1. Impact of residential environment on Systemic Lupus Erythematosus outcomes in a south European population
I. Gergianaki, MD
P. Sidiropoulos, Professor of Rheumatology, University of Crete
K. Souliotis, Professor of Health Policy,  University of Peloponnese
G. Bertsias, Ass. Professor of Rheumatology, University of Crete
Postgraduate Program in
"Public Health & Health Care Management"

2. SLE Heterogeneous manifestations, multiple organs affected.
Variability in disease activity, organ damage and severity.
Long term disease, comorbidities, (complexity)
Merril JT. Is SLE many single-organ diseases or an overlapping spectrum? Nat Rev Rheumatology 2015

3. Clinically overt autoimmunity
SLE Risk factors
Crystalline Silica (OR 1.6, 2.1, 4.3)
Current smoking (OR 1.5)
Endometriosis (HR=2.03;
Mercury (OR 3.6)
Pesticide mixing (OR 7.4)
Cosmetic worker (OR 10.2)
Asbestos. Solvents
Persistent organic pollutants
Organic dust
UV radiation
Outdoor work (OR 1.9)
Sunburn (OR 2.7)
Ionizing radiation
Epstein Barr virus
Alcohol consumption (OR 0.4)
Tuberculosis (OR 2.1)
Exposure to livestock (OR 0.55)
Vitamin D
Dietary antioxidants
Vaccinations
Oral contraceptive use (OR 1.5)
Postmenopausal hormones (OR 1.9)
Early menarche (OR 2.1)
Breastfeeding (OR 0.6)
Parity
Age at first birth
Genes (30%) UV
Genes
Environment
Pre-clinical
Clinically overt autoimmunity
Comorbidities
Time
Barbhaiya et. Environmental exposures and the development of systemic lupus erythematosus. Curr Opin Rheumatol ;28(5):
Bertsias G. et al. Ann Rheum Dis 2010; 69:1603–1611.

4. Lupus epidemiology Geographical area 9/105 Ukraine to 300/105 USA1
Ethnicity /SES Blacks&minorities x 5-9 incidence> whites2
Gender Females > males (9-15:1)
Age SLE in children more severe, late onset ↑ mortality
Place of Residence Scarce evidence
SLE is more frequent in cities4,5
Disease activity at diagnosis and the occurrence of renal disease over the disease course3,6
1Carter et. al 2016; Myles J.  Rheumatology 2016 ; Pons-Estel G Lupus. 2012;21(13):
4 Alamanos Y J Rheumatol ; 5 Siegel M. , Arthritis Rheum Abdul-Sattar Int J Rheum Dis. 2014:1-8

5. The impact of place on health
Rural Disadvantage
Urban Vulnerabilities
 Obesity
 Ischemic heart disease
 Suicide
 activity limitation due to chronic health conditions
Remoteness
Healthcare quality
Medical services availability
Asthma
 (x2 ) Psychosis
 Homicides, crime
 Injuries
 Stress in work
“Urban Poors”
(accessibility # affordability)
2014 Update of the US Rural-Urban Chart Book.

6. Objectives
To study the effect of rural vs. urban place in SLE patients with regards to:
disease occurrence (relative risk)
diagnosis delay
clinical manifestations, severity and non-reversible organ damage
comorbidities and hospitalization rates.

7. Methodology Cross-sectional study Data from Cretan Lupus Registry
medical records&enrollment questionnaires ( )
SLE patients (n=401)
ACR-1997 or SLICC-2012 classification criteria or rheumatologist
≥ 15 years old & complete residential history
Urban-Rural cut off: 10,000 inhabitants
Data for Crete population % R vs. 39 % U
ELSTAT (2011, National Census)

8. Statistical Analysis Tests used Sample size Calculation
At least n=196 pts
80% power for detecting a significant difference (a=0.05) of 60% vs. 40% of initial hypothesis
Students t- test or Mann-Whitney test (continuous variables)
Chi-Square or Fisher exact test (categorical variables)
P-value=0.05 or Bonferoni -adjusted in multiple comparisons
Bivariate Logistic Regression analysis

9. Main variable of interest (“exposure”)
Variables
Main variable of interest (“exposure”)
Outcomes
manifestations (ACR-1997 defined)
diagnosis delay (<1 y >2y)
severity (BILAG & therapy based)
damage (SDI=0, SDI>1).
comorbidities prevalence
Hospitalization (n)
Prevention measures
exclusively urban vs.
exclusively rural vs.
Mixed (both urban-rural)
Confounders for regression models
age
gender
ACR criteria number
disease duration
age at diagnosis

10. 460 questionnaires’ data sets
Results
Place of Residency of SLE Patients: Double Risk in those lived in cities
The relative risk of developing SLE in an urban versus a rural region was estimated to be 2.08 (95% Confidence Interval , p<0.001).
460 questionnaires’ data sets ↓
-50 (incomplete lupus)
-9 (incomplete data)
401 SLE patients:
43,1% exclusively urban
32,4% exclusively rural
24.4% mixed
(68.7% moved from R to U)

11. Geographical SLE mapping in Crete

12. Demographics
Lower educational, employment and higher female-to-male ratio in SLE patients of rural areas
>12 yrs education
9.2% vs 39.9% (p<0.001)
In paid work
25.4% vs. 48.6% (p<0.001)

