Multimorbidity of Psoriasis: A Large-Scale Population Study of Its Associated Comorbidities

Introduction: Psoriasis is a chronic disease of the skin with a prevalence of 2% in the general population. The high prevalence of psoriasis has prompted the study of its comorbidities in recent decades. We designed a study to determine the prevalence of psoriasis in a large-scale, population-based cohort, to exhaustively describe its comorbidities, and to analyze which diseases are associated with psoriasis. Methods: Retrospective, observational study based on the clinical information contained in the electronic health records of the individuals in the EpiChron Cohort with a diagnosis of psoriasis (31,178 individuals) in 2019. We used logistic regression models and calculated the likelihood of the occurrence of each comorbidity based on the presence of psoriasis (p-value < 0.05). Results: The prevalence of psoriasis was 2.84%, and it was more prevalent in men (3.31% vs. 2.43%). The most frequent chronic comorbidities were disorders of lipid metabolism (35.87%), hypertension (35.50%), and other nutritional-endocrine-metabolic disorders (21.79%). The conditions most associated with psoriasis were (odds ratio; 95% confidence interval) tuberculosis (2.36; 1.24–4.49), cystic fibrosis (2.15; 1.25–3.69), amongst others. We did not find a significant association between psoriasis and hypertension or neoplasms (0.90; 0.86–0.95). Conclusions: This study revealed significant associations between psoriasis and cardiac, psychological, and musculoskeletal comorbidities.


Introduction
Psoriasis is a chronic inflammatory disease of the skin; its pathogenesis is diverse and is influenced by genetic and environmental factors [1,2].It is the most frequent immunemediated skin disease, with a prevalence rate of around 2% in the general population [3,4].There are important differences in its prevalence depending on the origin of the population, being higher in countries such as the United States and Canada, where it is around 5%, and lower in Asia, where the prevalence ranges between 0.4 and 0.7% [4,5].In terms of severity, it is estimated that 27% of patients with this condition have severe psoriasis, while the rest present mild or moderate forms [6].Psoriasis can begin at any stage of life; however, there are two peaks of maximum incidence, the first in youth around 20-30 years old and another one in a mature stage around 50-60 years old [4].It has been described that women have an earlier onset of psoriasis than men [4,5].
Clinically, the disease occurs in flares and is characterized by well-demarcated erythematous plaques with whitish scales of variable distribution [6].There may be various clinical forms, such as pustular psoriasis, guttate psoriasis, and erythrodermic psoriasis, among others.Histologically, psoriasis is characterized by hyperkeratosis with parakeratosis, acanthosis of the epidermis, dilated vessels, and a perivascular inflammatory infiltrate with a predominance of lymphocytes [6].
While the skin lesions caused by psoriasis are the most visible symptoms of the disease, psoriasis is often associated with several other health conditions, known as psoriasis comorbidities [7,8].Research has connected psoriasis to various other illnesses, including psoriatic arthritis, type 2 diabetes, metabolic syndrome, lung disease, non-alcoholic fatty liver disease (NAFLD), uveitis, and mental health conditions.However, the relationship between psoriasis and some illnesses, such as neoplasms and multiple sclerosis, is still unclear [9].While diet and obesity are thought to play a role in some psoriatic complications, it is also demonstrated that psoriasis is a systemic inflammatory condition that can cause atherosclerosis and increase the risk of cardiovascular (CVD) and cerebral diseases [10,11].
It is essential to enhance our understanding of comorbidities accompanying psoriasis to provide optimal patients' care, which should take into account the presence of multiple comorbidities.The comprehensive analysis of the comorbidity profile of individuals with psoriasis, including not only the most common conditions but also those that are consistently linked to psoriasis regardless of their frequency, might shed light on the connections between this condition and other diseases.This information could help to develop personalized and comprehensive care plans for patients with psoriasis that consider all of their health concerns.
The objective of this study is to determine the prevalence of psoriasis in a largescale, population-based cohort in the Spanish region of Aragon, to exhaustively describe its comorbidities, and to analyze which diseases are systematically associated with the presence of psoriasis.

Study Design and Population
We conducted a retrospective observational study in the EpiChron Cohort, which links socio-demographic and clinical data from all the users of the public health system in the Spanish region of Aragón.This cohort is based on the information registered in the electronic health records (EHRs) and clinical-administrative databases of approximately 98% of the inhabitants of Aragón (reference population: 1.3 million people).For this analysis, we included all the 31,178 patients from the cohort with a diagnosis of psoriasis in 2019.Our research group has conducted other studies on chronic dermatological conditions, such as atopic dermatitis, using a similar methodology [12].
The Clinical Research Ethics Committee of Aragón (CEICA) approved this study (The approval code is ESPI17/0024) on 15 February 2017, and waived the requirement to obtain informed consent from patients given the epidemiological nature of the project, which used anonymized data.

