Clinical and Epidemiological Factors Predicting the Severity of Psoriasis

Introduction: Psoriasis, a systemic disease with a chronic course, is associated with a high degree of comorbidities and decreased quality of life. Aims: The aims of the study were to analyze epidemiological data of a large cohort of patients diagnosed with psoriasis over 8 years and to assess factors related to psoriasis severity and impact on quality of life. Research methods: A transversal study was performed on 1236 persons diagnosed with psoriasis in an OutPatient Dermatology Center between January 1, 2004 and December 31, 2011. Clinical examination was done and medical records were complied including: type of psoriasis, number of body locations at the onset and at the moment of examination, severity index, family history of psoriasis, comorbidities, past and current treatments, demographic characteristics, residence, level of education, working status and income, smoking, and alcohol intake. Linear regression was used for multivariable analysis. Key results of the chapter: Comorbidities were present in 36.1% of patients with mild form of psoriasis, 44.05% with moderate forms, and in 19.64% of severe psoriasis. Onset and clinical examination age, education level, residence, job, gender, and smoking were significant factors associated with severity of psoriasis.


Introduction
One of the most common T-cell-mediated diseases, psoriasis, is widely spread, potentially affecting 125 million people, or nearly 3% of the world's population [1][2][3]. Reports show that psoriasis affects as much as 2% of the UK population [4]. A significant number of UK psoriatic patients have a Dermatology Life Quality Index (DLQI) of >10, indicating that the disease strongly affects their lives [4]. Social factors such as stigmatization, psychological factors such as depression, and physical factors such as pruritus, pain, and other comorbidities have a great impact on the patient's life [5,6].
Recent studies show that psoriatic patients have relatively higher risks of heart disease, stroke, hypertension, and diabetes. Furthermore, due to social isolation, patients are more prone to develop depression and anxiety compared to the general population [4][5][6]8]. A national study in Taiwan performed on 51,800 patients diagnosed with psoriasis revealed a high prevalence ratio (relative risk (RR); [95% confidence interval (CI)]) for rheumatoid arthritis (3. [8].
Psoriasis, a systemic disease with a chronic course, is associated with a high degree of comorbidities and decreased quality of life.
Psoriasis can vary tremendously in its severity. A number of studies investigated the factors that affect severity [9,10]. They reported significant associations between psoriasis severity and comorbid diseases [10], male gender, younger age [11,12], localization of the lesions [13], the presence of family history of psoriasis [14], smoking, and alcohol consumption [15]. The factors that affect severity are still not well characterized.
2. An overview of the transversal study 2

.1. Aims and objectives of the study: methods and materials
The aim of this study was to evaluate clinical and epidemiological characteristics of the psoriatic population for establishing prevention strategies and optimal clinical management.
The objectives of this transversal study were to analyze epidemiological data of a large cohort of patients diagnosed with psoriasis over a period of 8 years and to assess factors related to psoriasis severity and impact on their quality of life (validated by Psoriasis Area and Severity Index (PASI) index and DLQI).
All the investigations were conducted in an outpatient clinic specialized for psoriasis and investigative dermatology, in the north-eastern region of Romania, over a period of 8 years. Study was performed on 1236 persons diagnosed with psoriasis between January 1, 2004 and December 31, 2011.
Participants were examined for psoriasis by the same two dermatologists, under similar conditions. All patients had a complete physical examination and their medical history was recorded.
Psoriasis was diagnosed by dermatological examination and was confirmed by punch skin biopsy, when needed. Skin biopsies were performed at a representative psoriatic plaque of each patient.
In other articles [16,17], psoriasis is classified as mild, moderate, and severe, based on clinical evaluation tools such as the extent of the affected skin surface. In this study, in order to quantify the severity of the disease, PASI was used; patients were categorized into mild (PASI: 0.0-4.0), moderate (4.1-9.9), and severe (10 or higher) psoriasis.
Patient data and medical history were collected from the Specialized Psoriasis Clinic, over a period of 8 years. Written informed consent was obtained from all patients.
The data collected by our dermatologists included the following: 1. demographic characteristics: gender, date of birth, age of the patients at the moment of examination, level of education, occupation (jobs distribution, respectively, socioeconomic status), residence; 2. psoriasis-clinical-related data: family history of psoriasis, age distribution at the onset of psoriasis, distribution of psoriatic lesions at the moment of diagnosis and at the moment of clinical inspection, number of areas involved, symptoms such as pruritus; 3. comorbidities such as thyroid abnormalities, cardiovascular disease (CVD), hypertension, other concomitant skin disorders, and others; 4. severity of lesions in relation to evolution characteristics: smoking history, alcohol consumption, past and current therapies with topical steroids.

