Increased Risk of Systemic Lupus Erythematosus in Patients with Chronic Urticaria: A Systematic Review and Meta-analysis

Introduction: The association between systemic lupus erythematosus (SLE) and chronic urticaria (CU) has been suggested in the literature although the amount of evidence is still relatively limited. We aimed to combine all available studies on this association using systematic review and meta-analysis technique. Methods: Potentially eligible studies were identified from Medline and EMBASE from inception to February 2023 using search strategy that comprised of terms for “chronic urticaria” and “systemic lupus erythematosus”. The eligible study must consist of one group of patients with CU and another group of comparators without CU and must compare the prevalence of SLE in each group and report effect size with 95% confidence intervals (95% CIs). We extracted such data from each study to calculate a pooled odds ratio using the generic inverse variance method with random-effect model. Funnel plot was used to evaluate publication bias. Newcastle-Ottawa Scale was used to appraise the methodological quality of the included studies. Results: A total of 5,155 articles were identified. After two rounds of independent review by four investigators, five studies met the eligibility criteria and were included in the meta-analysis. The meta-analysis found an increased prevalence of SLE among patients with CU compared with individuals without CU with the pooled odds ratio of 5.03 (95% CI, 2.57–9.85, I2 of 93%). Conclusion: This systematic review and meta-analysis found that patients with CU had a significantly increased risk of SLE compared to individuals without CU.

taneous manifestations, such as malar rash, discoid rash and photosensitive dermatitis, are parts of classification criteria.] Chronic urticaria (CU) is defined as the presence of urticaria for more than 6 weeks.When exogenous trigger can be identified, it is called chronic inducible urticarias (CIndU).However, such trigger is not identifiable in the majority of patients (up to 90%) and, thus, is called chronic spontaneous urticaria (CSU).Although the pathogenesis of CSU is not fully understood, autoinflammation is thought to play a pivotal role. 5n association between CU and some autoimmune conditions, such as autoimmune thyroid diseases, type I diabetes, rheumatoid arthritis, and celiac disease has been reported. 6The relationship between CU and SLE has been reported as well although the number of studies is still relatively limited.In this review, we aimed to combine all available current studies and investigate the association between CU and SLE using systematic review and meta-analysis technique.

Design
This systematic review and meta-analysis was carried out following the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.

Search strategy
Potentially eligible studies were identified from publications indexed in Medline and Embase from inception to February 2023, which was independently conducted by two investigators (PW, NC).Search terms were derived from terms related to "Chronic urticaria" and "Systemic lupus erythematous".Detailed search strategy is provided in Supplemental Material 1.No language limitation was applied.

Study selection criteria
The eligible study must be cohort study that consisted of one cohort of patients with CU and another cohort of comparators without CU.The study must compare prevalence of SLE in each group and report effect size with 95% confidence intervals (95% CIs).Four investigators (PW, NC, BP, AJ) independently reviewed the eligibility of the retrieved articles.Different opinions were resolved by discussion with the senior investigator (PU).If two studies utilized the same database, only the study with the largest number of participants would be included.

Data extraction
We used a standardized collection form for data extraction: last name of the first author, country of the study, study design, publication year, number of participants, recruitment of participants, diagnosis of CU, diagnosis of SLE, mean age of participants, percentage of female participants, comorbidities, and variable adjusted in multivariate analysis.

Quality assessment
Two investigators (PW and NC) independently evaluated the quality of each study using the Newcastle-Ottawa quality assessment scale. 7Different opinions were resolved by discussion with the senior investigator (PU).

Statistical analysis
Statistical analysis was performed using Review Manager 5.3 software from the Cochrane Collaboration.Point estimates with standard errors were retrieved from each study and were combined using the generic inverse variance method as described by DerSimonian and Laird. 8andom-effect model, instead of fixed-effect model, was used as the included studies had different background populations and methodology/protocols.The Cochran's Q test was used to determine statistical heterogeneity.This statistic was further adjunct with the I 2 statistic which quantifies the proportion of the total variation across studies that is from heterogeneity rather than coincidence.A value of I2 of 0 -25% represents insignificant heterogeneity, 26-50% represents low heterogeneity, 51-75% represents moderate heterogeneity and >75% represents high heterogeneity. 9Funnel plot was used to investigate for the presence of publication bias.