Study Variables
For each participant, we studied sex, age, residence area (rural vs. urban), deprivation index of the area, country of birth, and all chronic conditions and some acute diseases of interest registered in their EHRs.Diagnoses were initially coded using the International Classification of Primary Care, First Edition (ICPC-1) and mapped to the International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9-CM) codes using a codifier system.Then, each ICD-9-CM code was sorted into 226 mutually exclusive clinical categories using the Clinical Classifications Software (CCS) [13]; 153 of them were classified as chronic using the Chronic Condition Indicator (CCI) [14] open-source tool.This tool defines chronic as those conditions with a duration of ≥12 months and that meet at least one of the two following criteria: (a) demand continuous care with a high risk of recurrence, and/or with implications for the management of the patients; (b) have limitations on self-care, independent living, and social interactions.We also included the following ten acute conditions considered clinically relevant by the three clinical experts of the research team (M.A.-B., T.G.-C., Y.G.) after a bibliographic review: unspecified local infection of skin and subcutaneous tissue (staphylococcal, streptococcal; ICD-9-CM 686.9), streptococcal infections of the upper respiratory tract (ICD-9-CM 034.0), other upper respiratory diseases (CCS 134, acute and chronic codes), other upper respiratory infections (CCS 126, except ICD-9-CM 034.0, which was a separate category), allergic rhinitis (ICD-9-CM 477), conjunctivitis (ICD-9-CM 370 and 372.0), acne (ICD-9-CM 706.0 and 706.1), otitis media (ICD-9-CM 381 and 382), external otitis (ICD-9-CM 380.1 and 380.2), and ear wax (ICD-9-CM 380.4).Some of the diagnostic labels were renamed or grouped/ungrouped by clinical experts with minor changes to facilitate their clinical interpretation.

Statistical Analysis
We performed a descriptive analysis of the frequency and prevalence (%) of psoriasis in the study population based on sex, age (i.e., 0-11, 12-17, 18-44, 45-64, and ≥65 years), country of birth, residence area, and deprivation index of the area.We used logistic regression models to calculate the likelihood of presenting psoriasis according to each of the categories of the aforementioned variables in the form of crude and age-and sexadjusted odds ratios (ORs).Adjusted ORs were compared, setting statistical significance at p < 0.05.We then analyzed the socio-demographic characteristics and comorbidity profile of patients affected by psoriasis.Results were calculated as means and/or frequencies with their corresponding standard deviations and/or 95% confidence intervals (CI).
In the analysis of psoriasis comorbidity, we first described the frequency and prevalence of chronic and acute diseases of interest.Then, for the identification of the comorbidities systematically associated with psoriasis, we used logistic regression models and calculated the likelihood of occurrence of each comorbidity (dependent variable) based on the presence of psoriasis (independent variable) as crude and sex-and age-adjusted ORs.
All the analyses were performed in RStudio software (version 1.4.1106,Rstudio, Boston, MA, USA).

Prevalence and Socio-Demographics of Psoriasis
A total of 31,178 cohort patients had a diagnosis of psoriasis during the study period (mean age 46.54 years, SD 18.40, 45.90% women), resulting in an overall prevalence of 2.84% (Table 1).This prevalence was significantly lower in women compared to men (2.43% vs. 3.31%; OR 0.73, 95% CI 0.71-0.74;Table 1).Spanish individuals were more frequently affected by psoriasis than those of different nationalities (ORs from 0.21 to 0.82); only North Americans and Western Europeans had a similar prevalence to Spanish people (OR 0.98, 95% CI 0.87-1.10;Table 2).The difference in the prevalence of psoriasis between men and women stood out in the Asian and North African populations, with women having half the prevalence of men: the Asian population (2.82% in men vs. 1.48% in women) and the North African population (2.36% in men vs. 1.35% in women).The prevalence of psoriasis in the population of Sub-Saharan Africa was also striking (0.63%; OR 0.21, 95% CI 0.17-0.27).Regarding the area of residence, psoriasis was slightly less prevalent in rural areas (2.78% vs. 2.88%; OR 0.96, 95% CI 0.94-0.98).No relevant differences in the prevalence of psoriasis according to the deprivation index of the area were observed.

