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A variety of neuropsychiatric findings may complicate systemic lupus erythematosus (SLE) and pose diagnostic and therapeutic dilemmas. We describe the clinical and radiographic features of posterior reversible encephalopathy syndrome (PRES) and distinguish PRES from other conditions seen in SLE. Patient charts and magnetic resonance imaging (MRI) findings of four patients with SLE on immunosuppressive therapy with acute or subacute neurologic changes initially suggesting cerebritis or stroke were reviewed. The English language literature was reviewed using the Medline databases from 1996—2006 for other reports of PRES with SLE. Literature review yielded 26 other SLE cases reported with PRES. SLE patients with PRES were more commonly on immunosuppressive drugs, had episodes of relative hypertension, and had renal involvement. Characteristic findings are seen on MRI, which differentiate PRES from other CNS complications of SLE. Clinical and radiographic resolution of abnormalities within 1—4 weeks is typically seen. PRES has been increasingly recognized. Reversible changes are found on brain MRI accompanied by sometimes dramatic signs and symptoms. The therapeutic implications for separating PRES from stroke or cerebritis are important. We propose that PRES should be considered in the differential diagnosis in SLE patients with new-onset neurologic signs and symptoms. Lupus (2007) 16, 436—443.

BackgroundOmega-3 fatty acids play a critical role in regulating inflammation. Patients with SLE have been reported to be deficient in omega-3 fatty acids, and deficiency could play a role in the ongoing inflammation characteristic of this disease. Previous work has produced conflicting results regarding the capacity of Omega-3 supplementation to control SLE disease activity.ObjectivesThe goals of this study were to determine the level of omega-3 deficiency in SLE patients and to determine whether supplementation with a concentrated extract of krill oil rich in omega-3 fatty acids (AKBM-3031) could overcome the deficiency in SLE patients and decrease disease activity.MethodsThis was a randomized double blind controlled multicenter study of patients with active SLE (SLEDAI >/= 6). Patients meeting entry criteria were randomized to receive AKBM-3031 (4 grams/day) or identical placebo capsules containing mixed oils simulating that in a western diet (NCT03626311). Patients received investigational product or placebo daily for 24 weeks, at which time placebo patients could opt to receive AKBM-3031 for the subsequent 24 weeks, whereas those receiving AKBM-3031 continued on the medication. The primary outcome was the correction of the red blood cell omega-3 index determined by OmegaQuant. Changes in clinical features and adverse events were collected throughout the trial.Results79 subjects were enrolled in the study; 97% of the patients were women and 56% were of European and 35% of African Ancestry. At baseline, the mean omega-3 index was 4.65+/- 1.09, below the lower limits of normal for the North American population (6.0). After 4 weeks of treatment with AKBM-3031, the Omega-3 index significantly increased from 4.65+/- 1.09 to 7.21+/-1.37, (p < 0.0001), whereas no significant change was noted in the patients receiving placebo. Increases in the Omega-3 index in AKBM-3031 treated patients persisted throughout the 48 weeks of the trial. Notably, when patients were changed from placebo to AKBM-3031 at 24 weeks, there was a rapid increase in the Omega-3 index (4.62+/-1.39 to 6.58+/- 1.85, p=0.0001). The total number of adverse events was less in the AKMB-3031group (186) than in the placebo group (342), most were mild or moderate and no serious adverse events were noted. Although there were no significant changes in disease activity when the entire groups were examined, there was a significant decrease in disease activity measured by SLEDAI-2K at 4, 8 and 16 weeks (p=0.0007, 0.04, 0.02, respectively) in the patients receiving AKBM-3031with high disease activity at baseline (SLEDAI >/=9).ConclusionTreatment of SLE patients with AKBM-3031 rapidly corrects the Omega-3 deficiency characteristic of these patients. AKBM-3031 was safe and decreased disease activity in those with more active SLE. These results suggest benefit of Omega-3 deficiency correction with AKBM-3031 in SLE patients with active disease and warrant a more extensive evaluation.Figure 1.Acknowledgements:This work was support by Aker BiomarineDisclosure of InterestsNone Declared.

