Abstract: Mesenchymal stem cells (MSCs) are potent immunosuppressive cells that have shown promise in the treatment of rheumatoid arthritis (RA). Deciphering the intrinsic characteristics of MSCs that correlate with their biologic activity will facilitate their clinical use. Recently, the role of glucocorticoid‐induced leucine zipper (GILZ) in the development of RA has been documented. The aim of this study was to evaluate whether GILZ expression by MSCs may contribute to their therapeutic effect. Methods MSCs were isolated from GILZ‐deficient (GILZ −/− ) mice and wild‐type mice. MSCs (1 × 10 6 cells) were injected twice via the tail vein into mice with collagen‐induced arthritis (CIA). Results In vitro, we showed that GILZ is a key factor involved in the immunosuppressive potential of MSCs. MSCs derived from GILZ −/− mice did not suppress the proliferation of CD4+ T cells and were less efficient than MSCs derived from WT mice in altering Th17 cell polarization. Thus, we investigated the role of GILZ in an experimental model of arthritis and demonstrated that although WT MSCs significantly reduced paw swelling in arthritic mice, GILZ −/− MSCs did not. Moreover, the magnitude of the effects of GILZ −/− MSCs on Th17 cell frequency was significantly lower than that of WT MSCs. The therapeutic effect of MSCs correlated with the generation of Treg cells bearing the CD4 + RORγt+IL‐17 low IL‐10+ signature, and Th17 cell polarization was GILZ dependent. Conclusion This study demonstrates that GILZ has an essential role in the therapeutic effectiveness of MSCs in arthritis by favoring Th17 cell polarization toward a regulatory phenotype. Therefore, potentiation of GILZ expression in MSCs could represent a means to enhance their therapeutic effect in autoimmune diseases.

Abstract: Lupus low disease activity state (LLDAS) attainment has been reported to be associated with reduced damage accrual, flare, and mortality, as well as improved quality of life, in cohorts of SLE patients with established disease. Whether these associations are present in recent-onset disease is less well known. Objectives To evaluate the associations of LLDAS attainment with outcomes in patients with recent onset SLE. Methods Data from a 13-country longitudinal SLE cohort (ACR/SLICC criteria) were collected prospectively between 2013 and 2020 using standard templates. Organ damage and flare were captured using SLICC Damage Index and SELENA-SLEDAI Flare Index, respectively. LLDAS was defined as Golder et al. , 2019 [1]. An inception cohort was defined based on duration since SLE diagnosis 〈 1 year at enrolment. Patient characteristics between inception and non-inception cohorts were compared using Wilcoxon rank-sum (continuous variables) or Pearson’s Chi-squared tests (categorical variables). Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare. Results The study cohort included 4,106 patients of whom 680 (16%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the non-inception cohort, inception cohort patients were significantly younger, had higher disease activity (SLEDAI-2K and physician global assessment), used more glucocorticoids and immunosuppressants but had less organ damage at enrolment and only 88 (13.6%) patients accrued damage during a median 2.2 years follow-up (Table 1). Table 1. Non-inception cohort Inception cohort p-value n=3426 n=680 Age at enrolment (years), median [IQR] 40 [31, 51] 33 [25, 44] 〈 0.001 Age at diagnosis (years), median [IQR] 28 [21, 38] 33 [25, 43] 〈 0.001 SLE duration at enrolment (years), median [IQR] 10 [5, 16] 1 [0, 1] 〈 0.001 Study duration (years), median [IQR] 2.5 [1.0, 5.4] 2.2 [0.9, 3.7] 〈 0.001 Females, n (% ) 3155 (92.1%) 623 (91.6%) 0.68 Asian ethnicity, n (% ) 3037 (89.1%) 595 (88.1%) 0.49 Prednisolone (PNL) use - ever, n (% ) 2865 (83.6%) 620 (91.2%) 〈 0.001 Time adjusted mean (TAM)-PNL, median [IQR] 5.0 [2.2, 8.6] 6.2 [3.2, 10.3] 〈 0.001 Cumulative PNL (g), median [IQR] 3.4 [0.5, 9.7] 3.8 [1.1, 8.5] 0.26 Anti-Malarial use - ever, n (% ) 2669 (77.9%) 569 (83.7%) 〈 0.001 Immunosupressant use -ever, n (% ) 2367 (69.1%) 521 (76.6%) 〈 0.001 AMS (TAM-SLEDAI-2K), median [IQR] 2.8 [1.2, 4.6] 3.1 [1.6, 5.0] 0.002 TAM-PGA, median [IQR] 0.4 [0.2, 0.7] 0.4 [0.3, 0.8] 〈 0.001 Mild/moderate/severe flare ever, n (% ) 1789 (52.2%) 391 (57.5%) 0.012 Organ damage accrual, n (% ) 629 (20.8%) 88 (13.6%) 〈 0.001 LLDAS at baseline, n (% ) 1730 (50.5%) 195 (28.7%) 〈 0.001 LLDAS-ever (at least once), n (% ) 2637 (78.2%) 492 (73.9%) 0.014 ≥50% time in LLDAS (LLDAS-5), n (% ) 1612 (50.6%) 256 (41.1%) 〈 0.001 Significantly fewer