13. Risk Factors
Pesticides use and obesity prevalence higher in rural while smoking percentage higher among urban dwellers.
Pesticides, ever use
36.5% in R vs. 10 % in U, p<0.001)
28,3% in SLE pts grown up in a village vs. pts spent their childhood in a town (13%, p=0.01)
Obesity (BMI>30)
39.4% (R) vs. 28.5% (U), p=0.049)
p=0.07

14. Diagnosis
Lower age of diagnosis in urban lupus patients and those grown at cities without significant differences in diagnosis delay as compared with rural dwellers.
Age at diagnosis (years, mean± SD)
Urban
Rural
P-value
38.3 ± 13.1
45.0 ± 15.3
p=0.024
Urban Upbringing
Rural
Upbringing
P-value
38.09 ± 14.2
46,37 ± 12,19
p=0.024
Delay from symptom onset to diagnosis
> 2 years (% of patients )
Urban
Rural
P-value
39.1%
49.4.%
p=0.5

15. Clinical Characteristics
25.8% in rural vs 16.4% in urban environment
(p<0.046)
presented with a “pattern” that included mucocutaneus ((malar rash, ulcers) and musculoskeletal features (arthritis)
No statistical significant differences on:
ACR-1997 clinical criteria
Nephritis
Neurophsychiatric Lupus
self-reported symptoms
Photosensitivity (as defined in ACR classification criteria) by urban/rural place of residency (p=0.03)

16. Immunologic Characteristics
Immunologic Feature
Rural
Urban
p-value
Anti-nuclear antibodies (ANA) (>1/160 titre)
93.6%
84.2%
0.03
Anti-dsDNA, anti-Sm, anti-phopholipid antibodies
32.2%
39.2%
0.5
Anti-phopholipid antibodies
14%
20.5%
0.04

17. 38.5% in rural vs. 37.6% in urban (p=0.003)
Preventive measures
Measure*
Rural
Urban
p=0.001
Pap-smear test
52.3%
48.0%
Mammography
46.9%
41.65
p=0.007
Colonoscopy
13.1%
11.6
p=0.7
Immunization against influenza
39.2%
24.9%
p=0.009
Immunization against pneumoniococcus
32.3%
23.7%
p=0.014
*As indicated by age-gender
Hospitalizations
38.5% in rural vs. 37.6% in urban (p=0.003)

18. Comorbidities* Higher in Urban SLE patients
Higher in Rural SLE patients
# allergic rhinitis: 13.9 vs 4.6, p=0.027 # rubella 15.6% vs. 6.9%, p=0.033 # chicken-pox 25.4% vs 12.3%, p=0.02).
#Thyroid disease 44.6% vs. 37.0, p=0.015 #Menopause 46.9% vs. 26.0%, p<0.001 #Hypertension, diabetes and dyslipidemia, heart disease, osteoporosis and cancer (NS)
*Mean age at enrollment (±SD ) 45±13.1, vs ± 13.9, p=0.07

19. The effect of place of residence on severity
Rural
Mixed
Urban
Total
Mild
40.8%
45.9%
52.9%
47.2%
Moderate/
Severe
59.2%
54.1%
47.1%
52.8% Β
p-value OR
95% C.I.
Urban Residence
-.691
.021
.501
Adjusted with total number of ACR-1997 classification criteria, gender,
age at diagnosis, disease duration,

20. Key messages URBAN LIVING RURAL LIVING
Possible Double Risk of Developing SLE
Younger age of onset
6.5:1 female-to-male ratio
Higher antiphospholipid Abs
Increased percentage of childhood infections
Lower immunizations and other preventive measures
Later onset by 6,5 years in those lived in a village and 8 years in those grown up in a village than a city
Higher photosensitivity
Higher Severity
Lower SES
Higher pesticide use, obesity, thyroid disease, chronic diseases
Higher rates of hospitalizations

21. Discussion Implication& Strengths Limitations & further suggestions
First Study to update the effect of place on SLE
Confirms that SLE is more frequent in urban areas 1,2,3
Confirms no significant differences in delay or long term damage 7
Results imply that there are two phenotypes of SLE with different clinical patterns, age diagnosis, possible risk factor burden, immunological disturbances and severity.
Strengths: monoethnic & genetically homogenous environment with low rates of translocations
No detailed history on exposures
No activity (flares) comparison 4 6
Use of more sophisticated rurality/urbanicity indexes would be an advantage
1,Alamanos et. al, 2003;
2 Siegel M. , Arthritis Rheum. 1970
3 Barnabe et al 2012
4 Pons-Estel G. et al 2012
5Pons-Estel G. et al 2015
6Abdul-Sattar AB nt J Rheum Dis. 2014:
7 Stummvoll G et al. 2017 

22. Conclusion
MPH class
Communities at different urbanization levels differ in their health characteristics.
The components of the landscape remain largely uncharacterized.
The results of our study suggest an important effect of the living environment on SLE risk and phenotype, which warrants further investigation.
“We shall not cease from exploration and the end of all our exploring will be to arrive where we started and know the place for the first time”
T. S. Eliot
Thank you!