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BACKGROUNDPrimary Sjögren's syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20+ B cells. Combined, these 2 mechanisms may achieve synergistic effects.METHODSThis 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab.RESULTSOverall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20+ B cells and a greater and more sustained depletion of peripheral CD19+ B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren's syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo.CONCLUSIONThe safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes.TRIAL REGISTRATIONClinicalTrials.gov NCT02631538.FUNDINGFunding was provided by GSK.

ObjectiveThis population-based study aimed to determine timing and incidence of arterial and venous thromboembolic events (TE) and antiphospholipid syndrome (APS) relative to systemic lupus erythematosus (SLE) onset and assess relationships between TE, APS and anti-phospholipid antibodies (aPL) during follow-up.MethodsWe included all medical-record confirmed new-onset SLE patients in Southeast Norway (population 2.9 million) 2000–2017 who fulfilled the 2019 European Alliance of Rheumatology Associations/American College of Rheumatology classification criteria. APS was defined by the 2006 Sydney classification criteria, and aPL positivity was determined following international guidelines. Key outcomes were APS, TE and death. We estimated outcome-free survival using Kaplan-Meier methods.ResultsAmong 700 new-onset SLE patients followed for a mean of 8 years (SD 5.0), 13% (89/700) experienced a new TE. TE incidence peaked at 59 per 100 person-years (95% CI 38 to 87) in the first year of SLE among aPL positive patients diagnosed with APS, falling to 12 (95% CI 6.2 to 21) in the subsequent 4 years. In patients without APS, corresponding TE incidences were 2.6 (95% CI 1.4 to 4.3) and 0.9 (95% CI 0.5 to 1.4), respectively. The lowest TE incidence was in aPL-negative patients aged <50 years, with 1-year TE-free survival of 0.99 (95% CI 0.97 to 1.0). Beyond the first year, TE-free survival rates did not differ between SLE patients positive and negative for aPL. Standardised mortality rate in patients with and without APS was 4.7 (95% CI 1.8 to 10.7 and 1.7 (95% CI 1.2 to 2.3).ConclusionsThis population-level study reveals high risk of TE, particularly for aPL positive patients around the time of SLE diagnosis. The elevated TE risk requires attention and early preventive strategies in newly diagnosed SLE.

The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p < 1 × 10−4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 × 10−4) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 × 10−7). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.

ObjectivesTo compare the sensitivity of 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria against 1997 ACR criteria for systemic lupus erythematosus (SLE), for incident SLE cases in the presumably complete population-based Nor-SLE cohort from Southeast Norway (2.9 million inhabitants).MethodsAll cases International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coded as SLE during 2000–2017 were individually reviewed. Those with a confirmed SLE diagnosis by expert clinical assessment were included in the Nor-SLE cohort. Core clinical data were recorded, and the cases were classified according to 2019 EULAR/ACR and 1997 ACR criteria. Juvenile SLE was defined as <16 years at diagnosis and adult SLE was defined as ≥16 years at diagnosis.ResultsWe included 737 incident SLE cases (701 adults, 36 juveniles). At diagnosis, 2019 EULAR/ACR criteria were more sensitive than 1997 ACR criteria for adults (91.6% vs 77.3%; p<0.001), but not for juveniles (97.2% vs 88.9%). The 2019 EULAR/ACR counts at diagnosis differed by age group and ethnicity, being higher in young cases and those originating from Asia. From time of diagnosis to study end the fulfilment rate of 2019 EULAR/ACR criteria for the adult cohort increased from 92.5% and 86.5% to 94.6% and 91.0%, respectively, for females and males (mean disease duration of 7.5 years).ConclusionShowing 92% criteria fulfilment already at time of SLE diagnosis by 2019 EULAR/ACR criteria versus 77% by 1997 ACR criteria, the results from this population-based study suggest that the 2019 EULAR/ACR criteria will achieve its goal of capturing more early-SLE cases for clinical trials.