Comorbidity of Psoriasis
Approximately three in four patients with psoriasis showed multimorbidity, with a mean disease burden of 3.75 (SD 2.97) chronic diseases (Table 3).The most frequent chronic comorbidities in patients with psoriasis of all ages and for both sexes were disorders of lipid metabolism (35.87%), hypertension (35.50%), and other nutritional-endocrine-metabolic disorders (21.79%), among others.All these comorbidities were more prevalent in the population with psoriasis, except for hypertension (Table 4).Acute upper respiratory tract infection (49.13%), other upper respiratory diseases (Pharyngitis and tonsillitis) (14.35%), wax in the ear (8.71%), and otitis media (5.50%) were among the most prevalent acute conditions in this cohort of patients with psoriasis.On the other hand, there were also some relevant comorbidities that did not show or showed an inverse association with psoriasis, including peripheral and visceral atherosclerosis (1.10; 0.99-1.22),hypertension (0.98; 0.96-1.01),and neoplasms (0.90; 0.86-0.95),among others.

Discussion
This study utilized real-world data from 1,098,383 patients in the Spanish public health system to examine psoriasis prevalence.The comorbidities of 31,178 patients diagnosed with psoriasis were exhaustively analyzed, with an emphasis on the most common chronic diseases and those with the strongest association with psoriasis, regardless of their overall frequency.
The prevalence of psoriasis obtained in our population (2.84%) is similar to that found in other studies carried out in Spain (2.90%) [1,4].Differences in the frequency of psoriasis between men and women are inconsistent across various studies and geographical locations [4].Some studies found no difference in the frequency of psoriasis between genders [15][16][17][18], while others reported a slightly higher prevalence in females [19].Some studies also reported a higher prevalence in men compared to women [15,20,21].In our cohort, it seems that being a woman is less associated with psoriasis.Women only presented a higher percentage of psoriasis (0.72% vs. 0.50%) at younger ages (0-11 years old).
The differences in prevalence between rural and urban populations were minimal, although statistically significant.Previous studies have already demonstrated a higher prevalence of psoriasis in urban areas without pointing to a specific cause [22].As for socioeconomic factors, other studies also found no differences in prevalence [23].In our case, we used the deprivation index of the area as an aggregated proxy variable for socio-economic status, and the differences found were minimal and difficult to explain since there was no correlation of prevalence with greater or lesser economic status.
To comprehensively understand the comorbidity profile of psoriasis patients, we employed a two-step strategy.Firstly, we outlined the most common comorbidities, regardless of their relationship to psoriasis.Secondly, we highlighted those comorbidities that have an increased probability of occurring in individuals diagnosed with psoriasis.The interplay between psoriasis and these comorbidities is complex and may involve causal, resulting, or shared etiological factors.Our study supports previous research, revealing that patients with psoriasis are frequently plagued by multimorbidity, with almost three in four presenting with multiple diseases and symptoms of different origins.
Previous studies have shown a correlation between psoriasis and altered lipid levels, including decreased HDL levels and increased LDL, VLDL, and triglycerides [24,25].The prevalence rates of disorders of lipid metabolism, the most frequent psoriatic comorbidity in our population, were similar (35.87%) to those reported in other studies (18.9-44%) [24,26,27].However, the wide range of dyslipidemia percentages indicates that psoriasis is not equally associated with dyslipidemia in all populations, being lower in countries such as Taiwan and higher in the US [24,28].In addition, dyslipidemia can be worsened by obesity.The association between obesity and psoriasis has been demonstrated in several studies [7,29].The prevalence of obesity in our cohort was 12.21%, very similar to that of other populationbased studies in Spain (14.5%) [27].Other international studies show higher obesity frequencies of up to 20.3% [24].
One of the most common comorbidities associated with psoriasis is type 2 diabetes.Studies have shown that the severity of psoriasis is directly linked to the presence of type 2 diabetes.This is thought to be due to the production of cytokines, such as interleukin-17, which are involved in both psoriasis and type 2 diabetes.The association between diabetes mellitus and psoriasis oscillates in the different studies with ORs between 1.4 and 1.9 [30,31], in our case it is somewhat lower (1.05; 1.02-1.09).Another comorbidity that is often associated with psoriasis is NAFLD [7,32], a condition in which fat accumulates in the liver, causing inflammation and scarring.In our case, we did not directly study NAFLD, but we did observe a significant OR for other liver diseases (1.57; 1.46-1.68)containing NAFLD.
Additionally, psoriasis is also associated with an increased risk of CVD, such as heart attacks and strokes.This is thought to be due to the underlying inflammation that is present in psoriasis, which can also contribute to the development of CVD.Hypertension is a risk factor for cardiovascular diseases, and there is a positive association between psoriasis and hypertension [7,9].However, in our cohort, no statistically significant association between hypertension and psoriasis was demonstrated.Nor was a significant association observed with CVD like peripheral and visceral atherosclerosis, other circulatory diseases, aortic and peripheral arterial embolism, thrombosis, or acute myocardial infarction.Different studies in populations similar to ours have demonstrated the association between psoriasis and comorbidities integrated into these groups [7,10,28,30].The findings should raise the question of whether this association is true, whether our population has differential characteristics, or whether the statistical adjustments are different.
Musculoskeletal comorbidities, such as osteoarthritis, rheumatoid arthritis and related diseases, other bone diseases, musculoskeletal deformities, and spondylosis, were more frequent in psoriatic patients.Among the musculoskeletal pathologies, the comorbidity with the highest association with psoriasis is psoriatic arthritis, with a prevalence of about 25% [33,34].In our cohort, the diagnosis of psoriatic arthritis would be included in osteoarthritis, with a much lower prevalence of around 13.47%, which would indicate that our patients are underdiagnosed.
Psoriasis has been linked to several psychiatric comorbidities, including depression, anxiety, and alcoholism [9,11,35].The prevalence of these diseases and their OR in patients with psoriasis is always positive when reviewing the literature, but highly variable depending on the type of study and the screening tool used [35][36][37][38].Our results are somewhat lower than those reviewed for these comorbidities: alcohol-related disorders, sexual disorders, anxiety disorders, depression, and mood disorders.This could be due to the fact that the result of our variable is not extracted from a proactive screening but has to have been detected by the patients' physician.
