Chronic Urticaria Is Associated With an Increased Risk of Psoriasis: An Observational and Validation Study

Both chronic urticaria (CU) and psoriasis are autoimmunity-driven non-communicable chronic inflammatory skin diseases (CISDs) and can significantly affect patients' quality of life and carry significant healthy and economic burden [1, 2]. Various mediators, such as tumour necrosis factor (TNF)-α, interleukin (IL)-1, IL-4, IL-5, IL-6, IL-8 and IL-16, have been identified in the skin lesion and peripheral blood of CU patients [3]. In addition, IL-17 produced by T helper (Th) cell and responses of T helper (Th) 2 initiated by cytokines have been indicated as a possible molecular target in the future for CU patients [4, 5]. Psoriasis shares common immune cells and mediators with urticaria to some large extent. Many of these mediators stimulate keratinocyte hyperproliferation, perpetuating a cycle of chronic inflammation [6]. Given that various mediators have been identified and Th-17 plays an important role in the pathogenesis of in these two CISDs [5, 7], it is reasonable to hypothesize there may be an association between these two non-communicable CISDs. However, to date, there is no evidence available to support this relationship. Therefore, we hypothesis that CU may play a causal role in psoriasis development and show for the first time in this observational and mendelian randomization study. Our retrospective cohort study utilised all the outpatients and inpatients data from Longitudinal Health Insurance Database 2000 (LHID2000), a sub-dataset of National Health Insurance Research Database (NHIRD) in Taiwan. We identified all patients with newly diagnosed CU between 2000 and 2010 and selected a comparison cohort without CU diagnosis, propensity score matching (PSM) them in terms of age, sex and all baseline comorbidities at a 1:1 ratio. The follow-up period for each patient started from the index date till the first diagnosis of psoriasis, or the patient was censored due to withdrawal from the insurance programme (such as death, immigration) or end date of December 31, 2013. The relative risk (RR), hazard ratio (HR) and computed incidence rate (IR) per 1000 person-year of psoriasis for patients exposed and not exposed to CU were computed. Cox proportional hazards regression model and subgroup analysis were constructed adjusting with covariates (age, sex and baseline comorbidities). To verify our results, a two-sample Mendelian randomization (MR) analyses were performed. A total of 27,481 patients with and 27,481 patients without CU were included in the study. After PSM, age, sex and comorbidities were similar between both groups at baseline. Univariate and multivariate analyses revealed that CU had a significantly higher risk of developing psoriasis compared to the controls. The Kaplan–Meier analysis demonstrated the cumulative risk of psoriasis was significantly higher in the CU cohort than that in the control cohort (p < 0.001). The subgroup analysis revealed that a consistently higher risk of psoriasis in individuals with CU across most subgroups (Table 1). Overall, the results indicate a consistently higher risk of psoriasis in individuals with CU across most subgroups. Interestingly, MR replicated this risk in genetically predicted urticaria patients in Asian (OR: 3.61 per 1.28 increased risk for psoriasis vulgaris and 1.44 per 0.36 for psoriasis), but not vice versa. All clinical, results mentioned but not shown in Table 1 can be found in the online repository, at https://osf.io/fh3nt. The present study revealed that CU patients had an approximately 3.6-fold higher risk of developing psoriasis than controls, this risk was consistent across different subgroups. MR replicated this risk in genetically predicted urticaria patients in Asian, but not vice versa. This is the first longitudinal follow-up study to investigate an increased risk of psoriasis in patients with CU, which was validated by MR analyses. Although the nonsignificant risk of psoriasis vulgaris or psoriasis is found in MR analyses, it should be noted that the occurrence of a disease is always multifactorial, not just caused by genes. Currently, our study was not capable of identifying the mechanism underlying this positive association between CU and psoriasis, but some possible explanations can be proposed. The shared common inflammatory cell, proinflammatory cytokines, chemokines may play an important role. Despite our interesting findings, information about the laboratory could not be established from the NHIRD database, therefore, we were unable to address the association between autoantibodies, cytokines or chemokines and psoriasis, which can only be inferred from the published literature. Further studies are needed to address the underlying mechanisms. In addition, our results are specific to the population of Taiwan, therefore, may not be broadly applicable to all population. Lastly, misclassification errors were inevitable since the NHIRD contains administrative data, which might affect our outcomes. However, validation of the NHIRD data studies showed consistent accuracy of primary diagnoses ranging from 88.4% to 95.9% [8, 9]. Despite these limitations, our study might be helpful for further studies on the pathogenesis and therapies of urticaria-related psoriasis. All authors critically revised the manuscript for important intellectual content. Specific roles included: study design (L.-H. Shi, Y.-H. Wang, J.C.-C. Wei), data collection and analysis (Y.-H. Wang) and drafting of manuscript (Jenny Shi, A.-P. Huo, Y.-H. Wang, J.C.-C. Wei). We would like to show our appreciation to the supported from the Ministry of Health and Welfare, Taiwan; China Medical University Hospital; Academia Sinica Stroke Biosignature Project; MOST Clinical Trial Consortium for Stroke; Tseng-Lien Lin Foundation (Taichung, Taiwan); and Katsuzo and Kiyo Aoshima Memorial Funds (Japan). This study was approved by the Ethical Committee to fulfil the condition for exemption by the Institutional Review Board of China Medical University (CMUH104-REC2-115(CR-3)). The consent requirement was specifically waived by this board. Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.