ObjectiveSome genome-wide significant SLE risk loci associate with SLE development only while other associate with other diseases, such as type 1 diabetes (T1DM) and rheumatoid arthritis (RA). Our objective: to investigate what clinical phenotype associate with high polygenic scores (PRSs) for SLE-specific and multitrait-associated SLE loci.MethodsPatients with SLE (ACR-97 or SLICC-12, n=1498) and healthy controls (n=1947) were genotyped using Illumina’s Global Screening Array. SLE-associated single nucleotide variants (SNVs) (European ancestry) at GWAS significance (p<5×10–8) were identified through the GWAS catalog. After filtering 112 SNVs were identified. SNVs were considered multitrait if associated with ≥1 additional disease. Two PRSs were constructed; one including SLE specific SNVs (n=79) and one including multitrait SNVs (n=33). Groups were compared using logistic regression, adjusting for age and sex. 50% of patients with the highest SLE-specific PRS were selected and from them the 50% with the lowest multitrait PRS were selected. This group (highSLE-lowMultitrait, 25% of total) was then compared with the other patients (75% of total). The same method was used for the highMultitrait-lowSLE group.ResultsBoth PRSs were higher in patients in comparison with healthy controls, p<2×10–6. Besides SLE, the most common diseases associated with the multitrait SNVs were RA (SNV=10), T1DM (SNV=8), multiple sclerosis and ulcerative colitis (SNV=6).The highSLE-lowMultitrait group had higher prevalence of malar rash (OR 1.28(1.00–1.66), p=0.04), neurologic manifestations (OR 1.44(1.10–2.08), p=0.048), thrombocytopenia (OR 1.47(1.06–2.04), p=0.022), anti-Sm antibodies (OR 1.80(1.12–2.80), p=0.009), low complement (OR 1.70(1.25–2.30), p <0.001) and lower prevalence of hemolytic anemia (OR 0.55(0.32–0.97), p=0.038) compared with the other group.The highMultitrait-lowSLE group had higher prevalence of anti-SSA (OR 1.49 (1.14–1.94), p= 0.003) and anti-SSB antibodies (OR 1.79 (1.34–2.39), p <0.001) and lower prevalence of discoid rash (OR 0.72(0.52–1.0), p=0.038) compared with the other group.ConclusionsComparative analysis of multitrait and SLE-specific SNVs shed light on SLE heterogeneity. Leveraging data for shared genetic associations can be important for determining the genetic background influencing SLE subphenotypes, but also common disease manifestations among autoimmune diseases.AcknowledgementsSupported by the Swedish Society for Medical Research (S20–0127), the Swedish Rheumatism Association, King Gustaf V’s 80-Year Foundation, the Gustafsson Foundation.