inception cohort patients were in LLDAS at enrolment than the non-inception cohort (29% vs. 51%, p 〈 0.001). However, 74% of inception and 78% of non-inception cohort patients achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrolment, time to first LLDAS attainment was assessed: inception cohort patients were 60% more likely to attain their first LLDAS (HR = 1.60 (95%CI: 1.40, 1.82), p 〈 0.001) than non-inception cohort patients. LLDAS attainment was significantly protective against flare in the inception (HR, 95% CI) and non-inception (HR, 95% CI) cohorts. Trends towards protection against damage accrual in association with LLDAS in the inception cohort were not significant. Conclusion LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed, due to low rates of damage accrual in the first years after SLE diagnosis. References [1]Golder, V., et al., Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study. The Lancet Rheumatology, 2019. 1 (2): p. e95-e102. Acknowledgements We thank all patients participating in the Asia Pacific Lupus Collaboration (APLC) cohort, and all data collectors for their ongoing support for APLC research activities. The APLC has received unrestricted project grants from AstraZeneca, BMS, Eli Lily, Janssen, Merck Serono, and UCB to support data collection contributing to this work. Disclosure of Interests Vera Golder: None declared, Rangi Kandane-Rathnayake: None declared, Worawit Louthrenoo: None declared, Yi-Hsing Chen Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra & Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Consultant of: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra and Zeneca, Sanofi, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead, Grant/research support from: Yes. Clinical trials and/or research grants from Pfizer, Norvatis, BMS, Abbevie, Johnson & Johnson, Roche,Sanofi, Guigai, Roche, Boehringer Ingelheim, UCB, MSD, Astra-Zeneca,Astellas, Gilead, Jiacai Cho: None declared, Aisha Lateef: None declared, Laniyati Hamijoyo Speakers bureau: Pfizer, Novartis, Abbot, Shue Fen Luo: None declared, Yeong-Jian Jan Wu Speakers bureau: Pfizer, Lilly, Novartis, Abbvie, Sandra Navarra Speakers bureau: Pfizer, Johnson & Johnson, Novartis, Astellas, Grant/research support from: Astellas, Johnson & Johnson, Leonid Zamora: None declared, Zhanguo Li Speakers bureau: Eli, Lilly, Novartis, GSK, AbbVie, Paid instructor for: Pfizer, Roche, Johnson, Consultant of: Lilly, Pfizer, Grant/research support from: Pfizer, Yuan An: None declared, Sargunan Sockalingam Speakers bureau: Yes. Pfizer, Roche, Novartis, Grant/research support from: Roche and Novartis, Yasuhiro Katsumata Speakers bureau: Chugai Pharmaceutical Co., Ltd., Glaxo-Smithkline K.K., and Sanofi K.K., Masayoshi Harigai Speakers bureau: MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc.,Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd, Consultant of: MH is a consultant for AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co.,Ltd. and Teijin Pharma., Grant/research support from: MH has received research grants from AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc.,Eisai Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Sekiui Medical, Shionogi & Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Yanjie Hao: None declared, Zhuoli Zhang Speakers bureau: Norvatis, GSK, Pfizer, BMDB Basnayake: None declared, Madelynn Chan Speakers bureau: AbbVie, Novartis, Consultant of: Advisory Board member for Pfizer, Eli-Lilly, Jun Kikuchi: None declared, Tsutomu Takeuchi Speakers bureau: AbbVie AYUMI Pharmaceutical Corp. Bristol-Myers Squibb Chugai Pharmaceutical Co, Ltd. Daiichi Sankyo Co., Ltd. Eisai Co., Ltd. Eli Lilly Japan, Gilead Sciences, Inc. Mitsubishi-Tanabe Pharma Corp. Pfizer Japan Inc. Sanofi K.K., Consultant of: Astellas Pharma, Inc. Chugai Pharmaceutical Co, Ltd. Eli Lilly Japan, Mitsubishi-Tanabe Pharma Corp., Grant/research support from: AbbVie Asahikasei Pharma Corp. Chugai Pharmaceutical Co, Ltd. Mitsubishi-Tanabe Pharma Corp. Sanofi K.K, Sang-Cheol Bae: None declared, Sean O’Neill Paid instructor for: Advisory board member for GSK, Fiona Goldblatt: None declared, Shereen Oon: None declared, Kathryn Gibson Speakers bureau: UCB, Consultant of: Novartis – co-chair for NSW and steering committee member for ARISE meeting Feb 2021 Janssen Pharmaceuticals – advisory board, Grant/research support from: Novartis, Employee of: Eli Lilly, Kristine Ng Speakers bureau: speaker fees and advisory board (Abbvie, Novartis, Janssen), Annie Law: None declared, Nicola Tugnet: None declared, Sunil Kumar: None