Statistical analysis
All statistical analyses were conducted using Statistical Analysis System software.
Patient data were presented as proportions, standard deviations, means, and ranges. Linear regression was used for multivariable analysis of factors affecting psoriasis severity. Specified variables were included in the analysis of index severity. Spearman's rank coefficient of correlation was used as a nonparametric measure of dependence. Pearson's chi-squared test to quantify differences was used. All statistical tests had a confidence interval of 95% and the significance level was set at p < 0.05.

Age distribution at the moment of examination
The highest incidence of the disease was noticed for the age group 30-50 years old (43.12%); the minimal incidence was over 70 years (5.83%) and under 20 years (5.5%). Statistically 50% of cases were over 40 years and 25% under 33 years.
The median value for age was 44.94 ± 15.84 standard deviation (SD), with a great variability from 6 to 91 years old. Psoriasis can occur at any age; patients should seek medical advice regardless of age.

Distribution of cases reported to residence
As shown in Table 1, urban patients prevail. People living in villages have low incidence of psoriasis, reflecting a real reduced number of cases or a smaller addressability to medical care (Figure 1).

Level of education
The level of education correlates with the prevalence of psoriasis (  (Figure 2). No parent-of-origin effect in transmission of psoriasis from affected parent to offspring was observed, and there were no significant differences in the clinical profiles of the disease between patients grouped by transmission pattern of psoriasis.

Age of the patients at the onset of psoriasis
Results of the study showed the following: 7.77% of patients did not recall the age at which the first lesions appeared, 46.04% had the first diagnosis of psoriasis somewhere between 10 and 30 years old, and the fewest cases were detected over the age of 50 (11.17%).
The median age at the diagnosis is 29.34 ± 15.24 SD, with the youngest patient being 6 months (neonatal psoriasis) and oldest 76 years.
Statistically 50% of cases were less than 27 years old at the moment of first medical seek and 25% over 39 years old when they accepted psoriasis as a diagnosis ( Psoriasis has been reported as a chronic disease that begins in one-third of the patients during the first two decades of life [18]. Several prevalence studies have published their results showing that one-third of psoriatic patients develop the disease during childhood [19]. A fast increase in the incidence rate of psoriasis until the age of 30-35 years was recently reported [20]. Childhood onset of psoriasis was not proven to be a risk factor for higher frequencies of cardiovascular and metabolic comorbidities during adulthood in a recent French study [21]. Moreover, the age of onset of psoriasis had no impact on the severity of the disease in another retrospective study conducted in Greece [22]. No evidence was found that under 18 years may influence the disease severity in later life [23].  Psoriasis in children should not be considered as underreported because parents seek for medical care for their children at the first signs of skin injury. Children with psoriatic arthritis (PsA) were not included in the study.

The distribution of psoriatic lesions at the moment of diagnosis (Single lesion or multiple distributions of cutaneous manifestations declared by patients)
The majority of cases (91.18%) had a unique lesion of psoriasis when they were first diagnosed, multiple locations being much rarer (8.82%). Among the unique first clinical signs, most of the patients (28.07%) reported scalp being involved, followed by elbows (11.89%), palms (7.93%), feet (7.12%), and trunk (5.18%). A significant number of persons involved in the study were not able to remember the first location of psoriasis (10.36%).

The distribution of psoriatic lesions at the moment of clinical inspection (Single lesion or multiple distributions of cutaneous manifestations)
The majority of patients (82.85%) had multiple skin lesions at the moment of clinical inspection ( Table 4).
The distribution of psoriasis was recorded. Active lesions were noted on the scalp, face, trunk, anogenital area, arms, legs, hands, feet, or nails, that is, in 10 different locations (Figure 3

Number of areas involved at the moment of clinical inspection (By single or multiple cutaneous lesions)
Out of the 1236 patients enrolled in the study, an approximately equal distribution was observed among patients with solitary lesion or two, three, or four body areas involved ( Table 5).
More generalized forms were very rare (Figure 4).