ObjectiveTo estimate occurrence of thromboembolic event in a population-based setting and compare characteristics of new-onset Systemic Lupus Erythematosus (SLE) with and without Antiphospholipid Syndrome (APS).MethodsWe included all new-onset SLE cases residing in the Southeast Norway area 1999–2017. Follow-up ended 31 December 2017.All cases had diagnosis confirmed by chart-review, fulfilled the 2019 EULAR/ACR classification criteria and were captured within one year of diagnosis.All APS fulfilled the 2006 Sapporo classification criteria. Arterial thromboembolic events included ischemic stroke, transient ischemic attack, myocardial infarction or angina pectoris identified either by individual-level chart-review or by ICD-code (G45–46, I63 excluding I63.6, I20-I25, R96) in The National Cause of Death Register. Venous thromboembolic events included syndromes caused by occlusion of major venous vessel identified by chart-review. We estimated incidence rates per 100 person-years at risk and 95% confidence intervals (CI) using Poisson distribution.ResultsOf the 749 cases with new-onset SLE 1999–2017, 84 (11%) had coexisting APS. APS cases were more prone to develop thrombocytopenia, neuropsychiatric disease and anti-dsDNA positivity during the disease course than cases without APS (table 1).By the end of follow-up, 174 (23%) cases had ever experienced at least one arterial or venous event (TE). APS cases were younger at their first TE than those without APS (mean age 37 versus 59, p-value<0.001). TE tended to coincide with SLE diagnosis in APS cases (figure 1).In the 675 cases without previous TE at SLE diagnosis, 38 and 69 TE occurred within one year and five years disease duration. Overall 5-year incidence rate for TE was 2.6 (95% CI 2.0–3.3). APS cases exhibited a high incidence of TE the first year after SLE diagnosis (51.1, 95% 33.4–74.8), that decreased to 8.6 (95% CI 4.7–14.7) one to five year after SLE diagnosis. Cases without APS had a considerable lower first-year incidence of TE (2.3, 95% CI 1.4–3.8) and the decline were not as pronounce (1–5-year incidence 0.8, 95% CI .0.5–1.2).ConclusionsThe risk of APS-related thromboembolic events are high around the time of SLE diagnosis. Awareness of thromboembolic events around the time of SLE diagnosis appear crucial, especially in cases with antiphospholipid antibodies.AcknowledgementsThis work was supported by the The Norwegian Women’s Public Health Association, The DAM Foundation, Vivi Irene Hansens Foundation, Ragna and Egil Eiken`s Foundation and the Norwegian Rheumatism Association.Abstract O35 Figure 1Timing of thromboembolic events in new-onset Systemic Lupus Erythematosus with and without Antiphospholipid SyndromeAbstract O35 Table 1Demographic, cumulative clinical features, medication use and outcome parameters in in new-onset Systemic Lupus Erythematosus with and without Antiphospholipid Syndrome Antiphospholipid Syndromea p-value No Yes Number of cases 665 84 Baseline demographics Age at SLE diagnosis, years µ (SD) 40 (17) 37 (15) 0.116 Female, n (%) 555 (85) 67 (80) 0.216 Of European ancestry, n (%) 549 (83) 74 (88) 0.201 Juvenile-onsetb, n (%) 35 (5) 4 (5) 1.0 Smoking (ever), n (%) 43 (51) 250 (38) 0.016 Cumulative clinical features EA criteriac, score at study end, µ (SD) 22 (8) 25 (8) 0.004 Malar erythema, n (%) 254 (38) 32 (38) 0.931 Oral ulcers, n (%) 189 (28) 27 (32) 0.460 Photo sensibility, n (%) 375 (56) 50 (60) 0.822 Non-erosive arthritis, n (%) 361 (54) 50 (60) 0.365 Hemolytic anemia, n (%) 60 (9) 13 (15) 0.067 Thrombocytopenia, n (%) 132 (20) 28 (33) 0.004 Leukopenia, n (%) 281 (42) 31 (37) 0.484 Serositis, n (%) 170 (26) 22 (26) 0.901 Lupus nephritisd, n (%) 209 (31) 31 (37) 0.311 Neuropsychiatric diseasee, n (%) 21 (3) 8 (10) 0.004 Antibody profile (ever) Anti-double-stranded DNA ab, n (%) 476 (72) 71 (85) 0.012 Anti-Smith ab, n (%) 133 (20) 15 (18) 0.210 Anti-SSA and/or SSB ab, n (%) 335 (50) 40 (48) 0.634 Low C3 and/or C4, n (%) 337 (51) 51 (61) 0.083 Anti-cardiolipin ab, n (%) 148 (22) 51 (81) <0.001 Lupus anticoagulant ab, n (%) 125 (19) 73 (87) <0.001 Anti-beta-2-glycoprotein ab, n (%) 87 (13) 33 (39) <0.001 Two or more antiphospholipid ab, n (%) 98 (15) 49 (58) <0.001 Triple positive antiphospholipid ab, n (%) 636 (5) 24 (29) <0.001 Missing antiphospholipid status, n (%) 51 (8) 0 na Medication use (ever)f Hydroxychloroquine, n (%) 591 (89) 77 (92) 0.502 Methotrexate, n (%) 148 (22) 13 (15) 0.142 Azathioprine, n (%) 233 (35) 35 (42) 0.248 Mycophenolate mofetil, n (%) 159 (24) 20 (24) 0.983 Cyclophosphamide, n (%) 106 (16) 16 (19) 0.498 Outcome parameters Follow-up yearsg, µ (SD) 8 (5) 10 (6) 0.010 Arterial or venous thromboembolic event (ever), n (%) 101 (15) 73 (87) <0.001 Arterial thromboembolic event (ever), n (%) 72 (11) 28 (33) <0.001 Venous thromboembolic event (ever), n (%) 37 (6) 54 (64) <0.001 aDefined by 2006 Sapporo classification criteria, bSLE diagnosis before age 16 years, cThe 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus, dLupus nephritis defined cThe 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus, eNeuropsychiatric disease defined by The 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus, tUse of medication six months or more, gFrom inception at SLE diagnosis to last follow-up n: number; µ: mean, SD: Standard Deviation, ab: antibody, na: not applicable