declared, Cherica Tee: None declared, Michael Tee: None declared, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen, Grant/research support from: Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen, C.S. Lau Shareholder of: Pfizer, Sanofi and Janssen, Mandana Nikpour Speakers bureau: Actelion, GSK, Janssen, Pfizer, UCB, Paid instructor for: UCB, Consultant of: Actelion, Boehringer Ingelheim, Certa Therapeutics, Eli Lilly, GSK, Janssen, Pfizer, UCB, Grant/research support from: Actelion, Astra Zeneca, BMS, GSK, Janssen, UCB, Alberta Hoi Consultant of: AH is on the advisory board for Abbvie and GSK, Grant/research support from: AH has received research support from AstraZeneca, GSK, BMS, Janssen, and Merck Serono, Eric F. Morand Speakers bureau: AstraZeneca, Paid instructor for: Eli Lilly, Consultant of: AstraZeneca, Amgen, Biogen, BristolMyersSquibb, Eli Lilly, EMD Serono, Genentech, Janssen, Grant/research support from: AstraZeneca, BristolMyersSquibb, Eli Lilly, EMD Serono, Janssen

Abstract: In SLE patients, episodes of high disease activity state (HDAS, SLEDAI-2K≥10) are associated with worse outcomes even if only experienced once. We investigated whether attainment of the lupus low disease activity state (LLDAS) was associated with protection against adverse outcomes in SLE patients after an episode of HDAS. Objectives To compare LLDAS attainment between HDAS and non-HDAS patients. Methods Data on 4,106 SLE patients from a multinational cohort, collected prospectively between 2013 and 2020, were analysed. Disease activity was assessed using SLEDAI-2K. Patients who had SLEDAI-2K≥10 at least once were defined as HDAS patients. For the purpose of evaluating long term outcomes, each HDAS patient’s first visit with SLEDAI-2K≥10 was assigned as baseline, and for non-HDAS patients, recruitment was considered as baseline. Patients in LLDAS continuously for ≥6 months were defined as in sustained LLDAS (≥6months- and ≥12months-sustained LLDAS). Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare. Results 1076 patients (26%) had HDAS at least once (HDAS-ever). Compared to patients who never experienced HDAS (HDAS-never), HDAS-ever patients were younger, had shorter disease duration at enrolment, and a longer study follow-up period. HDAS-ever patients had higher disease activity across the observation period measured by time-adjusted mean SLEDAI-2K and PGA; higher PNL and IS use, more flares, organ damage, and damage accrual. None of the HDAS cohort and 42% of HDAS-never group were in LLDAS at baseline (HDAS-never/not LLDAS BL). 66% of HDAS-ever and 57% of ‘HDAS-never/not LLDAS BL’ patients attained LLDAS at least once during the study observation period. Proportions of patients in sustained LLDAS and who had cumulative LLDAS ≥ 50% of observed time (LLDAS-50) were lower in HDAS-ever patients (Table 1). LLDAS-50 attainment was protective from damage accrual and flare in both HDAS-ever and HDAS-never patients (Table 1). Sustained LLDAS was similarly protective from damage accrual and flare in both ‘HDAS-ever’ and ‘HDAS-never/not LLDAS BL’ groups (Table 1). Table 1. HDAS-never/not LLDAS BLn=1215n (%) HDAS-evern=1076n (%) Patients with organ damage accrual 212 (18.8%) 269 (27.5%) patients with flare 613 (50.5%) 894 (83.1%) LLDAS-ever (at least once) 688 (56.6%) 713 (66.4%) ≥50% cumulative time in LLDAS (LLDAS-50) 371 (33.1%) 182 (18.6%) ≥6-months in sustained LLDAS 391 (32.2%) 287 (26.7%) ≥12-months in sustained LLDAS 243 (20.0%) 143 (13.3%) Longitudinal associations with HR (95% CI), p-value HR (95% CI), p-value Organ damage accrual t LLDAS t-1 0.54 (0.41,0.71), p 〈 0.001 0.49 (0.36,0.67), p 〈 0.001 LLDAS-50 t-1 0.67 (0.49,0.90), p=0.009 0.61 (0.38,0.98), p 〈 0.04 ≥6m sustained LLDAS t-1 0.68 (0.45,1.01), p=0.06 0.43 (0.26,0.73), p=0.002 ≥12m sustained LLDAS t-1 0.54 (0.31,0.94), p=0.03 0.29 (0.11,0.74), p=0.01 Flare t LLDAS t-1 0.83 (0.71,0.97), p=0.019 0.67 (0.59,0.77), p 〈 0.001 LLDAS-50 t-1 0.84 (0.69,1.01), p=0.059 0.59 (0.48,0.72), p 〈 0.001 ≥6m sustained LLDAS t-1 0.47 (0.37,0.60), p 〈 0.001 0.48 (0.38,0.60), p 〈 0.001 ≥12m sustained LLDAS t-1 0.41 (0.30,0.56), p 〈 0.001 0.29 (0.20,0.42).p 〈 0.001 Conclusion Sustained or majority LLDAS was less achievable in SLE patients after an episode of HDAS in HDAS-ever compared to HDAS-never patients, but protective associations of LLDAS against organ damage accrual and flare were similar regardless of HDAS. LLDAS attainment is protective from adverse outcomes even after high disease activity. Acknowledgements We thank all patients participating in the Asia Pacific Lupus Collaboration (APLC) cohort, and all data collectors for their ongoing support for APLC research activities. The APLC has received unrestricted project grants from AstraZeneca, BMS, Eli Lily, Janssen, Merck Serono, and UCB to support data collection contributing to this work. Disclosure of Interests Rangi Kandane-Rathnayake: None declared, Vera Golder: None declared, Worawit Louthrenoo: None declared, Yi-Hsing Chen Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra & Zeneca, Sanofi, MSD, Guigai, Astellas Inova Diagnostics, UCB Agnitio Science Technology, United Biopharma, Thermo Fisher, Consultant of: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra and Zeneca, Sanofi, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead, Grant/research support from: Pfizer, Norvatis, BMS, Abbevie, Johnson & Johnson, Roche,Sanofi, Guigai, Roche, Boehringer Ingelheim, UCB, MSD, Astra-Zeneca,Astellas, Gilead, Jiacai Cho: None declared, Aisha Lateef: None declared, Laniyati Hamijoyo Speakers bureau: from Pfizer, Novartis, Abbot, Shue Fen Luo: None declared, Yeong-Jian Jan Wu Speakers bureau: Pfizer, Lilly, Novartis, Abbvie, Sandra Navarra Speakers bureau: Pfizer, Johnson & Johnson, Novartis, Astellas, Grant/research support from: Astellas, Johnson & Johnson, Leonid Zamora: None declared, Zhanguo Li Speakers bureau: Eli Lilly, Novartis, GSK, AbbVie., Paid instructor for: Pfizer, Roche, Johnson, Consultant of: Eli Lilly, Pfizer, Grant/research support from: Pfizer, Yuan An: None declared, Sargunan Sockalingam Speakers bureau: Pfizer, Roche, Novartis, Grant/research support from: Roche and Novartis, Yasuhiro Katsumata Speakers bureau: YK has received honoraria from Chugai Pharmaceutical Co., Ltd., Glaxo-Smithkline K.K., and Sanofi K.K., Masayoshi Harigai Speakers bureau: MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc.,Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Consultant of: MH is a consultant for AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co.,Ltd. and Teijin Pharma., Grant/research support from: MH has received research grants from AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc.,Eisai Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Sekiui Medical, Shionogi & Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Yanjie Hao: None declared, Zhuoli Zhang Speakers bureau: Norvatis, GSK, Pfizer, BMDB Basnayake: None declared, Madelynn Chan Speakers bureau: AbbVie, Novartis, Consultant of: Advisory Board member for Pfizer, Eli-Lilly, Jun Kikuchi: None declared, Tsutomu Takeuchi Speakers bureau: AbbVie AYUMI Pharmaceutical Corp. Bristol-Myers Squibb Chugai Pharmaceutical Co, Ltd. Daiichi Sankyo Co., Ltd. Eisai Co., Ltd. Eli Lilly Japan, Gilead Sciences, Inc. Mitsubishi-Tanabe Pharma Corp. Pfizer Japan Inc. Sanofi K.K., Consultant of: Astellas Pharma, Inc. Chugai Pharmaceutical Co, Ltd. Eli Lilly Japan, Mitsubishi-Tanabe Pharma Corp., Grant/research support from: AbbVie Asahikasei Pharma Corp. Chugai Pharmaceutical Co, Ltd. Mitsubishi-Tanabe Pharma Corp. Sanofi K.K., Sang-Cheol Bae: None declared, Shereen Oon: None declared, Sean O’Neill Consultant of: GSK, Fiona Goldblatt: None declared, Kathryn Gibson Speakers bureau: UCB, Consultant of: Novartis, Janssen Pharmaceuticals, Grant/research support from: Novartis, Employee of: Eli Lilly, Kristine Ng Speakers bureau: Abbvie, Novartis, Janssen, Annie Law: None declared, Nicola Tugnet: None declared, Sunil Kumar: None declared, Cherica Tee: None declared, Michael Tee: None declared, Yoshiya Tanaka Speakers bureau: Y. Tanaka has received speaking fees and/or honoraria from Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen, Grant/research support from: Y. Tanaka, has received research grants from Abbvie, Mitsubishi-Tanabe, Chugai, Asahi-Kasei, Eisai, Takeda, Daiichi-Sankyo., C.S. Lau Shareholder of: Pfizer, Sanofi, and Janssen, Mandana Nikpour Speakers bureau: Actelion, GSK, Janssen, Pfizer, UCB, Paid instructor for: UCB, Consultant of: Actelion, Boehringer Ingelheim, Certa Therapeutics, Eli Lilly, GSK, Janssen, Pfizer, UCB, Grant/research support from: Actelion, Astra Zeneca, BMS, GSK, Janssen, UCB, Eric F. Morand Speakers bureau: AstraZeneca, Paid instructor for: Eli Lilly, Consultant of: AstraZeneca, Amgen, Biogen, BristolMyersSquibb, Eli Lilly, EMD Serono, Genentech, Janssen, Grant/research support from: AstraZeneca, BristolMyersSquibb, Eli Lilly, EMD Serono, Janssen, Alberta Hoi Consultant of: AH is on the advisory board for Abbvie and GSK, Grant/research support from: AH has received research support from AstraZeneca, GSK, BMS, Janssen, and Merck Serono.

