Psoriasis is an inflammatory skin disease mediated by cells and molecules of both the innate and adaptive immune systems (1). The pathogenesis of psoriasis is complex, including immune response, genetic susceptibility and environmental factors. Psoriasis is a disease more than skin, and it is associated with systemic disorders (2). Patients with psoriasis are at an increased risk of developing other chronic diseases. These comorbid diseases of psoriasis include psoriatic arthritis, Crohn’s disease, cancer, depression, metabolic syndrome, and cardiovascular disorders (3, 4), imposing an excessive burden on both individuals and society. Studies have shown a connection between psoriasis and a number of autoimmune disorders, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) (5), indicating that these disorders share pathophysiological pathways.

Antiphospholipid syndrome (APS), characterized by thromboembolic events and persistent antiphospholipid antibodies (aPL), is strongly linked to autoimmune diseases like SLE and RA (6). Despite overlapping immunological dysfunction (e.g., autoantibody production, endothelial injury), the association between psoriasis and APS remains underexplored, necessitating rigorous epidemiological studies to clarify potential risks.

In order to reduce the influence of confounding variables, a statistical technique called propensity score matching (PSM) pairs patients with specific medical conditions with those who do not. In this study, we utilized the TriNetX database, which provides real-time electronic medical record data from a global collaborative health research network. We used PSM to adjust for demographic variables, comorbidities, and medication use, trying to investigate whether patients with psoriasis have an increased risk of developing APS. Our findings may bring new viewpoints for clinical practice and more individualized advice for psoriasis patients.

In this study, we investigated the impact of psoriasis on the risk of APS using a large-scale, real-world data from the TrinetX network. We compared with the non-psoriasis group, patients with psoriasis or patients with PsA are more likely to develop APS. The risk of APS in psoriasis group was higher in non-psoriasis group after conducting PSM and adjusting for potential confounders. The subgroups also indicated higher risks of developing APS in patients with psoriasis. To our knowledge, this is the first study to investigate the risk of APS in patients with psoriatic diseases.

A previous study found that patients with psoriatic arthritis have a higher odds ratio for the development of SLE, Sjögren syndrome, systemic sclerosis, celiac disease, giant cell arteritis, hemolytic anemia and even surgery (7, 8). Our study demonstrated an association between psoriatic disease and APS, consequently providing novel viewpoints on the risk variables that underlie this correlation.

Here are some possible explanations for this connection. Psoriasis is an inflammatory mediated disease. The pathophysiology of the development of psoriasis involves both the innate and adaptive immune systems (9). There is a brisk immune cell infiltrate composed of dendritic cells (DCs) and CD4⁺ T cells within the upper papillary dermis and CD8⁺ T cells within the epidermis (10). CD4⁺ and CD8⁺ T cells producing IL-17 have been identified in psoriasis lesions (11, 12). Additionally, there was an increase in the production of interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-22, and IL-23 (13). While in APS, immunothrombosis participated in the pathogenesis. Anti-beta-2 glycoprotein I antibodies (a major pathogenic antibody in APS) engage TLR4 signaling and trigger monocytes to express tissue factors and proinflammatory cytokines such as TNF-α and IL-1β (14). The subsequent activation of the innate immune response was considered the second hit in the thrombotic mechanism in APS (15). Besides, high levels of neutrophil extracellular traps (NETs) remnants are found in the circulation of patients with APS (16). NETs can trigger thrombosis in the original place through multiple mechanisms in APS (17). While, in psoriasis, extracellular DNA has recently been shown in the epidermis in association with NETs (18).

On the other hand, the role of complement activation is confirmed in APS. Complement products C3a and C5a were believed to cause placental inflammation (19). Activation of the complement cascade might provoke thrombosis (20). There is evidence supporting activation of the classical and alternative complement pathways in patients with catastrophic APS (21), and eculizumab (a humanized anti-C5a monoclonal antibody) has been successfully used in catastrophic APS (22). However, C3a and C5a were found in psoriasis lesions for nearly four decades (23). The complement activation may contribute to the relationship between psoriasis and APS. There is also some common mechanism between psoriasis and APS, such as endothelial cell activation and the production of vascular endothelial growth factor (VEGF) (24, 25).

Our subgroup studies shed additional light on which psoriasis individuals might be most susceptible to APS. Sex hormones and genetic predispositions may be the cause of the well-documented female tendency for autoimmune diseases like APS, there is a subtype of APS named obstetric APS (26). A number of factors, such as sample size, genetic differences, socioeconomic inequities, and access to healthcare, are probably involved in the relatively high risk of APS among Black or African American individuals with psoriasis. Asians did not have a higher risk, which might be because they have comparatively lower disease activities. Other chronic diseases like diabetes mellitus, metabolic disorders and ischemic heart disease were more common in APS (27, 28). Our results highlight the need for personalized screening and management strategies for patients with psoriasis at the greatest risk for comorbid conditions.

However, there are several potential limitations in the present study. First, the follow-up data of patients is not available in the TriNetX platform. So, we cannot provide the follow-up time of the study individuals. Second, the data were sourced from TriNetX, which was developed to collect information primarily from US and European health care organizations, and therefore may not be representative of the broader world population. Third, confounding bias may exist in this retrospective study even through we used propensity score matching to balance the covariates, and we adjusted for baseline characteristics. Additionally, this study was unable to capture the specific clinical manifestations regarding APS phenotypes (e.g., thrombotic, obstetric, non-thrombotic, or combined presentations) or antibody profiles (anticardiolipin, anti-β2 glycoprotein I, and lupus anticoagulant) used to confirm the diagnosis of antiphospholipid syndrome (APS), as such information is not available in the database. The identification of APS relied on ICD-10-CM coding assigned by physicians, diagnostic codes may not distinguish between clinical diagnosis and formal classification, which can lead to over- or underestimation of APS cases.

In conclusion, we conducted a large-scale retrospective cohort study to investigate the impact of psoriasis on the incidence of APS. We revealed that there is an increased risk of APS in patients with psoriasis and patients with psoriatic arthritis. Psoriatic diseases have a more intensive relationship with connective tissue diseases.