ObjectiveGenetic contribution is crucial for SLE pathogenesis, but linking risk variants to specific mechanisms in SLE is challenging. We utilize UK Biobank data and a large well defined SLE cohort to investigate associations between SLE risk loci, blood biomarkers and clinical phenotype. Our objective: to study potential combinatorial effects of multiple biomarker associated SLE SNVs in clinical SLE data.MethodsWe extracted SLE associated SNVs from published European ancestry GWAS data (with p<5×10–8) and selected 112 SNVs. Associations (p<5×10–8) between these SNVs and blood biomarkers in the UK Biobank were investigated and a 17 SNV cluster associated with 38 biomarkers was identified. Patients with SLE (ACR-97 or SLICC-12, European decent, n=1498) were genotyped using Illumina’s Global Screening Array and clinical data was collected. A weighted polygenic risk score (PRS) including the 17 SNVs identified in the cluster analysis was calculated for each patient and clinical manifestations (ACR-97 criteria, antibodies) of patients with a high (50%) and low (50%) PRS were compared by logistic regression with age and sex covariates. ResultsWe identified a cluster of 17 SLE risk SNVs associated with multiple blood biomarkers in the general population. The biomarkers associated with the highest number of these SNVs include eosinophil percentage (SNV=16), aspartate aminotransferase (SNV=12), apolipoprotein A (SNV=12) and cystatin C (SNV=11). Patients with high PRS had higher total ACR -97 SLE criteria score (OR 1.35 (1.06–1.69), p=0.014) and higher prevalence of anti-SSA (OR 2.71 (2.16–3.40), p<0.001) and anti-SSB antibodies OR 4.58 (3.39–6.61) p<0.001) compared with other patients. Further, high PRS was associated with lower prevalence of thrombocytopenia (OR 0.63 (0.48–0.84), p=0.001) and anti-Sm antibodies (OR 0.59 (0.39–0.89), p=0.011).ConclusionsWe identified a cluster of SLE risk variants associated with multiple blood biomarkers in the UK Biobank. A PRS including these loci associate with an unspecific SLE phenotype including increased number of classification criteria and presence of SSA/SSB antibodies. Further studies are needed to clarify the role of these potential pleiotropic SLE risk loci in lupus pathogenesis.AcknowledgementsSupported by the Swedish Society for Medical Research(S20–0127), the Swedish Rheumatism Association, King Gustaf V’s 80-Year Foundation, the Gustafsson Foundation.

ObjectiveB cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile.MethodsFemale patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina’s Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases.ResultsDouble-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 −/− (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/− or −/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048).ConclusionsHigh genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.

ObjectivesSystemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE.MethodsWe undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS).ResultsWe identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes.ConclusionsOur results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.

ObjectiveTo investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations.MethodsPatients with SLE (ndiscovery cohort=776, nreplication cohort=836) were genotyped using the 200K Immunochip single nucleotide polymorphisms (SNP) Array (Illumina) and a custom array. Sixty SNPs with SLE association (p<5.0×10−8) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in in vitro stimulated peripheral blood mononuclear cells from healthy controls (n=45).ResultsIn the discovery cohort, smoking was associated with myocardial infarction (MI) (OR 1.96 (95% CI 1.09 to 3.55)), with a greater effect in patients carrying any rs11889341 STAT4 risk allele (OR 2.72 (95% CI 1.24 to 6.00)) or two risk alleles (OR 8.27 (95% CI 1.48 to 46.27)).Smokers carrying the risk allele also displayed an increased risk of nephritis (OR 1.47 (95% CI 1.06 to 2.03)). In the replication cohort, the high risk of MI in smokers carrying the risk allele and the association between the STAT4 risk allele and nephritis in smokers were confirmed (OR 6.19 (95% CI 1.29 to 29.79) and 1.84 (95% CI 1.05 to 3.29), respectively).The interaction between smoking and the STAT4 risk allele resulted in further increase in the risk of MI (OR 2.14 (95% CI 1.01 to 4.62)) and nephritis (OR 1.53 (95% CI 1.08 to 2.17)), with 54% (MI) and 34% (nephritis) of the risk attributable to the interaction. Levels of interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells were higher in smokers than in non-smokers (mean geometric fluorescence intensity 1063 vs 565, p=0.0063).Lastly, the IL12A rs564799 risk allele displayed association with MI in both cohorts (OR 1.53 (95% CI 1.01 to 2.31) and 2.15 (95% CI 1.08 to 4.26), respectively).ConclusionsSmoking in the presence of the STAT4 risk gene variant appears to increase the risk of MI and nephritis in SLE. Our results also highlight the role of the IL12−STAT4 pathway in SLE-cardiovascular morbidity.