Belimumab is approved for the treatment of systemic lupus erythematosus (SLE) in >75 countries [1]. Clinical trials and long-term extension (LTE) studies have demonstrated the consistent safety profile of belimumab in patients with SLE receiving standard therapy (ST) [2-4]. A pooled analysis of LTE studies could provide a more robust dataset to explore the long-term safety of belimumab. To evaluate the long-term safety of belimumab in adult patients with SLE using pooled data from three multicentre, LTE studies. This post hoc analysis pooled data from three belimumab LTE studies: LBSL02 LTE (Phase 2; GSK Study 112626) [2], BLISS-76 LTE (including US patients only; Phase 3; GSK Study 112233) [3], and BLISS-52 + BLISS-76 LTE (excluding US patients from BLISS-76; Phase 3; GSK Study 112234) [4]. Patients were eligible for LTE studies if they completed treatment through Week 72 (LBSL02 and BLISS-76 trials), or Week 48 (BLISS-52 trial). LBSL02 LTE also required an improvement in physician global assessment at Week 72 or 68 versus at first belimumab dose. From the start of each LTE, all enrolled patients received open-label belimumab 10 mg/kg intravenously every 28 days plus ST, regardless of study drug allocation in prior trials. Adverse events (AEs) were assessed at each infusion visit and summarised (based on observed data) any time post baseline (first belimumab dose in prior trial or LTE), and in each year. In total, 1304 patients were enrolled into the three LTE studies and 1299 (99.6%) received ≥1 dose of study drug (pooled safety population). Cumulative belimumab treated patient-years was 7040.1. Overall, 604 (46.5%) patients completed their respective studies. The main reasons for withdrawal included ‘withdrawal by patient’ (18.3%) and ‘AE’ (10.6%). In the pooled safety population, 1054 (81.1%) and 618 (47.6%) patients received steroids and immunosuppressants at baseline, respectively. Over 11+ years, 1267 (97.5%) patients had ≥1 AE (incidence generally decreased yearly; Table 1), while 525 (40.4%) had ≥1 serious AE (SAE) and 139 (10.7%) experienced ≥1 AE resulting in study drug discontinuation (incidence of each was stable over time). By system organ class, infections and infestations were the most frequent AE, SAE, and AE resulting in study drug discontinuation. The most common AE of special interest was post-infusion systemic reactions (9.7 events per 100 patient-years). There were 21 (1.6%) deaths in total, 3 (0.2%) were considered possibly related to study drug (cardiogenic shock, lung infection pseudomonal, and pneumonia cytomegaloviral [all n=1]). Among a large, pooled population of patients with SLE treated with belimumab plus ST for over 11+ years, the incidence of AEs generally decreased or remained stable over time. No new safety concerns were observed. This analysis was limited by use of a self-selected population that had not withdrawn from prior trials, and the open-label nature of the study. [1]Levy RA et al. Lupus 2021;11:1705–21 [2]Wallace DJ et el. Arthritis Rheumatol 2019;7:1125–34 [3]Furie RA et al. Arthritis Rheumatol 2018;6:868–77 [4]van Vollenhoven RF et al. Rheumatol 2020;2:281–91 Study funded by GSK (GSK Studies 112626, 112233 and 112234). Medical writing support was provided by Robert Bloxham, PhD, Fishawack Indicia Ltd, UK, part of Fishawack Health, and was funded by GSK. Aneela Mian Shareholder of: GSK, Employee of: GSK, Paula Curtis Shareholder of: GSK, Employee of: GSK, christine henning Shareholder of: GSK, Employee of: GSK, MUNTHER KHAMASHTA Shareholder of: GSK, Employee of: GSK, Ricard Cervera Speakers bureau: GSK, Consultant of: GSK, Grant/research support from: GSK, Daniel J. Wallace Speakers bureau: GSK, Consultant of: GSK, Grant/research support from: GSK, Maria Tektonidou: None declared, Tatsuya Atsumi Speakers bureau: GSK, Consultant of: GSK, Grant/research support from: GSK. Table 1Incidence of treatment-emergent AEs over time* (pooled safety population, N=1299)n (%)Any time post baseline†(N=1299)Year 0–1 (N=1299)Year 2–3 (N=1140)Year 4–5 (N=867)Year 6–7 (N=541)Year 8–9 (N=175)Year 10–11 (N=131)Year 11+ (N=88)AEs1267 (97.5)1168 (89.9)907 (79.6)631 (72.8)361 (66.7)160 (91.4)105 (80.2)45 (51.1)Serious AEs525 (40.4)152 (11.7)141 (12.4)91 (10.5)59 (10.9)28 (16.0)14 (10.7)7 (8.0)AEs resulting in study drug discontinuation139 (10.7)18 (1.4)30 (2.6)12 (1.4)8 (1.5)3 (1.7)2 (1.5)0 (0.0)Deaths21 (1.6)3 (0.2)3 (0.3)2 (0.2)2 (0.4)0 (0.0)0 (0.0)0 (0.0)*AEs occurred on or after first belimumab dose (in prior trial or LTE); post hoc data shown for every other year†Post-baseline data include follow-up visits. Data from Year 0 up to last visit in the treatment period are shown by years of study participation. Note: patients may be counted in ≥1 year interval