Evolution of psoriatic lesions from diagnosis to present clinical inspection
Few patients (1.21%) with multiple onset lesions later turned to have unique lesions, while 7.61% of them preserved the initial multiple lesions; 15.94% of patients with onset single lesions remained with a unique cutaneous psoriasis stigma (the same of different location) ( Table 6).
The vast majority of cases (75.24%) with declared unique psoriatic lesion at the onset of the disease developed multiple skin manifestations over short or long periods of time.
The statistical report shows no marked relationship between the lesions location at the time of the first diagnosis of psoriasis and at the moment of onset evaluation (r = 0.1406, χ 2 = 1.018, p = 0.312, 95% CI).
The comparison between unique onset lesion and multiple lesions at the moment of clinical examination is presented in ( Table 7).

Symptoms: pruritus and psoriasis
Previous dermatology dogma suggested that atopic dermatitis is itchy and psoriasis is not! The aim of the present study was to assess the incidence of pruritus in patients diagnosed with psoriasis ( Figure 5); data were collected based on patients' responses and pruritus was certified by declaration.  Pruritus was admitted by 293 persons (23.7%) and denied by 943 (76.3%). The presence and intensity of pruritus were independent of age, gender, marital status, family history of psoriasis, job, level of education, type of psoriasis, alcohol, smoking, duration of the disease, number of lesions, and severity index.
Pruritus may be unrecognized and underestimated by the patients and/or medical staff.

Comorbidities: overview
Comorbidities present at the moment of diagnosis and/or in the medical history of patients ( Figure 6, Table 8).
Out of the 1236 patients enrolled in the study, 59.22% (732 psoriatic patients) had no comorbidities at the moment of diagnosis or in their medical history ( Table 8).

Comorbidities: psoriasis and psoriatic arthritis
Psoriatic arthritis is a chronic, inflammatory, seronegative form of arthritis occurring in subjects with psoriasis. PsA usually occurs over the age of 40 and it affects both sexes equally [24,25].       In our study, the estimated PsA prevalence based on rheumatologic evaluation (Moll and Wright criteria) was 0.16% among 1236 patients with psoriasis (Table 9), NOT in accord with several European revisions.
An extensive study in Germany on 1511 patients revealed a total PsA prevalence of 20.5% [31]. In Greece, a retrospective analysis on 278 patients with psoriasis revealed that PsA prevalence was 30%. This subgroup of patients with PsA showed significantly higher rates of comorbidities including CVD, hypertension, diabetes mellitus type 2, and hypercholesterolemia compared to non-PsA patients [24]. Other studies show PsA prevalence ranging between 0.17 and 0.35% in the general Greek population [32,33]. Other two publications report remarkably lower rates of PsA prevalence among patients with psoriasis, 7.23% in Croatia, respectively, 9.3% in Serbia [26].

Comorbidities: coexistence of psoriasis with other skin diseases at the moment of diagnosis
Out of the 1236 patients enrolled in the study, only 26 psoriatic patients had other skin diseases at the moment of diagnosis (Table 10), including 10 with vitiligo, 3 with dermatomyositis, 3 with Rosacea, and 2 with Alopecia areata.

Comorbidities: coexistence of psoriasis with cardiovascular diseases at the moment of diagnosis
Psoriasis has been associated with high cardiovascular morbidity and mortality. Recent studies suggest that psoriasis, particularly if severe, has a 58% increased risk of major adverse cardiovascular events such as arrhythmia, myocardial infarction, or stroke, and has a 57% increased risk of cardiovascular death, beyond the risk of death associated with traditional cardiovascular risk factors [34][35][36].
Of the 1236 patients enrolled in the study, 162 psoriatic patients had cardiovascular diseases at the moment of diagnosis (

Comorbidities: prevalence of thyroid abnormalities among psoriatic patients
Of the 1236 patients diagnosed with psoriasis, only 22 were spotted with thyroid abnormalities (