Statement of Human and Animal Rights
This article does not contain any studies with human or animal subjects.

RESULTS
We identified 5,679 articles from EMBASE and MEDLINE database, in which 524 were duplication articles, leaving 5,155 articles for title and abstract review.Of these, 5,083 articles were excluded as they did not satisfy the eligibility criteria based on study design and type of article.The remaining 72 articles were considered of interest and their full articles were retrieved for detailed evaluation.1][12][13]  A SYSTEMATIC REVIEW AND META-ANALYSIS cohorts were cross sectional studies.Adjustment for the analysis of the association between CU and risk of SLE varied considerably across the included studies, ranging from none to extensive adjustment for demographic data and comorbidities.Most studies were of high quality as reflected by the high Newcastle-Ottawa score (Table 1).

Association between CU and SLE
The meta-analysis found that patients with CU had a significantly higher risk of SLE with the pooled OR of 5.03 (95% CI, 2.57-9.85)with high statistical heterogeneity with I2 of 93% (Figure 2).Funnel plot of the meta-analysis of the studies was relatively asymmetric (Figure 3), indicating that publication bias may have been present.

DISCUSSION
The current study is the first systematic review and meta-analysis that comprehensively investigates the association between CU and SLE.We found that patients with CU had approximately five-fold increased risk of SLE compared with individuals without CU.Although the exact underlying mechanism behind this observed association is not completely understood, there are some possible explanations.The first possible explanation is shared immunopathogenesis as studies have revealed common immunologic markers in patients with CU and SLE.] In addition, patients with SLE have increased circulating IgG antibody to the α subunit of the high affinity IgE receptor (IgG anti-FcεRIα), which is believed to play an important role in activation of mast cell in CU. 16 It is therefore possible that presence of these autoantibodies seen in CU may trigger systemic autoimmunity of SLE in the same individuals later in their life.3][24] This notion is supported by the evidence that probiotics consumption in patients with SLE 21,25 and CSU 26 may mitigate clinical severity of the diseases by altering gut microbiota composition.Additionally, studies have shown that presence of Helicobacter pylori infection is another common risk of both CSU and SLE. 27It has been proposed that H. pylori triggers gut dysbiosis by producing the virulence factor cytotoxin-associated gene A and inducing hypochlorhydria and hypergastrinemia. 28here are some potential limitations in our study.First, some of the included studies did not provide a clear definition of CU, thereby jeopardizing the reliability of case identification.Second, the statistical heterogeneity of the meta-analysis was high (I 2 93%).This is likely due to different study design and participant characteristics.Third, publication bias may have been present.Additionally, most included studies did not adjust their outcomes and, therefore, the pooled results may be subjected to confounding effects.The association of CU and SLE may have a clinical implication regarding screening for SLE as CU can be the first manifestation of SLE 29 and may also suggest an unfavourable prognosis. 30Surveillance for other signs and symptoms of SLE as well as screening for autoantibodies could be helpful but further investigation is still needed.

CONCLUSION
This systematic review and meta-analysis found that patients with CU had a significantly increased risk of SLE compared to individuals without CU.

Study identification and literature review process 3 Figure 1 .
Figure 1.Study identification and literature review process.

Figure 2 .
Figure 2. Forest plot of the meta-analysis of cohort studies.

Figure
Figure 3. Funnel plot of the metaanalysis of cohort studies.

Table 1 .
Figure 1 demonstrates the search methodology and selection process of this study.The characteristics of the included cohort studies are summarised in In summary, among the five included studies, four of them including studies from Taiwan, Israel, Denmark, and Korea, were retrospective populational-based cohort.Only the study from Canada by Le et al. was prospective, single centred, and focused paediatrics.Most of the studies used diagnostic code for diagnosis of CU and SLE.All 123 TITLE INCREASED RISK OF SYSTEMIC LUPUS ERYTHEMATOSUS IN PATIENTS WITH CHRONIC URTICARIA:

Table 1 .
3.Funnel plot of the metaanalysis of cohort studies.Main characteristics of the cohort studies included in the meta-analysis.

Table 1 .
Main characteristics of the cohort studies included in the meta-analysis.