Belimumab (BEL), a monoclonal antibody that antagonizes B-lymphocyte stimulator, was first approved in 2011 for active, autoantibody-positive systemic lupus erythematosus (SLE). BEL has been studied for over 10 years; and while safety data from individual trials have been informative, a large integrated safety analysis has not yet been conducted. Perform pooled analyses to evaluate the safety of BEL in adult patients with SLE. Aggregate analyses were performed using safety data for patients ≥18 years of age pooled from six randomised, placebo (PBO)-controlled BEL clinical trials (GSK studies: LBSL02, 110752, 110751, 112341, 113750, and 115471). Patients from GSK studies LBSL02, 110752, and 110751 received intravenous (IV) BEL 1, 4 (LBSL02 only), or 10 mg/kg, or PBO on Days 1, 14, 28, and every 28 days thereafter. Patients from GSK studies 113750 and 115471 received IV BEL 10 mg/kg or PBO on Days 1, 14, 28, and every 28 days thereafter. Patients from GSK study 112341 received subcutaneous (SC) BEL 200 mg, or PBO weekly. Safety analyses included the incidence of adverse events (AEs), serious AEs (SAEs), severe AEs, AEs of special interest (AESI), and mortality of BEL (all doses and formulations combined) vs PBO at Week 52. The pooled analysis included 4170 patients. Overall, 81.0% (n=2280/2815) of patients receiving BEL and 76.6% (n=1038/1355) of patients receiving PBO completed their respectively enrolled study; the most common reason for withdrawal was occurrence of an AE in both groups. The majority of patients were female (BEL: 94.5%; PBO: 93.6%), the mean age in both groups was 38 years, and baseline characteristics (race, SLE duration, disease activity, SLE damage, complement levels, anti-dsDNA binding, SLE medication usage) were similar between treatments. The incidence of patients experiencing ≥1 AE, ≥1 SAE, and mortality was similar across treatments (Table 1); the most commonly reported SAEs in both groups were infections and infestations (BEL: 5.4% [n=151/2815]; PBO: 5.9% [n=80/1355]). The mean duration of treatment exposure was similar between groups (BEL: 334.1 days; PBO: 325.3 days). A greater proportion of patients experienced AESI with BEL vs PBO for post-infusion/injection systemic reactions (from IV or SC administration) and depression/suicide/self-injury (Table 1). The proportion of patients experiencing an AESI of infections and malignancies was similar between groups. Consistent with individual studies, BEL demonstrated a similar safety profile to PBO in this large integrated safety analysis of six trials. These results support a positive benefit–risk profile of BEL in the treatment of adult SLE. GSK Medical writing assistance was provided by Helen Taylor, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK. Daniel J. Wallace Speakers bureau: GSK, Consultant of: GSK, Tatsuya Atsumi Speakers bureau: GSK, Consultant of: GSK, Grant/research support from: GSK, Mark Daniels Shareholder of: GSK, Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Paige Meizlik Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK, Andreas Schwarting Speakers bureau: Novartis, Roche, GSK, Pfizer, Amgen, Consultant of: GSK, Grant/research support from: AbbVie, Pfizer, Novartis, GSK, Actelion, Fengchun Zhang: None declared, David Roth Shareholder of: GSK, Employee of: GSK Table 1Pooled AE dataN (%)PBO (IV + SC)N=1355BEL (IV + SC)N=2815AE1184 (87.4)2440 (86.7)SAE230 (17.0)421 (15.0)Severe AE (severe or life threatening)209 (15.4)377 (13.4)AE resulting in study drug discontinuation109 (8.0)184 (6.5)Death6 (0.4)16 (0.6)AESIPost-infusion/injection systemic reactions*110 (8.1)286 (10.2)Serious2 (0.1)13 (0.5)All infections of special interest (OIs, HZ, TB, sepsis)97 (7.2)173 (6.1)Serious17 (1.3)40 (1.4)All OIs92 (6.8)157 (5.6)Active TB5 (0.4)4 (0.1)All HZ59 (4.4)106 (3.8)All sepsis10 (0.7)20 (0.7)Malignancies excluding NMSC2 (0.1)8 (0.3)Including NMSC3 (0.2)12 (0.4)Depression (inc. mood disorders and anxiety)/suicide/self-injury92 (6.8)210 (7.5)Serious5 (0.4)9 (0.3)*Occurring on or within 3 days of infusion/injection date.HZ, herpes zoster; NMSC, non-melanoma skin cancer; OIs, opportunistic infections; TB, tuberculosis