Comorbidities: psoriasis and tuberculosis
In this transversal study, the incidence of tuberculosis was quantified from the medical history and at the moment of the clinical examination for patients diagnosed with psoriasis. Of the 1236 patients diagnosed with psoriasis, over a period of 8 years (2004-2011) comorbidities were present in 40.78% of cases, and 12 of them (0.97%) had a history of tuberculosis: 5 were men (41.67%), 8 cases of pulmonary tuberculosis (66.67%), 2 pleural effusions (16.67%), 1 genital tuberculosis (8.34%), and 1 case of kerato-conjunctivitis (8.34%). Of the 12 patients with psoriasis and past tuberculosis, 1 had arterial hypertension and chronic nephritis, 1 obesity, 1 erythema nodosum, and 1 with gastric carcinoma (Figure 7).
Psoriasis could represent an independent risk factor for tuberculosis, because a high prevalence was reported in recent studies: 18.0%-Bordignon et al. [37]. In another study, latent tuberculosis infection was more reported in psoriasis (50%) than inflammatory bowel disease patients (24.2%), prior to the onset of any anti-tumor necrosis factor (TNF)-α treatment [38].

Evolution characteristics 2.2.4.1. Severity of lesions in relation to risk factors
The number of psoriatic lesions is in direct relation with the risk factors, including residence, gender, index severity, presence of comorbidities, alcohol intake, smoking, work status, and family history of psoriasis (Table 13).

Severity of lesions in relation to risk factors: smoking and psoriasis
Most of the patients enrolled in the study were nonsmokers, by declaration (Figure 8) but there is a significant correlation between the smoking and the severity of the disease (r = 0.254, χ 2 = 10.49, p = 0.00527, 95% CI).

Severity of lesions in relation to risk factors: alcohol intake (by declaration) and psoriasis
Of 1236 patients with psoriasis, alcohol consumption was declared by 410 persons, representing 33.17% of all (Table 14).

Severity of lesions in relation with topical steroids
Topical steroids: most of the patients were several years treated with steroids topically before presenting to the clinical appointment (Table 16).

Correlations with the severity of psoriasis (Risk factors)
Severity index of the disease at the moment of clinical examination (Table 17) are as follows: Within psoriasis patients, 43.37% were diagnosed with mild form of the disease, 40.45% with moderate, and only 16.18% with severe type.

Correlations between demographic data and the severity index of psoriasis 2.3.1.1. Gender distribution versus severity index
There is a strong correlation between gender and severity of the disease (r = 0.378, p = 0.00023, χ 2 = 16.706, p = 0.00024, 95% CI) ( Table 18). Among severe cases, 19.8% were men and only 11.82% women, in comparison with mild cases where 47.62% were women (Figure 9).  Our data support a male predominance in all forms of psoriasis (54.13% versus 45.87%) and greater severity in men (Table 19).

Age of patients at the moment of clinical examination versus severity index
The mean (medium) age of patients presents important differences reported to the severity of the disease (F = 45.780, p ≪ 0.01, 95% CI) (Figure 10) Table 19. Results of the study: correlations between gender distribution and the severity index.  Psoriasis is a disease of all ages but predominant around 40 years of age; early psoriasis (manifesting before 40 years of age) is associated with increased severity index, while late psoriasis (manifesting after 40 years of age) appears to be milder (Table 21). We do not see the peak in the age groups 20-30 and 40-50, but there is a quite uniform distribution starting with the age group 20 and ending with age group 60 years old (Figure 11). The most active age group 30-50 years is affected by psoriasis (  An Interdisciplinary Approach to Psoriasis

Age of the patients at the onset of psoriasis versus severity index
The first diagnosis of psoriasis was made at the age 10-30 for the most of the patients and the percentage of psoriasis de novo falls with age ( Table 23). This could mean that majority of patients were diagnosed previously or they do not seek special care in the older age. Our findings suggest that there is a march over time toward greater severity in the disease.
The medium of age of onset shows statistical differences related to severity of psoriasis (F = 11.69, p = 0.000009, 95% CI): for mild forms were 27.15 ± 14.92 SD (

Distribution of cases reported to residence/location versus severity index
The present study confirms the higher prevalence of psoriasis in urban area, but mild cases were diagnosed compared with severe and untreated forms seen in people living in rural areas (Figure 12). Explanations can be found in reduced accessibility of people living in villages far away from a specialized medical center; long period of no treatments especially in milder forms considering the disease an esthetic problem rather than a disease; stress-less life, open air activity with many hours of sun bathing/exposure; different nutrition habits (less industrialized and processed food, less meat, and more vegetables), type of water, skin-care practices, tobacco, alcohol, smaller exposure to drugs, and other chemicals ( Table 26).
Major association exists between index severity and residence of the patients (r = 0.319, p = 0.0037, χ 2 = 9.507, p = 0.0086, 95% CI). Although the prevalence of psoriasis is higher in urban area, mild cases are diagnosed, severe and untreated forms are seen in people living in rural areas ( Table 27).