Abstract: The recent prospectively validated definition of the lupus low disease activity state (LLDAS) allows characterisation of patients not achieving a treatment goal, providing impetus for an analysis of unmet needs in SLE using formal definitions. Other recently described definitions of high disease burden include disease activity over time, high disease activity status (HDAS) episodes, and the combination of high disease activity, serological activity and glucocorticoid (GC) use (HDAS+SA+GC). Objectives: To determine the prevalence of formal categories of unmet need, and the association of these with adverse outcomes, in SLE. Methods: Data from a 13-country longitudinal SLE cohort (ACR/SLICC criteria) were collected between 2013 and 19 using standard templates. Unmet need was defined as (i) patients never attaining LLDAS defined as in Golder et al. , 2019 [1], (ii) having persistently active disease (time adjusted mean SLEDAI-2K (AMS) 〉 4), (iii) ever exhibiting high disease activity status (HDAS; SLEDAI-2K ≥10[2]), or (iv) ever exhibiting all of SLEDAI≥10, serological activity, and glucocorticoid use (HDAS+SA+GC)[3] . Health-related quality of life (HRQoL) was assessed using SF36 (v2) surveys and damage accrual using SLE Damage Index (SDI). Results: 3,384 SLE patients were followed for 30,313 visits over median [IQR] 2.4 [0.4, 4.3] years. 53% of all visits were not in LLDAS; 813 patients (24%) never achieved LLDAS during observation. Median AMS was 3.0 [1.4, 4.9] and 34% of patients had AMS 〉 4 throughout the study. 25% of patients had at least one episode of HDAS, representing 8% of visits. 702 patients (21%) had at least one episode of HDAS+SA+GC, representing 8% of visits. Each of never-LLDAS, AMS 〉 4, ever-HDAS, and ever-HDAS+SA+GC were associated with significantly greater number of physician visits, higher mean glucocorticoid dose, lower HRQoL and higher mortality. 31%, 58% and 83% of never-LLDAS, AMS 〉 4, and ever-HDAS patients respectively were also HDAS+SA+GC on at least one occasion. Conclusion: Data from a multinational longitudinal SLE cohort indicate that unmet need, defined by LLDAS-never, AMS 〉 4, HDAS, or HDAS+SA+GC, is prevalent in SLE, and that these definitions are associated with poor outcomes. References: [1]Golder, V., et al., Lupus low disease activity state as a treatment endpoint for systemic lupus erythematosus: a prospective validation study. The Lancet Rheumatology, 2019. 1 (2): p. e95-e102. [2]Koelmeyer, R., et al., High disease activity status suggests more severe disease and damage accrual in systemic lupus erythematosus. Lupus Sci Med, 2020. 7 (1). [3]van Vollenhoven, R.F., et al., Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Annals of the Rheumatic Diseases, 2012. 71 (8): p. 1343-1349. Acknowledgements: The APLC acknowledges all the Data Collectors and Patients for their valuable contributions to research. Disclosure of Interests: Rangi Kandane-Rathnayake: None declared, Worawit Louthrenoo: None declared, Alberta Hoi Consultant of: Abbvie and GSK, Grant/research support from: AstraZeneca, GSK, BMS, Janssen, and Merck Serono, Vera Golder: None declared, Yi-Hsing Chen Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, AstraZeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Consultant of: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, AstraZeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead, Grant/research support from: Pfizer, Norvatis, BMS, Abbevie, Johnson & Johnson, Roche, Sanofi, Guigai, Roche, Boehringer Ingelheim, UCB, MSD, Astra-Zeneca, Astellas, Gilead, Shue Fen Luo: None declared, Yeong-Jian Jan Wu Speakers bureau: Pfizer, Lilly, Novartis, Abbvie, Aisha Lateef: None declared, Jiacai Cho: None declared, Laniyati Hamijoyo Speakers bureau: Pfizer, Novartis, Abbot, Chak Sing Lau Shareholder of: Pfizer, Sanofi, and Janssen, Sandra Navarra Speakers bureau: Pfizer, Johnson & Johnson, Novartis, Astellas, Grant/research support from: Astellas, Johnson & Johnson, Leonid Zamora: None declared, Zhanguo Li Speakers bureau: Eli, Lilly, Novartis, GSK, AbbVie, Paid instructor for: Pfizer, Roche, Johnson., Consultant of: Lilly, Pfizer, Grant/research support from: Pfizer, Yuan An: None declared, Sargunan Sockalingam Speakers bureau: Pfizer, Roche, Novartis, Grant/research support from: Roche and Novartis, Yasuhiro Katsumata Speakers bureau: Chugai Pharmaceutical Co., Ltd., Glaxo-Smithkline K.K., and Sanofi K.K., masayoshi harigai Speakers bureau: AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc.,Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Consultant of: AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co.,Ltd. and Teijin Pharma., Grant/research support from: AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc.,Eisai Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Sekiui Medical, Shionogi & Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Yanjie Hao: None declared, Zhuoli Zhang Speakers bureau: Norvatis, GSK, Pfizer, Jun Kikuchi: None declared, Tsutomu Takeuchi Speakers bureau: AbbVie AYUMI Pharmaceutical Corp. Bristol-Myers Squibb Chugai Pharmaceutical Co, Ltd. Daiichi Sankyo Co., Ltd. Eisai Co., Ltd. Eli Lilly Japan, Gilead Sciences, Inc. Mitsubishi-Tanabe Pharma Corp. Pfizer Japan Inc. Sanofi K.K., Consultant of: Astellas Pharma, Inc. Chugai Pharmaceutical Co, Ltd. Eli Lilly Japan, Mitsubishi-Tanabe Pharma Corp., Grant/research support from: AbbVie, Asahikasei Pharma Corp. Chugai Pharmaceutical Co, Ltd. Mitsubishi-Tanabe Pharma Corp. Sanofi K.K., BMDB Basnayake: None declared, Fiona Goldblatt: None declared, Madelynn Chan Speakers bureau: AbbVie, Novartis, Consultant of: Pfizer, Eli-Lilly, Kristine Ng Speakers bureau: Abbvie, Novartis, Janssen, Sang-Cheol Bae: None declared, Shereen Oon: None declared, Sean O’Neill Consultant of: GSK, Kathryn Gibson Speakers bureau: UCB, Consultant of: Novartis, Janssen, Grant/research support from: Novartis, Sunil Kumar: None declared, Nicola Tugnet: None declared, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen, Grant/research support from: Abbvie, Mitsubishi-Tanabe, Chugai, Asahi-Kasei, Eisai, Takeda, Daiichi-Sankyo, Mandana Nikpour Speakers bureau: Actelion, GSK, Janssen, Pfizer, UCB, Paid instructor for: UCB, Consultant of: Actelion, Boehringer Ingelheim, Certa Therapeutics, Eli Lilly, GSK, Janssen, Pfizer, UCB, Grant/research support from: Actelion, Astra Zeneca, BMS, GSK, Janssen, UCB, Eric F. Morand Speakers bureau: AstraZeneca, Paid instructor for: Eli Lilly, Consultant of: AstraZeneca, Amgen, Biogen, BristolMyersSquibb, Eli Lilly, EMD Serono, Genentech, Janssen, Grant/research support from: AstraZeneca, BristolMyersSquibb, Eli Lilly, EMD Serono, Janssen.

Abstract: We examined the clinical relevance of urinary concentrations of B-cell–activating factor of the tumour necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) in systemic lupus erythematosus (SLE). Methods We quantified urinary BAFF (uBAFF) by enzyme-linked immunosorbent assay in 85 SLE, 28 primary Sjögren syndrome (pSS), 40 immunoglobulin A nephropathy (IgAN) patients and 36 healthy controls (HCs). Urinary APRIL (uAPRIL) and monocyte chemoattractant protein 1 (uMCP-1) were also quantified. Overall and renal SLE disease activity were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000. Results uBAFF was detected in 12% (10/85) of SLE patients, but was undetectable in HCs, IgAN and pSS patients. uBAFF was detectable in 28% (5/18) of SLE patients with active nephritis vs 5/67 (7%) of those without ( p = 0.03), and uBAFF was significantly higher in active renal patients ( p = 0.02) and more likely to be detected in patients with persistently active renal disease. In comparison, uAPRIL and uMCP-1 were detected in 32% (25/77) and 46% (22/48) of SLE patients, respectively. While no difference in proportion of samples with detectable uAPRIL was observed between SLE, HCs and IgAN patients, both uAPRIL and uMCP-1 were significantly detectable in higher proportions of patients with active renal disease. Conclusions uBAFF was detectable in a small but a significant proportion of SLE patients but not in other groups tested, and was higher in SLE patients with active renal disease.