BackgroundDysregulated humoral immunity is a hallmark of primary Sjögren’s Syndrome (pSS). This dysregulation involves aberrant B-lymphocyte activity resulting in abnormally high immunoglobulin G (IgG) levels and the production of autoantibodies, particularly those reactive with Ro/La ribonuclear complexes. pSS can affect almost any organ system, and current evidence-based therapies only offer some symptom relief, but no licensed therapy has been shown to alter the disease course. Nipocalimab is a high-affinity, fully human monoclonal antibody that reduces circulating IgG levels by selectively blocking the interactions of IgG, including pSS autoantibodies, with the neonatal Fc receptor (FcRn). Nipocalimab has previously induced rapid, safe, and durable serum IgG reductions in healthy volunteers (NCT02828046)[1] and in autoantibody-driven generalized myasthenia gravis (gMG) in adults (Vivacity-MG; NCT03896295)[2], suggesting that nipocalimab may treat a broad range of autoimmune disorders associated with autoantibodies, immune complexes and B-lymphocyte hyperactivity, including pSS.ObjectivesHere, we describe the key data from Vivacity-MG that illustrate the therapeutic potential of nipocalimab in IgG autoantibody-driven conditions and review the design of a phase 2 study evaluating the efficacy and safety of nipocalimab in patients with pSS (NCT04968912).MethodsStudy feasibility assessments involved evaluating results from the phase 2 placebo-controlled trial Vivacity-MG. Of the 68 patients enrolled, 54 patients were randomized 1:1:1:1:1 to 4 treatment groups or a placebo group.ResultsIn Vivacity-MG, there were no discontinuations due to treatment-emergent adverse events (TEAEs), severe AEs, or related serious AEs with nipocalimab. The incidence of infections and headaches with nipocalimab were comparable to placebo (Table 1). Treatment with nipocalimab resulted in rapid and dose-dependent reductions in serum total IgG levels and anti-AChR IgG autoantibodies (Figure 1), as compared to placebo. The safety and pharmacodynamic data from Vivacity-MG support the hypothesis that nipocalimab has the potential to treat pSS through lowering pathogenic IgGs. As such, we developed a phase 2, multicenter, randomized, placebo-controlled, double-blind study enrolling adults with moderately-to-severely active pSS. The pSS study consists of a ≤6-week screening period, a 24-week double-blind treatment period, and a 6-week follow-up period. Participants are randomized 1:1:1 to treatment every 2 weeks with intravenous nipocalimab (low or high dose), or placebo, through Week 22. The primary efficacy endpoint is change from baseline in Clinical European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (clinESSDAI) score at Week 24. Safety assessments include TEAEs, abnormal vital signs, and laboratory parameters.ConclusionVivacity-MG demonstrated that nipocalimab has the potential to offer an important new and targeted treatment option for patients with IgG-mediated diseases. The ongoing phase 2 study evaluates the safety and efficacy of treatment with nipocalimab in patients with moderately-to-severely active pSS.References[1]Ling LE, et al. Clin Pharmacol Ther. 2019;105(4):1031-1039.[2]Ramchandren S, et al. MGFA 2022. Poster 90.Table 1.TEAE OverviewNipocalimab (n=54)Placebo (n=14)Patients with TEAE, n (%)44 (81.5)11 (78.6)Patients with grade ≥3 TEAE, n (%)04 (28.6)Most frequent TEAEs, n (%)Exacerbation of MG02 (14.3)Headache6 (11.1)1 (7.1)Nasopharyngitis6 (11.1)0Diarrhea6 (11.1)1 (7.1)Patients who discontinued due to TEAEs, n (%)02 (14.3)Patients with serious TEAE, n (%)1 (1.9)*2 (14.3)*Patients with TEAEs deemed related to study drug by investigator, n (%)21 (38.9)1 (7.1)MG, myasthenia gravis; TEAE, treatment-emergent adverse event.*Serious TEAE deemed unrelated to study drug.Acknowledgements:NIL.Disclosure of InterestsJonathan Hubbard Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Kim Campbell Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Kathy Sivils Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Robert Hoffman Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Kim Hung Lo Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Jocelyn H Leu Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Simon Bowman Consultant of: Abbvie, Astra Zeneca, Galapagos, and Novartis Pharmaceuticals, Sophia Liva Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Qing Zuraw Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Anne M. Stevens Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Leona Ling Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Keith Karcher Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Sindhu Ramchandren Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, Hong Sun Employee of: Janssen Research & Development, LLC and may own Johnson & Johnson stock or stock options, R Hal Scofield: None declared, Raphaèle Seror Consultant of: GlaxoSmithKline, Boehringer, Janssen and Novartis; Grant/research support from: GlaxoSmithKline and Amgen, Daniel J. Wallace Consultant of: Amgen, Eli Lilly and Company, EMD Merck Serono, and Pfizer.