Level of education versus severity index
High level of education was recognized in patients severely affected by psoriasis. Persons in worrying conditions were related to income/job such as retired people, with no income or social-assisted developed severe forms of psoriasis ( Table 28).  Level of education points out a strong correlation with severity (r = −0.413, p ≪ 0.01); patients with less than 12 years of school presented more cases with psoriasis type moderate-severe (Table 29). Although high educated persons, with university degree are more often diagnosed with psoriasis, cases are less severe.
Although higher education suggests a higher prevalence of psoriasis, a lower level of education correlates strongly with moderate-severe forms of psoriasis.
Education may be related to multiple confounding factors including alcohol intake, smoking, and access to specialized dermatological care.

Jobs distribution/income versus severity index
Among pupils and students, the most frequently diagnosed form of psoriasis was mild one (66.48%), severe disease being reported to only 2.75%, while persons without any occupation presented severe psoriasis 24.16%, respectively, 24% ( There was a positive family history of psoriasis in 29.53% of subjects, 16.18% first-degree relatives, 9.30% second-degree, 2.91% third-degree, and 1.13% fourth-degree (Table 32).

The distribution of (unique/multiple) psoriatic lesions at the moment of clinical inspection versus severity index
The results (Table 34) prove the absence of an important correlation between the severity index and type of lesions at the onset of psoriasis (unique/multiple lesions) (r = 0.0249, p = 0.381, 95% CI) ( Table 35). One can notice that in 19.27% cases of severe psoriasis, patients describe multiple lesions at the first diagnosis (Figure 13).

Presence of general comorbidities versus index severity
Comorbidities were present in 36.1% of patients with mild form of psoriasis, 44.05% with moderate forms, and in 19.64% of severe psoriasis (Figure 14, The results (r = 0.41, χ 2 = 18.79, p = 0.00008, 95% CI) confirm a strong association between the presence of comorbidities and severity of psoriasis (Table 37).

Risk factors: smoking versus index severity
Smokers are prone to severe forms of psoriasis (17.7%), and non-smokers with less severe ones (Table 42, Figure 17).

Conclusion
Our study has several strengths.
First of all, the study includes a high number of patients with psoriasis followed over a period of 8 years: 1236 persons were enrolled in the study.
Second, over a period of 8 years, detailed and updated information regarding a large variety of factors throughout the cohort follow-up was collected, thus allowing data correlation between psoriasis and various factors and/or different comorbidities.
Third, correlation between psoriasis and different factors permitted the investigation of potential associations over long durations such as the analysis of the association of psoriasis with several different comorbidities, demographic data, psoriasis severity.
Some limitations of this study include the following: it was performed only on Caucasians from predominantly the same region in Romania; therefore, generalizing the results to other ethnicities may be partial.
The study was conducted in an outpatient clinic specialized for psoriasis over a period of 8 years, so an increased number of patients diagnosed with psoriasis earlier had to self-report medical history with a small proportion of missing data. Despite this retrospective characteristic, the recall and the high completion rate for all questions on psoriasis were highly accurate.
Psoriasis is a common chronic systemic disease (not a simple skin disorder), spread worldwide, with a reported prevalence varying from 0.09 to 11.43% [39]. Psoriasis can touch any age, with a great variability: from 6 to 91 years old. The number of years should not be a reason for medical advice restriction.
This complex disease, with unknown cause, has many trigger factors, unpredictable course, severe comorbidities, and a great impact on quality of life. Further research is needed to identify these comorbidities and to take into consideration when evaluating the burdens of psoriasis such as costs, impact on quality of life, and integration of psoriatic patient in the society,therefore to be able to recommend the best management and treatment.