Abstract: In the absence of evidence-based treatment guidelines, medication use in SLE is highly variable. Low rates of remission and lupus low disease activity state (LLDAS) suggest that suboptimal responses to standard medications, which include glucocorticoids (GC), anti-malarial (AM) drugs and immunosuppressive (IS) agents, are common. Understanding the utility of current medications will facilitate the selection of patients for advanced therapies as they emerge. Objectives: To examine medication use patterns in a large multicentre SLE cohort. Methods: We used 2013-18 data from the Asia Pacific Lupus Collaboration (APLC) cohort in which disease activity (SLEDAI-2K) and medication details were captured at every visit. LLDAS was defined as in Golder et al. , 2019 (1). We examined the use of medication (med) categories (GC & /or AM & /or IS) by SLE disease activity and LLDAS at the visit level. Additionally, we performed Cox regression analyses to determine the time-to-discontinuation of meds stratified by SLE disease activity, ranked by time-adjusted mean SLEDAI-2K, and by percent-time spent in LLDAS. Results: We analysed data from 19,804 visits of 2,860 patients. We observed 8 med categories: no meds; GC, AM or IS only; GC+AM; GC+IS; AM+IS and GC+AM+IS (triple therapy). Triple therapy was the most frequent med pattern (32%); single agents were used in 21% of visits and biologicals in only 3%. Among visits where SLEDAI-2K was ≥10, triple therapy was used in 46%, with median [IQR] GC dose 10 [6, 24] mg/day; in contrast, among visits with SLEDAI-2K≤4 triple therapy was used in 28% (p 〈 0.01). Patients in LLDAS received less combination therapy than those who were not in LLDAS. Med persistence (survival analysis) varied widely, with lowest survivals for IS. Patients with time-adjusted mean SLEDAI-2K ≥10 had lower discontinuation of GC and higher discontinuation of IS including azathioprine, leflunomide and cyclosporine (Table 1). In contrast, increased time in LLDAS was associated with reduced discontinuation of AM and azathioprine. GC AM IS MPh MPhA AZA MTX CyA LEF Overall med survival, days to 25% discontinuation (95%CI) 1048 (938, 1197) 1267 (1113, 1428) 175 (175, 182) 387 (252, 756) 409 (350, 476) 525 (219, 686) 268 (182, 350) 329 (190, 524) Univariable associations,HR (95% CI) p-value Disease activity ≤4 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 〉 4 & 〈 10 0.69 (0.56, 0.84) p 〈 0.001 1.15 (0.92, 1.44) 0.2 0.92 (0.80, 1.05) 0.2 1.37 (0.78, 2.42) 0.3 1.16 (0.97, 1.39) 0.11 1.11 (0.72, 1.71) 0.6 1.26 (0.90, 1.77) 0.18 1.88 (1.07, 3.30) 0.03 ≥10 0.65 (0.35, 1.21) 0.18 1.56 (0.94, 2.59) 0.08 0.84 (0.45, 1.57) 0.6 1.92 (0.80, 4.63) 0.14 2.69 (1.86, 3.91) p 〈 0.001 1.85 (0.92, 3.71) 0.08 2.66 (1.36, 5.21) 0.004 1.62 (1.13, 2.32) 0.009 LLDAS 〈 50% 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 ≥50% 1.30 (1.09, 1.55) 0.003 0.67 (0.54, 0.84) 〈 0.001 1.22 (1.08, 1.40) 0.002 0.83 (0.44, 1.57) 0.6 0.83 (0.69, 1.00) 0.054 0.70 (0.46, 1.07) 0.10 1.29 (0.92, 1.83) 0.14 0.43 (1.5, 1.25) 0.12 Conclusion: In a large multicentre SLE cohort, most patients were receiving combination treatment. AM treatment survival was high and associated with low disease activity, GC survival was high and associated with high disease activity, while IS survival was low. Patients with high disease activity received more medication combinations but had reduced IS survival. These data suggest ongoing unmet need for improved medications for treatment of SLE. Reference: Golder, V., et al Lancet Rheum. 2019 1(2):e95-102 Disclosure of Interests: Rangi Kandane-Rathnayake Grant/research support from: The APLC has received financial (non-restricted educational) grants from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen, EMD Serono, Eli Lilly and UCB for the LLDAS Validation Study., Worawit Louthrenoo: None declared, Shue Fen Luo: None declared, Yeong-Jian Wu Consultant of: Pfizer, Lilly, Novartis, Abbvie, Roche, Speakers bureau: Lilly, Novartis, Yi-Hsing Chen Grant/research support from: Taiwan Ministry of Science and Technology, Taiwan Department of Health, Taichung Veterans General Hospital, National Yang-Ming University, GSK, Pfizer, BMS., Consultant of: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra & Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead., Paid instructor for: Pfizer, Novartis, Johnson & Johnson, Roche, Lilly, Astra & Zeneca, Sanofi, Astellas, Agnitio Science Technology, United Biopharma., Speakers bureau: Pfizer, Novartis, Abbvie, Johnson & Johnson, BMS, Roche, Lilly, GSK, Astra & Zeneca, Sanofi, MSD, Guigai, Astellas, Inova Diagnostics, UCB, Agnitio Science Technology, United Biopharma, Thermo Fisher, Gilead., Vera Golder: None declared, Aisha Lateef: None declared, Jiacai Cho: None declared, Sandra Navarra Speakers bureau: Astellas, Novartis, Pfizer, Johnson & Johnson, Abbvie, Leonid Zamora: None declared, Laniyati Hamijoyo Speakers bureau: Pfizer, Novartis, Tanabe, Abbot, Dexa