Baricitinib (BARI), an oral, selective Janus kinase (JAK)1 and JAK2 inhibitor, improved disease severity in adults with systemic lupus erythematosus (SLE) receiving standard background therapy in a phase 2 trial1. There were no meaningful reductions in least squares mean change from baseline (BL) in levels of serologic biomarkers for SLE with BARI treatment, including anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies and complement component (C)3 and C41. Evaluate the median change from BL in serologic biomarkers in subgroups and the overall population of BARI-treated SLE patients, in addition to the Systemic Lupus Erythematosus Responder Index-4 (SRI-4) response by normalization of anti-dsDNA. Data were assessed from the phase 2 trial JAHH (NCT02708095). The median change from BL in anti-dsDNA, IgG, C3, and C4 was evaluated over time among the following populations at BL: anti-dsDNA positive (≥30 IU/mL), low C3 (<90 mg/dL), low C4 (<10 mg/dL), and all patients for IgG. Statistical tests were conducted for BARI 2-mg and 4-mg compared with placebo (PBO). Among patients who were anti-dsDNA positive at BL, SRI-4 responder rate was compared for those who stayed positive or achieved normal levels by Week (Wk) 24. Among patients who were anti-dsDNA positive at BL, significant decreases of anti-dsDNA antibodies were observed for BARI 2-mg and 4-mg compared to PBO beginning at Wks 2 and 4, respectively, and continuing through Wk 24 (Figure 1 and Table 1). Moreover, reductions of IgG levels were found for BARI-treated patients including significant decreases for BARI 4-mg compared to PBO at Wks 12 and 24 (Table 1). Among patients who had low levels of C3 and C4 at BL, no significant differences in median change from BL were observed over time with BARI compared to PBO. For patients who were anti-dsDNA positive at BL, no relationship in SRI-4 responder rate was observed for those who stayed positive or achieved normal levels by Wk 24, possibly due to the limited sample size. BARI treatment resulted in a rapid and sustained significant decrease in anti-dsDNA antibodies compared to PBO among anti-dsDNA positive SLE patients at BL, as well as a significant decrease in IgG levels in the 4-mg group at Wks 12 and 24. These data suggest that BARI may have an effect on B cell activity in SLE. [1]Wallace D et al. Lancet. 2018;392:222-231. [Display omitted] The authors would like to acknowledge Nicole L. Byers, of Eli Lilly and Company, for medical writing and process support. Thomas Dörner Speakers bureau: Eli Lilly and Company, Roche, and Samsung, Consultant of: AbbVie, Celgene, Eli Lilly and Company, Janssen, Novartis, Roche, Samsung, and UCB, Grant/research support from: Janssen, Novartis, Roche, Sanofi, and UCB, Ronald van Vollenhoven Consultant of: Abbvie, Biotest, BMS, Celgene, Crescendo, Eli Lilly and Company, GSK, Janssen, Merck, Novartis, Pfizer, Roche, UCB, and Vertex, Grant/research support from: Abbvie, Amgen, BMS, GSK, Pfizer, Roche, and UCB, Andrea Doria Speakers bureau: GSK, Janssen, Pfizer, and Roche, Consultant of: Celgene, Eli Lilly and Company, and GSK, Bochao Jia Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Damiano Fantini Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Jorge Ross Terres Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Maria Silk Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Stephanie de Bono Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Peter Fischer Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Daniel J. Wallace Consultant of: Amgen, Aurunia, Eli Lilly and Company, EMD Merck Serono, GSK, and Pfizer Table 1PBOBARI 2-mgBARI 4-mgWeek412244122441224Anti-dsDNA (IU/mL)a0.2 (-17.2, 17.3)2.6 (-14.8, 18.4)3.0 (-14.9, 28.3)-15.4** (-31.4, 1.9)-18.1* (-42.0, 4.1)-29.6** (-55.1, 10.3)-17.9** (-42.7, 1.8)-23.3*** (-50.9, -5.9)-15.1** (-71.9, -4.6)IgG (g/L)b-0.31 (-1.1, 0.4)0.09 (-1.1, 0.7)-0.04 (-0.9, 0.9)-0.60 (-1.3, 0.6)-0.30 (-1.3, 0.4)-0.51 (-1.7, 0.6)-0.56 (-1.2, 0.2)-0.65** (-1.3, 0.2)-0.60** (-1.7, 0.2)Data are median change from baseline (25th, 75th percentiles). aData were assessed for patients that were anti-dsDNA positive (≥30 IU/mL) at baseline (PBO N=51, BARI 2-mg N=56, BARI 4-mg N=53). bData were assessed for all patients (PBO N=105, BARI 2-mg N=105, BARI 4-mg N=104). *p≤0.05, **p≤0.01, ***p≤0.001 for BARI vs. PBO.

