Table 3. The Residence effect on SLE Severity THU0254 Twice increased risk of Systemic Lupus Erythematosus (SLE) in urban than rural environment Irini Gergianaki,1,2 Antonios Fanouriakis,3 Christina Adamichou,1 Giorgis Spyrou,1 Prodromos Sidiropoulos,1,2 Dimitrios T. Boumpas,2-6 George Bertsias* 1,2 1 Rheumatology, Clinical Immunology and Allergy, University of Crete School of Medicine, Iraklio, Greece; 2 Laboratory of Autoimmunity and Inflammation, Institute of Molecular Biology-Biotechnology, FORTH, Iraklio, Greece, 3 4th Department of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece, 4 Joint Rheumatology Program, National and Kapodistrian University of Athens Medical School, Athens, Greece, 5 University of Cyprus, Medical School, Nikosia, Cyprus, 6 Biomedical Research Foundation of the Academy of Athens, Athens, Greece *Corresponding author: gbertsias@uoc.gr Background and objectives SLE originates from the complex interplay between genetic, epigenetic and environmental factors, yet their effects remain elusive. A few studies suggest that SLE is more frequent in urban than rural regions.1 This was also shown in our region (Crete) (SLE prevalence: 165 per 105 inhabitants in urban vs. 123 per 105 in rural areas [p<0.001]; manuscript under peer review) Further, studies have reported higher SLE disease activity at diagnosis, increased occurrence of renal disease over time2 and more depression3 in rural vs. urban regions, but similar rates regarding the delay in the diagnosis,4 disease activity over the disease course, hospitalizations, damage and mortality.2 Herein, we aimed to evaluate the effect of rural (R) versus urban (U) place of residency with regards to: i) SLE occurrence; ii) delay in diagnosis; iii) clinical manifestations, severity and non-reversible organ damage; iv) comorbidities and hospitalizations. Results Disease Risk: By comparing the relative distribution of residence in our SLE patients against the population distribution in Crete, the relative risk of SLE in urban versus rural region was estimated at 2.08 (95% confidence interval [95% CI] 1.66–2.61, p<0.001). Demographics:The educational status was lower in patients in rural vs. urban areas (9.6% vs. 42.1% with >12 years of education, p<0.001), and employment rates were also lower (26.4% vs. 39.5% in paid work, p<0.001). About half of the rural living patients had a delay >1 year from the symptoms onset to diagnosis and this was onlyabout 10% more than the urban dwellers (59.09% in rural vs. 49.64% in urban (p=0.41). Differences in age of diagnosis and gender ratio are shown in Table 1 and Figure 1, respectively. In multivariable analysis, urban living was associated with lower risk for moderate/severe forms of SLE, as compared with rural living, independent of the effects of other factors such as the total number of ACR classification criteria (Table 3). 45.3% of the patients living in urban and 51.9% of patients in rural areas were free of organ damage (SDI=0) at the last follow- up (p=0.89). In multivariate analysis, the place of residency was not predictive for non reversible damage. Comorbidities: Among comorbidities assessed, Hashimoto thyroiditis was most common in urban patients (12.2% vs. 4.1% in mixed, 1.6% in rural, p<0.001). Allergic rhinitis was 2-fold higher in urban SLE patients (57.1% vs. 28.6% in rural, p=0.04). Mixed and urban dwellers reported more frequently past infection from rubella (17.3%, 15.7% vs. 7% in rural, p=0.02) and chicken- pox (25.6%, 16.3% vs 12.4% respectively p=0.03). Infectious mononucleosis was also higher in urban SLE patients (6.4% vs. 4.1% in mixed and 1.6% in rural, p=0.02). Differences in smoking, pesticide’s use and BMI are shown in Table 2. (obesity: p=0.049; smoking: p=0.07; pesticides: p<0.001) Table 3. The Residence effect on SLE Severity  Predictors B p-value OR 95% C.I. Disease duration .049 0.017 1.05 1.01 1.09 Age of diagnosis -.011 0.265 0.99 0.97 Gender 1.876 0.001 6.53 2.08 20.5 Residence (Rural as reference)   0.046 Mixed Rural/Urban -.102 0.747 0.90 0.48 1.68 Urban -.691 0.021 0.50 0.28 No. ACR criteria .495 0.000 1.64 1.25 2.14 Table 1. Age [median (IQR)] of SLE diagnosis in urban vs. rural areas Table 2. Comparison of Risk Factors by Residential Environment Urban Rural P-value 39 (19) years 46 (24) years p<0.001 Urban Upbringing Rural Upbringing P-value 41 (20) years 46 (24) years p<0.001 Obesity Exclusive Rural Mixed Exclusive Urban BMI 18.5-24.9 7.41% (8) 8.7% (8) 6.1% (10) BMI 25-29.9 25% (27) 23.91% (22) 40.24% (66) BMI 30-34.9 27.78% (30) 31.52% (29) 25% (41) BMI 35-39.9 0.00% (0) 1.09% (1) BMI >40 39.81% (43) 