Medica, Roche, Sargunan Sockalingam: None declared, Yuan An: None declared, Zhanguo Li: None declared, Yasuhiro Katsumata: None declared, masayoshi harigai Grant/research support from: AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., and Teijin Pharma Ltd. MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Oxford Immuotec, Pfizer Japan Inc., and Teijin Pharma Ltd. MH is a consultant for AbbVie, Boehringer-ingelheim, Kissei Pharmaceutical Co., Ltd. and Teijin Pharma., Yanjie Hao: None declared, Zhuoli Zhang: None declared, Madelynn Chan: None declared, Jun Kikuchi: None declared, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd., Fiona Goldblatt: None declared, Sean O’Neill: None declared, Chetan Karyekar Shareholder of: Johnson & Johnson, Consultant of: Janssen, Employee of: Janssen Global Services, LLC. Previously, Novartis, Bristol-Myers Squibb, and Abbott Labs., Jennifer H. Lofland Employee of: Janssen, Sang-Cheol Bae: None declared, Chak Sing Lau: None declared, Alberta Hoi: None declared, Mandana Nikpour: None declared, Eric F. Morand Grant/research support from: AstraZeneca, Consultant of: AstraZeneca, Speakers bureau: AstraZeneca

Abstract: Antibodies to Smith (Sm) have been described as one of the most specific autoantibodies for systemic lupus erythematosus (SLE). Other than its association with lupus nephritis, there is, however, limited understanding of its clinical significance 1,2 . Objectives To describe clinical associations and serum protein profiles of anti-Sm positivity in SLE. Methods Patients fulfilling SLE classification criteria who were followed longitudinally in a prospective multicentre cohort were studied according to their baseline anti-Sm antibody status. Comparison between Sm+ and Sm- patients was made using descriptive statistics. Clinical associations of Sm positivity with patient disease characteristics were studied using logistic regression. In a subset, 211 serum analytes were measured using Quantibody, Luminex and ELISA assays. Associations between serum proteins and Sm positivity were studied using Least Absolute Shrinkage and Selection Operator (LASSO) penalised regression, adjusting for demographics (age, sex, ethnicity) and medication use Results 383 patients were studied with median (IQR) follow-up of 4.9 (2,9) years; 65 (17%) had positive anti-Sm antibodies. Sm+ patients were significantly more likely to be of non-European ancestry (OR 2.73, 95% CI 1.55-4.82, p 〈 0.001), and to be positive for anti-dsDNA antibodies (OR 2.8, 95% CI 2.3-3.4, p 〈 0.001), anti-RNP antibodies (OR 15.7, 95% CI 13.9-17.8, p 〈 0.001), direct anti-globulin test (OR 2.36, 95% CI 2.07-2.7, p 〈 0.001) and hypocomplementemia (OR 7.73, 95% CI 5.1-11.7, p 〈 0.001). Sm+ patients were significantly more likely to have active disease during the observation period in a range of organ domains, including mucocutaneous, renal, vasculitis and fever. More Sm+ patients had episodes of High Disease Activity Status (HDAS, SLEDAI-2K ≧10) 3 (OR 3.07, 95% CI 1.70-5.54, p 〈 0.001) and persistent active disease (time-adjusted mean SLEDAI-2K 〉 4) (OR 3.23. 95% CI 1.84-5.70, p 〈 0.001). Conversely, fewer Sm+ patients attained LLDAS for ≥50% observed time (19.7% vs 41.8%, p=0.002). Sm+ patients were more likely to be treated with glucocorticoids, immunosuppressants, and rituximab. There was no significant difference in damage accrual between Sm + and Sm - patients. In serum protein analysis (n=197, 29 Sm+), LASSO modelling retained 3 proteins associated with Sm+ status, CXCL13, IL1RL1 and FLT1, along with Asian ethnicity and age. In analysis including pairwise interaction between predictors, 28 Sm+ associated proteins were identified, including CCL4, VCAM1, IL1RL1, Fcg R IIB/C, TDGF1, CEACAM1, TIMP1, BMP5, GDF15, and TNFRSF17. Conclusion Anti-Sm autoantibodies, present in 17% of SLE patients, were strongly associated with classical disease manifestations, more severe disease activity, and a specific serological and proteomic profile. These findings suggest anti-Sm+ SLE as a specific disease subset. References [1]Barada, FA., B.S. Andrews, J.S. Davis, R.P. Taylor, Antibodies to Sm in patients with systemic lupus erythematosus. Correlation of Sm antibody titers with disease activity and other laboratory parameters. Arthritis Rheum, 1981. 24 :1236-1244 [2]Arroyo-Avilla, M, Y. Santiago-Casas, G.McGwin, R.S. Cantor, M. Petri, R. Ramsey-Goldman, J.D. Reveille, R.P.Kimberly, G.S. Alarcon, L.M.Vila, E.E. Brown. Clinical Associations of anti-Smith antibodies in PROFILE: a multi-ethnic lupus cohort. 2015. 34 :1217-1223 [3]Koelmeyer, R., H.T. Nim, M. Nikpour, Y.B. Sun, A. Kao, O. Guenther, E. Morand, and A. Hoi, High disease activity status suggests more severe disease and damage accrual in systemic lupus erythematosus. Lupus Sci Med, 2020. 7 (1). Acknowledgements I would like to acknowledge participants and clinicians involved with the Australian Lupus Registry & Biobank Disclosure of Interests None declared