Background:Sjögren’s disease (SjD) is a complex systemic autoimmune disease with substantial morbidity and 21 known genetic associations. The International Sjögren’s Genetics Network (SGENE) is a growing international collaboration focused on understanding how genetic variants influence SjD pathology. As sample sizes increase, we are focusing our efforts on the analyses of clinical subsets, which few studies have done.Objectives:Our genome-wide association study (GWAS) aimed to identify additional risk loci of genome-wide significance (GWS, p<5E-08; suggestive, p<5x10E-5) in European-derived subsets of SjD.Methods:This study was conducted with IRB/EC approvals. All SjD patients met the 2002 AECG criteria for SjD. A total of 5058 cases and 25943 controls were genotyped on GWAS arrays. After QC, 4855 cases and 25408 controls were included in the analyses. Logistic regression was calculated, adjusting for ancestry using the first 4 principal components to identify SjD-associated SNPs. Cases were split into Ro/SSA+ (n=2898) and Ro/SSA- (n=1313), and analyzed vs. each other, controls, and all-SjD.Results:We observed many differences in the genomic architecture of Ro/SSA- compared to Ro/SSA+ and all SjD (Figure 1a,b), most notably, a complete loss of the significance of the association with MHC on chromosome 6 in the Ro/SSA- cases(Figure 1b). The Ro/SSA+ subjects had a much stronger HLA association with OR ≈ 4 (Figure 1a), while the overall SjD showed OR ≈ 3. While none of the associations observed in the Ro/SSA- population reached GWS, 8 regions (near PLXNA2, PCDH7, IRF5-TNPO3, DLD, LOC100134229, JAK3, LOC643529, and TMTC1) show suggestive associations (Figure. 1a). Of these, only two, IRF5-TNPO3 and LOC643529, are also suggestive in the Ro/SSA+ subset. However, while the Ro/SSA+ have both the IRF5 promoter effect and the extended haplotype through TNPO3, the Ro/SSA- lack the IRF5 promoter effect. Interestingly, previous studies have shown that lupus and systemic sclerosis have both haplotypes while primary biliary cholangitis only has the haplotype extending into TNPO3, similar to Ro/SSA- SjD [1]. When comparing Ro/SSA- to the all-SjD dataset, PLXNA2 and LOC100134229 showed no association; PCDH7, DLD, and TMTC1 showed some association but did not reach suggestive levels; and LOC643529, IRF5-TNPO3, and JAK3 surpassed the suggestive threshold, the latter two nearing or surpassing GWS. Two of the novel suggestive associations in Ro/SSA- are particularly intriguing. PLXNA2 is a member of a semaphorin co-receptor family that mediates repulsive effects on axon pathfinding during nervous system development; interestingly, Ro/SSA- SjD has a higher frequency of neurological involvement. JAK3 is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction; it is predominantly expressed in immune cells. Mutations in this gene are associated with autosomal severe combined immunodeficiency disease. Novel drugs target the JAK-STAT pathways, making this finding markedly relevant.Conclusion:Our findings highlight the relevance of expanding genetic studies to specific subphenotypes of the disease. While we continue to increase our GWAS sample size and explore other subphenotypes, more work is needed to increase the power of these studies to determine if the suggestive regions will surpass the GWS threshold.REFERENCES:[1] Kottyan LC, et al. Hum Mol Genet. 