The relationship between psoriasis and neoplasms has been the subject of much research in recent years.Some studies have found an increased risk of certain types of neoplasms in people with psoriasis, particularly skin, lymphoid, and gastrointestinal tumors [39].It is believed that the chronic inflammation associated with psoriasis may contribute to the development of certain types of cancer, but more research is needed to confirm this.In our study, the association between psoriasis and neoplasms as a whole has not been demonstrated; the prevalence was 5.12% (0.90; 0.86-0.95),very similar to other research (4.78%) [39].
Several studies show an increased risk of cutaneous colonization by S. aureus and severe skin infections in patients with psoriasis treated with systemic drugs [40,41].However, they do not report the prevalence of acute skin infections on a population basis.In our case, they were statistically significant: otitis externa, an unspecified local infection of the skin and subcutaneous tissue, streptococcal upper respiratory tract infections, and conjunctivitis-keratitis.These findings should lead us to pay more attention to the examination of the patient with psoriasis.
Finally, if we analyze the comorbidities most associated with psoriasis, they are: tuberculosis (2.36; 1.24-4.49),cystic fibrosis (2.15; 1.25-3.69),and otitis externa (1.65; 1.44-1.88).Before discussing the association between psoriasis and tuberculosis, some clarifications regarding the study methodology need to be addressed.The study was conducted using population-based data, and therefore, we cannot ascertain the individual treatment received by patients who developed tuberculosis.Moreover, the diagnosis of tuberculosis might result from positive serological screening tests and Mantoux tests carried out on psoriasis patients about to undergo immunosuppressive therapy.This diagnosis of latent tuberculosis could falsely increase the association with psoriasis and tuberculosis compared to the healthy population.A recent study on the Spanish cohort of BIOBADADERM reflects that in the population of patients with moderate to severe psoriasis in Spain, 20.5% of patients exposed to biological treatments were diagnosed with latent tuberculosis before starting the biological treatment [42].The prevalence of latent tuberculosis in our sample (0.03%) is much lower because it also includes patients with mild psoriasis, who comprise the majority.
The direct association between cystic fibrosis and psoriasis has not been explicitly described.Studies have been conducted on gene promoters to investigate if cystic fibrosis is associated with genetically inflammatory diseases, and in the case of psoriasis, no association was found [43].However, some similarities in immunopathogenic pathways or aggravating factors have been reported in both conditions.For example, S. aureus is a microorganism described as a colonizer in both diseases and an aggravating or triggering factor for them [40,44,45].The presence of S. aureus may contribute to skin inflammation along the Th17 axis in patients with psoriasis, and IL-17 is the major effector cytokine in the pathogenesis of this disease [40,46].The case of a patient presenting both psoriatic arthropathy and cystic fibrosis with poor response to treatments has been reported.There was suspicion that the cause might be due to the hyperactivation of Th17 lymphocytes triggered by the colonization of the respiratory tract by microorganisms [47].
Defensins and their associated antimicrobial peptides are fundamental components of the innate immune system [48].Inherited fluctuations in defensin gene expression could potentially contribute to susceptibility to several conditions, including psoriasis, otitis media, and cystic fibrosis [49].This alteration in defensins could help to explain the association of psoriasis with otitis media and cystic fibrosis in our study.
In patients with psoriasis, elevated levels of hBD2 and LL-37 have been observed in the skin, which may contribute to chronic inflammation and propagate inflammation through the TLR9-IFN connection [49].Furthermore, the increased expression of hBD2 and LL-37 in the skin of psoriasis patients has been found to be a result of chronic inflammation, and the expression of hBD2 and inflammation may form a positive feedback loop in patients with psoriasis [49].In the context of cystic fibrosis, defensins have been observed to play a pivotal role in the disease's pathophysiology.Within the realm of cystic fibrosis, defensins, particularly hBD1, are consistently expressed throughout the respiratory tract, indicating a significant role in defending against bacterial colonization [49].Nevertheless, it has been noted that hBD1 expression might be associated with colonization by Pseudomonas aeruginosa, a common pathogenic bacterium in cystic fibrosis patients [49].Finally, regarding otitis externa, we found cases of external otitis with psoriatic features have been described in 18% of patients with psoriasis, making its diagnosis complex [50].Additionally, the frequent involvement of the ears in patients with psoriasis could imply an alteration of the epidermal barrier, which could favor superinfection by S. aureus [51].We did find an association between middle ear infections and psoriasis based on mechanisms similar to those in cystic fibrosis.It has been demonstrated that defensins hBD1 and hBD2 exhibit antimicrobial activity against otitis media pathogens, and the dysfunction of these defensins in patients with psoriasis could potentially increase their susceptibility to suffering otitis media [52,53].
Our findings have the potential to improve the comprehension of psoriasis comorbidities and enhance its management for better patient outcomes.However, it is important to note that correlation does not imply causation, and these results should be approached with caution.While some of the connections we discovered align with previous research, others were not previously documented and may warrant further investigation to uncover the underlying biological links between psoriasis and various conditions.
The main strength of our work lies in its large-scale, population-based nature, as it included almost every patient with a psoriatic diagnosis belonging to the reference population area.Moreover, psoriasis comorbidities were exhaustively analyzed through the study of virtually all chronic diseases diagnosed in both primary and hospital care, not just the most prevalent or relevant ones.The use of EHRs guaranteed the reliability of the data, which underwent continuous quality control revisions to ensure its accuracy.The main limitation of our study was its cross-sectional nature, which made determining the chronological order of appearance of diseases impossible, thus hindering the identification of cause and-effect relationships between psoriasis and its comorbidities.