34.78% (32) 28.66% (47) Total 100% (108) 100% (92) 100% (164) Pesticides, use Never 63.53% (54) 79,22% (61) 90% (117) Ever 36.47% (31) 20,78% (16) 10% (13) 100% (85) 100% (77) 100% (130) Smoking 63.11%(77) 54.95%(50) 49.7%(84) Current 27.05%(33) 26.37%(24) 34.91%(59) Past 9.84%(12) 18.68%(17) 15.38%(26) 100%(122) 100%(91) 100%(169) Figure 1. Gender ratio among SLE patients who have lived exclusively in a rural vs. urban area (p=0.05) Methods Design: Cross-sectional study employing data from the Lupus Epidemiology & Surveillance registry in Crete, with comprehensive patient recruitment from the community to the tertiary referral centre, reducing the risk of selection bias of the more severe cases followed at the hospital. Settings: Crete is a Mediterranean island with genetically stable, monoethnic population (0.6M, 61% in rural (<10,000 people) and 47% in urban towns (>10,000 people) according to Hellenic Statistical Authority, National Census 2011). Eligibility Criteria: SLE aged ≥15 years old, ACR-1997 or SLICC-2012 defined, permanent residents at Crete. Sample & Data Sources: Demographics and detailed residency history were obtained from consecutive face interviews at enrolment (2012-2015) whereas clinical data from medical records reviews (n=399 patients). Variables: Patients with exclusively urban, exclusively rural (throughout all their lifespan up to enrolment) or mixed residence, were compared in relation to disease risk, diagnosis age, ACR-1997 classification criteria, disease severity, lifestyle/risk factors, renal/neuropsychiatric involvement, hospitalizations and organ damage (SLICC damage Index [SDI]). Statistical Methods: A stepwise binary logistic regression analysis (unadjusted and adjusted for gender, age at diagnosis, disease duration, total number of ACR and smoking was performed (SDI=0, no damage accrual, SDI≥1 any damage accrual up to last follow-up). In a second regression model, severity was categorized in mild/moderate vs. severe disease and was adjusted for ACR criteria, gender, disease duration and age at disease onset. Conclusion Our study confirms that SLE is more frequent in urban areas although there is no significant difference in the delay of diagnosis or organ damage. Our results suggest the existence of different phenotypes of SLE with different clinical and immunological features, age of onset/diagnosis, possible risk factor burden, and disease severity. Considering the rather homogenous genetic background of our population, these results imply a possible effect of the living environment on SLE risk and phenotype, which warrants further investigation. Clinical features: At the year of SLE diagnosis, renal disorder was twice as common in urban than rural environment (2.06:1, p<0.02). In terms of cumulative disease characteristics, malar rash, photosensitivity and arthritis were collectively more prevalent in rural SLE patients as shown in Figure 2a/b. Differences were noted in immunological characteristics and hospitalizations (Figure 3a/b). In a crude, unadjusted analysis, SLE patients from rural environments had less mild and more moderate/severe disease as compared with in those from urban areas. (Figure 4). Figure 2a. Disease pattern of malar rash, photosensitivity and arthritis in rural vs. urban SLE patients. Figure 2b. Photosensitivity (ACR-19997 classification criteria) by urban/rural place of residency (p=0.03) References 1. Alamanos Y, Voulgari PV, Siozos C, Katsimpri P, Tsintzos S, Dimou G, Politi EN, Rapti A, Laina G DA. Epidemiology of systemic lupus erythematosus in northwest Greece 1982- PubMed Commons. 2003;30(4):1-2. 2. Pons-Estel G, Saurit V, Alarcon G, et al. The impact of rural residency on the expression and outcome of systemic lupus erythematosus: data from a multiethnic Latin American cohort. Lupus. 2012;21(13):1397-1404. doi:10.1177/0961203312458465. 3. Abdul-Sattar AB, Abou El Magd S. Association of perceived neighborhood characteristics, socioeconomic status and rural residency with health outcomes in Egyptian patients with systemic lupus erythematosus: One center study. Int J Rheum Dis. 2014:1-8. doi:10.1111/1756-185X.12331. 4. Stummvoll G, Stamm T. The patients ’ perspective : living with lupus in Austria. 2017. doi:10.1007/s00508-017-1175-1. Acknowledgments Funding: Aristeia I. 2344 (D. Boumpas Figure 4. The effect of place of residence on SLE severity Hospitalizations due to active lupus differed significantly between the two groups (38.8% in rural versus 37.2% in urban, p<0.001). Figure 3a. Prevalence of antiphospholipids by residence (p=0.04) Figure 3b. Hospitalizations by residence (p<0.001)