2015 Jan 15;24(2):582-96.Acknowledgements:NIH/NIAMS R01 AR073855, P50 AR060804; NIH/NIDCR U01DE028891; Sjögren’s Foundation; Jerome L. Greene Foundation.Disclosure of Interests:Astrid Rasmussen: None declared, Marcin Radziszewski: None declared, Bhuwan Khatri: None declared, Kandice L Tessneer: None declared, Elena Pontarini: None declared, Michele Bombardieri: None declared, Maureen Rischmueller: None declared, Marie Wahren-Herlenius: None declared, Marika Kvarnström: None declared, Torsten Witte: None declared, Hendrika Bootsma: None declared, Gwenny M. Verstappen: None declared, Frans G.M. Kroese: None declared, Arjan Vissink: None declared, Sarah Pringle: None declared, Athanasios Tzioufas: None declared, Clio Mavragani: None declared, Alan Baer Received consulting fees from Bristol Myers Squibb (BMS) and iCell Gene Therapeutics., Marta Alarcon-Riquelme: None declared, Javier Martin: None declared, Xavier Mariette: None declared, Gaetane Nocturne: None declared, Jacques-Olivier Pers: None declared, Jacques-Eric Gottenberg: None declared, Wan-Fai Ng I have consulted for Novartis, BMS, Janssen, Sanofi, Abbvie, IQVIA, Argenx, Resolve Therapeutics., Caroline Shiboski: None declared, Kimberly E Taylor: None declared, Lindsey Criswell: None declared, Blake M Warner: None declared, A Darise Farris Grant/research support from Johnson and Johnson Innovative Medicine (formerly Janssen; ended 12/31/2023)., Judith A. James: None declared, R Hal Scofield Received consulting fees from Johnson and Johnson Innovative Medicine (formerly Janssen) and Merk Pharmaceuticals., Joel M Guthridge: None declared, Daniel J Wallace: None declared, Swamy Venuturupali: None declared, Michael T Brennan: None declared, Juliana Imgenberg-Kreuz: None declared, Lars Ronnblom: None declared, Eva Baecklund: None declared, Maija-leena Eloranta: None declared, Lara A Aqrawi: None declared, Øyvind Palm: None declared, Johan G Brun: None declared, Daniel Hammenfors: None declared, Malin V Jonsson: None declared, Silke Appel: None declared, Sara Magnusson Bucher: None declared, Helena Forsblad-d’Elia: None declared, Thomas Mandl Employee of UCB., Per Eriksson: None declared, Gunnel Nordmark: None declared, Christopher J Lessard Grant/research support from Johnson and Johnson Innovative Medicine (formerly Janssen; ended 12/31/2023).

Background:In our previous Sjögren’s Disease (SjD) Genome-Wide Association Study (GWAS) in European populations, significant single nucleotide polymorphism (SNP) peaks were identified between PRDM1 and ATG5 [1]. ATG5 is an autophagy-related protein that plays a crucial role in neutrophil extracellular trap (NET) formation, degranulation, and limiting autoantigens in blood. Dysregulated autophagy has been implicated in SjD and systemic lupus erythematosus (SLE) pathology and poor disease outcomes [2, 3]. The transcriptional repressor PRDM1 plays a role in regulating lymphocyte differentiation [4].Objectives:Identify and functionally evaluate SjD and SLE risk variants in the PRDM1-ATG5 risk locus.Methods:By conducting a meta-analysis of SjD and SLE GWAS datasets, we defined a credible SNP set in the PRDM1-ATG5 locus. A GWAS involving 15,691 SjD and SLE cases and 52,521 population controls of European ancestry was performed, and SNP-trait associations were tested using logistic regression models in PLINK. Bioinformatic analyses (RegulomeDB, HaploReg v4.2, promoter capture Hi-C, eQTLs, etc.) further prioritized SNPs. A CRISPR inhibition (CRISPRi) assay was used to assess the effects of these SNPs on ATG5 expression. Luciferase assays in A235 salivary gland epithelial cell line, PLB985 malignant myelomonoblasts, and GM12878 EBV-transformed B cells tested the activation and/or repressive activity of candidate SNPs.Results:Our investigation revealed several candidate functional SNPs within the PRDM1-ATG5 region. Among them, rs533733 (p=1.15E-18), rs34582442 (p=2.79E-08), rs34599047 (p=2.82E-08), rs77846660 (p=8.39E-04), and rs56886418 (p=4.23E-03) emerged as noteworthy, suggesting their involvement in the regulatory landscape of this locus. Expanding our focus, the inclusion of rs1152966 (p=3.39E-15), rs11152964 (p=7.18E-11), rs573775 (p=6.13E-06), and rs12175062 (p=2.67E-03) in the analysis revealed a broader understanding of eQTLs and chromatin accessibility and modification patterns associated with these SNPs. The extensive influence