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Background Lupus nephritis (LN) is one of the most common and severe manifestations of systemic lupus erythematosus (SLE). We tested the association of SLE-risk loci with LN risk in childhood- (cSLE) and adult-onset SLE (aSLE). Methods Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed Results Of 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk (OR=1.26; 95% CI: 1.09, 1.46, p=0.0006) as was increasing HLA GRS in Europeans (OR=1.55; 95% CI: 1.07, 2.25; p=0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. Conclusions We observed an association between known SLE-risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future directions will include incorporating SLE-risk SNPs specific to non-European ancestral groups and validating findings in an independent cohort. Funding Source(s): Dr. Hiraki: Canadian Institute of Health Research (CIHR) Project Scheme grant

Background The diagnosis of Systemic Autoimmune Rheumatic Diseases (SARD), including Systemic Lupus Erythematosus (SLE), relies on the presence of ANAs, many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals most of whom will not develop SARD. A number of cellular immune changes are seen in SARD, and thus could constitute potential biomarkers/treatment targets for SARD, however it is not known at what point in disease progression these develop. Methods Healthy ANA- controls (n=32) and ANA+ (≥1:160 by immunofluorescence) participants with no (asymptomatic ANA+, n=61), at least one (UCTD, n=35), or meeting SARD classification criteria (n=59) were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry. Results Consistent with previous reports, SARD patients had increased proportions of activated B cells (CD86+ or CD95+) and in the SLE patient subset there were increased proportions of plasma cells/plasmablasts, as compared to ANA- controls. SARD patients also had reduced proportions of iNKT and IFN-γ producing cells, as well as, increased proportions of memory Tfh (CD4+CXCR5hiPD1hi) and T regulatory (Treg, CD4+FOXP3+HELIOS+) cells, especially in the SLE and Sjogren’s Disease patient subsets. In asymptomatic ANA+ individuals and UCTD patients, similar increases in the proportion of activated B cells, Tfh, and Treg cells, and decreases in the proportion of iNKT and IFN-γ producing cells were seen to those in SARD. In asymptomatic ANA+ individuals and SARD patients, the extent of serologic changes (number of specific ANAs detected by Bioplex® 2200 ANA screening system) positively correlated with activation in the switched memory B cell compartment and the proportion of Tfh cells, with the later being an independent predictor of serologic status in a multivariate analysis. However, significantly elevated levels of Tfh cells could still be seen in asymptomatic ANA+ individuals who lacked specific ANAs. Consistent with a role for Tfh cell in ANA production there was a strong correlation between the proportion of Tfh and plasma cells in asymptomatic ANA+ individuals. In preliminary studies, the majority of Tfh cells in asymptomatic ANA+ and UCTD patients were Tfh2 cells, with a trend to increased proportions of Tfh2 cells and decreased proportions Tfh17 cells as compared to active SLE patients. Conclusions Tfh cells appear to play an important role in the development of a positive ANA and in the epitope spreading that may accompany disease progression, and therefore constitute a promising target for treatment of early disease.

Background Cognitive impairment (CI) is a common neurobehavioural manifestation of systemic lupus erythematosus (SLE). In our recent systematic review, the prevalence of CI was 38% (95% CI 33% to 43%) with a wide variation (15%–79%), which may be due to differences in CI definitions and selection of neuropsychological tests across studies. We aim to report the prevalence of CI in a large cohort using a comprehensive battery (CB) of tests in which we operationalized the classification of CI. Methods Consecutive consenting SLE patients, aged 18–65 years, who attended a single center (Jul 2016-Feb 2018) were recruited. Patients were administered a CB that evaluates the major cognitive domains: Manual motor speed and dexterity, simple attention and processing speed, visual-spatial construction, verbal fluency, learning and memory (visuospatial and memory), executive functioning (untimed and timed). Patient scores were compared to a normative sample of age- and gender-matched healthy controls to obtain z-scores. CI was operationalized on the CB as a z-score of ≤−1.5 (as compared to controls) on ≥2 domains or z≤−2.0 on ≥1 domain. Descriptive statistics were used. Results Of the 199 patients (89% female), the mean age at SLE diagnosis was 28.3±10.4 and disease duration at enrolment was 14.3±10.2 years. The prevalence of CI was 37.7% (z≤−1.5 in ≥2 domains) and 49.8% (z≤−2.0 in ≥1 domains). Prevalence of patients with domain z-scores of ≤−1.5 and ≤−2.0 varied from 3.0%–46.2% and 0.5%–25.1% respectively (figure 1). The most affected domain was learning and memory (visuospatial and memory) in 92 (46.2%) patients based on z≤−1.5 on ≥2 subtests and 50 (25.1%) patients based on z≤−2.0 in ≥1 subtest. Conclusion Prevalence of CI using our CB ranged between 37.7%–49.8% (z≤−1.5 in≥2 domains and z≤−2.0 in≥1 domains respectively), which was higher than the pooled prevalence from previous reports of 38%. These differences in CI prevalence across studies could be attributed to different factors including the heterogeneity in patients’ demographics/comorbidities, sample size, the use of different metrics to determine CI, and the lack of a standardized definition of CI. Further studies are required to identify the best definition for CI and its metrics. Acknowledgment This project is funded by the Arthritis Society and the Physicians’ Services Incorporated Foundation.