Conclusions
The present study highlights the high prevalence of psoriasis in the general population and its strong association with various non-dermatologic conditions, including musculoskeletal, neuropsychiatric, cardiometabolic, and infectious conditions, among others.These findings emphasize the need to monitor the comorbidities associated with psoriasis in order to improve its clinical management and prevent its development.
Future longitudinal studies are encouraged to further explore the underlying mechanisms involved in these associations and to provide further insight into the complex nature of psoriasis.Overall, the study highlights the importance of considering the full range of comorbidities in the clinical management of psoriasis to achieve better patient outcomes.

Table 2 .
Likelihood of presenting psoriasis based on sex, age, nationality, area of residence, and deprivation index of the area, calculated using logistic regression models.

Crude OR 1 p-Value Adjusted OR 2 p-Value
1Odds ratio;2Adjusted odds ratios for sex and age; 3 Deprivation index of the residence area according to 26 socio-economic indicators and categorized from least (Q 1 ) to most (Q 4 ) deprived.

Table 4 .
[1,3]lence of chronic comorbidities and of specific acute conditions (in italics) in patients with psoriasis in the EpiChron Cohort in 2019 (n = 31,178).Logistic regression models were used to calculate odds ratios (OR) of prevalence for each comorbidity (dependent variable) according to the presence or absence of psoriasis (independent variable).ICD-9-CM diagnoses included in each category of CCS code can be found at: https://hcup-us.ahrq.gov/toolssoftware/ccs/AppendixASingleDX.txt(accessed on 9 December 2023)[1,3].
1odds ratios adjusted by sex and age; 2 p-values for the adjusted OR.