of these SNPs was observed across various cell types, including minor salivary glands and blood cells, emphasizing their relevance in the pathogenesis of SjD and SLE. Functional assays further elucidated the allele-specific effects of selected SNPs. Notably, rs56885418 and rs3804333 demonstrated a significant decrease in enhancer activity, while rs533733 and rs62422881 exhibited an increase in enhancer activity, particularly in the A253 cell line. These findings underscore the dynamic regulatory impact of these SNPs on gene expression, providing valuable insights into the molecular mechanisms at play in the PRDM1-ATG5 locus.Conclusion:Functional characterization of SNPs in the PRDM1-ATG5 locus provides new insights into the regulatory mechanisms governing gene expression in SjD and SLE. Ongoing studies will focus on in vitro validation of predicted functional SNPs in A235 and GM12878 cells.REFERENCES:[1] Khatri B, et al. Nat Commun. 2022 Jul;13(1):4287.[2] Byun YS, et al. Sci Rep. 2017 Dec;7(1):17280.[3] Wible DJ, et al. Cell Discov. 2019; 5:42.[4] Kallies A, Nutt SL. Curr Opin Immunol. 2007 Apr;19(2):156-62.Acknowledgements:National Institutes of Health (NIH): R01AR071410, R01AR073855, R01AR065953, P50AR060804, U01DE028891; National Research Foundation of Korea (NRF-2021R1A6A1A03038899); Sjögren’s Foundation; Presbyterian Health Foundation; Jerome L. Greene Foundation.Disclosure of Interests:Marcin Radziszewski: None declared, Mandi M Wiley: None declared, Bhuwan Khatri: None declared, Astrid Rasmussen: None declared, Kandice L Tessneer: None declared, Kwangwoo Kim: None declared, Edward M. Vital: None declared, Nick Dand: None declared, Chen Gong: None declared, David Morris: None declared, Phil Tombleson: None declared, Elena Pontarini: None declared, Michele Bombardieri: None declared, Maureen Rischmueller: None declared, Marie Wahren-Herlenius: None declared, Marika Kvarnström: None declared, Torsten Witte: None declared, Hendrika Bootsma: None declared, Gwenny M. Verstappen: None declared, Frans G.M. Kroese: None declared, Arjan Vissink: None declared, Sarah Pringle: None declared, Athanasios Tzioufas: None declared, Clio Mavragani: None declared, Alan Baer Received consulting fees from Bristol Myers Squibb (BMS) and iCell Gene Therapeutics., Marta Alarcon-Riquelme: None declared, Javier Martin: None declared, Xavier Mariette: None declared, Gaetane Nocturne: None declared, Jacques-Olivier Pers: None declared, Jacques-Eric Gottenberg: None declared, Wan-Fai Ng I have consulted for Novartis, BMS, Janssen, Sanofi, Abbvie, IQVIA, Argenx, Resolve Therapeutics., Caroline Shiboski: None declared, Kimberly E Taylor: None declared, Lindsey Criswell: None declared, Blake M Warner: None declared, A Darise Farris Grant/research support from Johnson and Johnson Innovative Medicine (formerly Janssen; ended 12/31/2023)., Patrick M Gaffney: None declared, Judith A. James: None declared, R Hal Scofield Received consulting fees from Johnson and Johnson Innovative Medicine (formerly Janssen) and Merk Pharmaceuticals., Joel M Guthridge: None declared, Daniel J Wallace: None declared, Swamy Venuturupali: None declared, Michael T Brennan: None declared, Juliana Imgenberg-Kreuz: None declared, Lars Ronnblom: None declared, Eva Baecklund: None declared, Maija-leena Eloranta: None declared, Lara A Aqrawi: None declared, Øyvind Palm: None declared, Johan G Brun: None declared, Daniel Hammenfors: None declared, Malin V Jonsson: None declared, Silke Appel: None declared, Sara Magnusson Bucher: None declared, Helena Forsblad-d’Elia: None declared, Thomas Mandl Employee of UCB., Per Eriksson: None declared, Sang-Cheol Bae: None declared, Timothy J Vyse: None declared, Betty Tsao: None declared, Gunnel Nordmark: None declared, Christopher J Lessard Grant/research support from Johnson and Johnson Innovative Medicine (formerly Janssen; ended 12/31/2023).