0.01 \0.01
HsCRP level, mg/dL
5.1 ± 8.9 (n = 136)
2.3 ± 5.5 (n = 35)
\0.01
BMI body mass index, HDL high-density lipoprotein, hsCRP high-sensitivity C-reactive protein a
Reported as mean ± standard deviation unless otherwise indicated Table 4 Factors associated with the metabolic syndrome, according to a logistic mixed-effects model
Table 2 Distribution of psoriasis indices Psoriatic index
Psoriatic group, n (%) Psoriatic patient vs. control
PASI
Odds ratio
p [ |z|
95 % CI
1.96
0.006
1.22–3.14
Female vs. male
1.76
0.023
1.08–2.86
10–19.9, moderate
149 (38.2)
Ex-smoker vs. non-smoker
1.51
0.151
0.86–2.66
C20, severe
143 (36.7)
Smoker vs. non-smoker
1.43
0.233
0.79–2.60
390 (100)
Alcohol consumption: yes vs. no BMI, for unit increase
1.58 1.26
0.084 0.000
0.94–2.65 1.20–1.33
Age (years), for unit increase
1.04
0.000
1.03–1.06
\10, mild
98 (25.1)
Total PGA 0
4 (1.5)
1
72 (18.5)
2
163 (41.8)
3
79 (20.3)
4 5
56 (14.4) 14 (3.6)
Total
BMI body mass index, CI confidence interval
3.3 Influence of Psoriasis Severity on Metabolic Syndrome
390 (100)
PASI Psoriasis Area and Severity Index, PGA Physician’s Global Assessment
Table 3 Prevalence of the metabolic syndrome by patient group Group
Total
Psoriatic n
Control %
n
%
n
%
Metabolic syndrome Yes
102
26.84
52
15.16
154
21.3
No Total
278 380
73.16 100
291 343
84.84 100
569 723
78.7 100
Psoriatic patients with MetS had more severe psoriasis (mean PASI value 20.5 and median PASI value 18) than psoriatic subjects without MetS (mean and median PASI values 15.8 and 12.5, respectively). It was apparent that MetS prevalence increased according to PASI severity, with a prevalence of 20.4, 24, and 34 % in the mild, moderate, and severe classes, respectively. The estimated risk of being affected by MetS increased by 2.7 % (p = 0.043) for every unit increase in the PASI value, as shown by the results of the mixed-effects logistic regression model. 3.4 Diabetes Prevalence The prevalence of type 2 diabetes mellitus was 8.5 % overall in our cohort, ranging from 0 to 17.6 %, with high
Metabolic Syndrome Prevalence in Italian Psoriasis Patients
variability among the different study centers. It was slightly higher in men than in women (9.2 vs. 7.6 %, respectively) and in the psoriatic group (9.1 vs. 7.8 %), but the difference reached statistical significance only between age classes (\55 vs. C55 years: 1.7 vs. 15.6 %; p \ 0.0001). Only BMI and age were detected as significant risk factors for diabetes in the logistic mixed-effects model. 3.5 Diabetes Risk The risk of diabetes, as assessed in 236 patients, was affected by smoking, age, and BMI, but no significant difference between psoriatic patients and control subjects was detected. The diabetes risk in the psoriasis patients (138 assessable patients) showed a slight trend toward being greater in patients with higher PASI values, although the result in the hierarchical linear regression model was not statistically significant. 3.6 Cardiovascular Risk No significant difference in cardiovascular risk was detected between psoriatic patients and control subjects, but the analysis was affected by the small number of assessable observations: only 113 patients over 45 years of age (90 in the group with psoriasis and 23 in the control group).
4 Discussion We found that patients with psoriasis in our cohort of 734 Italian subjects had a higher prevalence of MetS than nonpsoriatic control subjects. Our psoriatic population displayed a doubled risk of MetS, when compared with the control subjects. In addition, psoriatic patients with MetS showed higher PASI values than psoriatic patients without MetS. Our findings are broadly in agreement with those of a hospital outpatient-based cross-sectional study published in 2007 and conducted in a smaller sample that was less representative of the entire Italian population [16]. That study found a prevalence of MetS of 30.1 % in psoriatic patients and 20.6 % in control subjects (OR 1.65) after controlling for age and sex, which compares with our findings of 26.84 versus 15.16 % (OR 1.96) for psoriatic patients versus control subjects. Perhaps of more relevance, a recent meta-analysis of 12 observational studies, which included nearly 42,000 psoriatic subjects in Europe, the USA, Japan, India, the Middle East, and North Africa found a pooled OR for MetS of 2.26 (95 % CI 1.70–3.01) compared with the general population [17]. As in our study, there was a correlation between psoriasis severity
and the prevalence of MetS. Results from the most recently published US National Health and Nutrition Examination Survey (2003–2006) found a multivariate OR of 2.16 (95 % CI 1.01–3.77) [18]. It is therefore clear that an increased risk of MetS in psoriatic patients is of worldwide concern, suggesting the importance of correcting modifiable cardiovascular risk factors in these patients. Emerging data suggest that MetS occurs early in the course of psoriasis, and that it is associated with obesity and elevated serum lipid levels [19]. In this study, it was demonstrated that increased psoriasis severity was frequently associated with a higher incidence of MetS. In addition, obesity, hypertriglyceridemia, and hyperglycemia demonstrate a ‘‘dose–response’’-like association with psoriasis severity, which is independent of other components [20]. These results suggest that psoriasis severity is a driving factor behind the metabolic disorders that are frequently observed in these patients or, alternatively, that metabolic disorders might lead to worsening in the severity of psoriasis. In agreement with a previous study in Italian psoriasis patients [21], our results confirmed that a smoking habit and alcohol consumption were more predominantly distributed among the psoriatic cohort. Although no difference in cardiovascular risk between the psoriasis group and the control group was detected in our study, this secondary outcome may have been subject to enrollment bias, which did not permit statistical significance to be reached for this outcome. In our study, we found an increased BMI and a greater waist circumference in patients with