Psoriasis is an immune-mediated inflammatory disease (IMID) of multifactorial pathogenesis characterized by well-demarcated, erythematous, silvery scaly plaques or papules involving skin surfaces, nails, and outside joints.1,2 IMIDs are chronic and highly disabling diseases that share inflammatory sequences and immunological dysregulations.3 In Spain, the overall prevalence of the IMIDs is 6%, being psoriasis the most common disease (3%).3 The prevalence of psoriasis varies across countries, being more common in countries more distant from the equator and ranging from <1% up to 11%.4,5 Psoriasis can occur at any age but frequently develops its first signs during young adulthood and is most common in middle-aged individuals, with no clear differences between women and men.2 Evidence suggests its prevalence and incidence have increased worldwide, becoming a problem of global public health.4,6,7

Numerous studies have associated psoriasis with different diseases, such as psoriatic arthritis, metabolic syndrome, lung disease, non-alcoholic fatty liver disease, uveitis and mental health problems, while others remain unclear, such as insomnia or multiple sclerosis.8–11 Many psoriatic complications have been attributed to diet and obesity; nevertheless, it was recently hypothesized that psoriasis per se is a systemic inflammatory condition, leading to atherosclerosis and a higher risk of cerebrovascular and cardiovascular diseases.12 Most studies on psoriasis-related comorbidities focus on specific chronic diseases; however, chronic diseases do not appear isolated but tend to group in disease patterns, that is, non-random disease associations. As far as we know, only two studies have analyzed psoriasis-related comorbidity patterns while considering very few common chronic diseases the two of them.13,14 Better and more comprehensive knowledge of its comorbidities and specifically its disease patterns could help us improve our understanding of the underlying pathogenic mechanisms of psoriasis for a comprehensive management of psoriatic patients.

In this challenging context, network science is a powerful tool that comprehensively analyses and visualizes the associations among diseases, applying clustering methods to identify disease patterns.15 Network analysis has been applied to study disease patterns in patients with specific index conditions obtaining relevant clinical results.16,17 Nevertheless, as far as we know, this method has not been applied to the study of psoriasis-related multimorbidity.

This study aims to comprehensively analyze and identify the existence of comorbidity patterns in psoriatic patients using network analysis and describe the patterns obtained from a clinical standpoint.

A better understanding of the pathogenesis of psoriasis has made us consider it a systemic chronic inflammatory disease.28–30 However, it is unclear how they impact each other.29,31

This study explored and identified the existence of different comorbidity patterns in psoriatic patients using a network analysis approach, which allowed us to identify different associations across comorbidities based on sex and age. Different clusters defined as cardio-metabolic, upper-respiratory, respiratory-mental, dyslipidemic, geriatric, genital disorders, among others, were identified based on age and gender. These clinical–epidemiological findings can help guide psoriatic patients in the primary, secondary, or even tertiary prevention of their comorbidities and shed some light on the understanding of the physiopathological mechanisms behind the existence of some disease associations.

The present research shows the cardiometabolic pattern as the most consistent one across all age groups and sexes. Cardiometabolic diseases have been associated with psoriasis in several epidemiological studies.31–33 Several studies have demonstrated that psoriatic patients – particularly younger patients and those with psoriatic arthritis or more severe forms of the disease – have a higher prevalence of metabolic syndrome and an increased risk of major cardiovascular events such as cerebrovascular disease, myocardial infarction, and peripheral arterial disease.34–36 The cardiometabolic pattern was more common in men across all ages in our study, although this pattern also appeared in women of adult age. The existence of this pattern confirms that psoriatic patients have comorbidities that are related to cardiovascular risk factors that tend to be associated throughout life.

Current evidence suggests that the association between psoriasis and cardiovascular disease is due to the underlying chronic inflammation present in both conditions.34 Observational studies confirm an independent relationship between moderate-to-severe psoriasis and certain risk factors for cardiovascular disease, including diabetes mellitus,37,38 hypertension,39 obesity12,40 and dyslipidemia.41 Furthermore, multiple epidemiological studies support the association between psoriasis and metabolic syndrome or some of its components, such as abdominal obesity, hypertriglyceridemia, and low levels of high-density lipoprotein.30,33,40,42 Augustin et al.,43 conducted the first spatiotemporal association between psoriasis prevalence and comorbidities in Germany, and the results indicated comparable spatial prevalence patterns for hypertension, obesity and type II diabetes mellitus. This means that the highest prevalence of comorbidities used to be found where the prevalence of psoriasis is higher.

On the other hand, thyroid metabolic disorders have also been associated with psoriasis. Recently, a meta-analysis showed a possible association between psoriasis and autoimmune thyroid disease. This meta-analysis of 11 available studies with data from 253,313 psoriatic patients and 1,376,533 controls showed that psoriatic patients had a higher prevalence of autoimmune thyroid disease vs controls (OR, 1.76, 95% CI, 1.35–2.28, Z=4.25; p <0.01).44

In children, it has been reported that there is an upper respiratory pattern, probably due to superantigens, some part of virus or bacteria proteins, which stimulate T cells and antigen-presenting cells, leading to systemic immune repose and inflammation, that can act as a trigger among the youngest.45 Two meta-analyses highlighted the relationship between psoriasis and COPD, suggesting that there is a strong association between these two chronic inflammatory diseases.46,47 It is thought that psoriasis-induced systemic inflammation acts de novo on respiratory organs, thus amplifying the preexisting chronic inflammation due to underlying diseases such as asthma or COPD. Two meta-analyses highlighted the relationship between psoriasis and COPD, suggesting that there is a strong association between these two chronic inflammatory diseases.46–49

The most common comorbidities in psoriatic patients are mental disorders, in particular affective disorders such as depression and anxiety, which can interact negatively with psoriasis and lead to a dangerous vicious circle.50 Depression in psoriatic patients has traditionally been explained as a response to psychosocial factors and impaired quality of life. Nevertheless, a new hypothesis linking depression and psoriasis through chronic inflammation offers insights that could help understand and treat these diseases. In this new approach, new drugs and lifestyle play an important role.51,52

In a similar way to what happens in the microenvironment of the skin, in the nervous system, the inflammatory response is maintained through the interaction between cytokine-receptors and cytokine-producing elements, such as microglia, astrocytes and oligodendrocytes.53 The hypothesis explains the connection between the neuroendocrinal and the immune system alterations that occur in certain forms of depression.

In patients older than 65 years, a geriatric-pattern was found in both sexes. Studies also show that there is a correlation between cognitive impairment and psoriasis.54 Psoriatic patients exhibit higher rates of mild cognitive impairment (44% vs. 11% in the controls; p=0.002),55 and individuals with a past medical history of psoriasis also have a higher odds ratio (OR) of dementia vs those without the disease (adjusted OR, 1.46, 95% CI, 1.23–1.73; p <0.001).56

Regarding the limitations of this study, the fact that the clinical information obtained from the EHRs was not originally designed for research, could have led to over- and under-diagnosis of some chronic disorders. Another limitation is the cross-sectional retrospective design of the study, with which there is no way of knowing about the longitudinal characteristics of the population or establishing cause-effect relationships. Chronic diseases associated with psoriatic patients were defined in our study as potential comorbidities. Our research establishes a map of diseases for future research without the ability to establish a direct physiopathological relationship with psoriasis. Additionally, we should consider the lack of some variables that could help us explain the results obtained, such as the severity of psoriasis, lifestyle information, socioeconomic factors, information on functional status, and analytical variables, among others.

One of the main strengths of our study is that we analyzed a population-based cohort, including 98% of the reference population. Moreover, data from the EpiChron Cohort undergoes continuous quality control checkups ensuring its accuracy and reliability for research purposes. Another important strength is the innovative method applied to understand comorbidities in psoriasis. Network analysis studies the interrelations across diseases and how patterns emerge from them. This paper shows the potentiality of applying this method to study and visualize the comorbidities of psoriasis and achieve a more holistic understanding of these patients. Of note, this study comprehensively analyzed all chronic diseases obtained from the patient's EHRs created by health professionals, and not just the most relevant, prevalent or self-reported diseases.

This is the first population-based study unraveling the comorbidity patterns of psoriatic patients through the network analysis of virtually all chronic conditions. We identified and described up to 10 and 11 patterns in men and women, respectively, whose complexity increased with age. These patterns included diseases from all systems and organs, which support the need for an interdisciplinary and comprehensive management of psoriasis. Our results are especially important for dermatologists so they can become aware of the high comorbidity burden of psoriasis, as well as for all health professionals having to deal with psoriasis in their everyday practice. Further studies are needed and encouraged to validate the results obtained across different clinical settings and populations and characterize the physiopathological mechanisms underlying the comorbidity patterns identified.

Conceptualization, Y.G., J.C.-P., M.A.-B., and A.G.-M.; methodology, J.C.-P.; formal analysis, J.C.- P.; data curation, B.P.-P.; writing – original draft preparation, M.A.-B. and J.C.-P.; writing – review and editing, M.A.-B., J.C.-P., T.G.-C., B.P.-P., C.L.-B., A.M.-J., A.N.-B., A.G.-M., and Y.G.; visualization, J.C.-P.; supervision, A.G.-M. and Y.G.; funding acquisition, J.C.-P. and Y.G. All authors have read and agreed to the published version of the manuscript.

Ethical approval for this study was obtained from the Clinical Research Ethics Committee of Aragón (CEICA) that approved the research protocol for this study (PI23/608).

This research was funded by Instituto de Salud Carlos III, Ministry of Science and Innovation (Spain), through the Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPS) awarded on the call for the creation of Health Outcomes-Oriented Cooperative Research Networks (grant number RD21/0016/0019), and by Gobierno de Aragón (grant No. B01_23R) and co-funded by the European Union NextGenerationEU funds. The sponsors were not involved in the study design, data collection and analysis, decision to publish, or drafting of the manuscript.

The authors have no conflict of interest to declare.