psoriasis than in the control group. This finding confirms epidemiological studies suggesting that obesity is a risk factor for development of psoriasis and is associated with a poorer longterm clinical outcome [22–24]. Indeed, adipose tissue is the main extrahepatic source of angiotensinogen, which is implicated in enhanced inflammation and development of atherosclerosis and hypertension [25]. In agreement with this evidence, we found higher systolic and diastolic blood pressure values in our patients with psoriasis. Some studies have shown that psoriatic patients exhibit clinically significant levels of insulin resistance [26]. Moreover, there is evidence to suggest that insulin resistance in psoriasis might be related to higher PASI values [26, 27]. In this regard, our results showed that fasting plasma glucose levels were higher in patients with psoriasis than in the control group. This might reflect the condition of insulin resistance accompanying this disease. In our cohort, we found that the prevalence of type 2 diabetes mellitus was 8.5 % overall and 9.1 % in patients with psoriasis. This result is in agreement with several reports showing an association between psoriasis and type 2 diabetes mellitus [28–30], and a recent systematic review and metaanalysis of 27 observational studies, which showed an increased prevalence and incidence of diabetes in psoriatic
A. Parodi et al.
patients [31]. We calculated the risk of type 2 diabetes mellitus in both groups and found higher values in patients with psoriasis, although the difference did not reach statistical significance. However, the expected risk of type 2 diabetes mellitus in psoriasis patients was higher in patients showing higher PASI values. These data are consistent with the risk observed in the meta-analysis by Armstrong et al. [31]. Serum lipid levels have been studied in several groups of psoriatic patients. In general, these studies revealed significant differences between psoriatic patients and control subjects with respect to lipid levels [32–34], which is in agreement with our observation of statistically significantly increased levels of total cholesterol, LDL cholesterol, and triglycerides, together with decreased serum HDL cholesterol levels, in psoriatic patients. Although our study did not find any significant difference in cardiovascular risk between patients with and without psoriasis, there is evidence that the risk of cardiovascular events is higher in psoriasis patients with more serious disease [35, 36]. It has been shown that when psoriatic patients were matched for age, gender, and known risk factors with a non-psoriatic population, psoriasis was identified as a risk factor for coronary artery calcification [37]. Indeed, the results of an observational study comparing 3,236 psoriatic patients with 2,500 non-psoriatic control subjects showed higher frequencies of ischemic heart disease, cerebrovascular disease, and peripheral vascular disease in the psoriasis patients [38]. Further study is required to confirm if a similar pattern is seen in the Italian psoriasis population. Our study had several limitations. As a cross-sectional study, the directionality of the association between psoriasis and MetS could not be determined. In addition, the definition of MetS is not universally agreed, although the NCEP– ATP III definitions [12] we utilized are widely accepted and used. A major strength of our study was our enrollment of a large number of patients broadly representative of the Italian psoriasis population across the entire country and with varying degrees of psoriasis severity. However, at the same time, we have to underscore how the risk of clinical bias (with studies such as this) must always be taken into consideration. Further, although some factors that are associated with the development of MetS, such as diet or physical activity levels, were not evaluated in our study, we employed statistical models designed to compensate for a range of known confounding factors and study center selection bias.
5 Conclusion Our findings on the prevalence of MetS and the risk of type 2 diabetes mellitus and cardiovascular events in a cohort of Italian psoriatic patients support the concept of psoriasis as a pre-atherosclerotic disease in the Italian
population, as has been suggested for other populations. The increased prevalence of MetS identified in Italian psoriasis patients in our study should be viewed against the associated increased risk of cardiovascular events and allcause mortality associated with MetS, even in the absence of baseline cardiovascular disease and diabetes. Our results reinforce the importance of treating psoriatic patients beyond the care of skin lesions, and highlight the need for consideration of the implications of metabolic comorbidities. Acknowledgments The authors would like to thank Annalisa Arcese and Raffaella Ceschini for their contribution to the study; and Ray Hill, an independent medical writer, who provided copy editing and journal styling prior to submission on behalf of Springer Healthcare. Sheridan Henness, PhD, of Springer Healthcare Communications, provided post-submission medical writing assistance. All medical writing assistance was funded by Pfizer Italy. Nicola Aste received support for travel to meetings and honoraria for participation in review activities, such as data monitoring boards, from Pfizer. Aurora Parodi received grants, consulting fees, and payment for lectures from AbbVie, Galderma, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme, Novartis, Pfizer, and Shire; support for travel to meetings from AbbVie, Galderma, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme, Novartis, and Pfizer; and honoraria for participation in review activities, such as data monitoring boards, from AbbVie, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme, Novartis, and Pfizer. Concetta Potenza received grants from AbbVie and Janssen-Cilag and payment for lectures from AbbVie. All other authors declare that they have no competing interests.
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