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Objectives: The lupus low disease activity state (LLDAS) allows for certain clinical and/or serological activity of SLE, provided overall disease activity does not exceed predefined cut-offs. This study aimed to evaluate the outcomes of patients who achieved LLDAS with clinical activity, serological activity only or neither clinical nor serological activity., Methods: Patients with SLE enrolled in a prospective multinational cohort from March 2013 to December 2020 who were in LLDAS at least once were included. Visits that fulfilled both LLDAS and Definition of Remission in SLE (DORIS) criteria were excluded., Results: 2099 patients were included, with median follow-up of 3.5 (IQR 1.3-5.8) years. At 6150 visits, patients were in LLDAS but not DORIS criteria; of these 1280 (20.8%) had some clinical activity, 3102 (50.4%) visits had serological activity only and 1768 (28.8%) visits had neither clinical nor serological activity. Multivariable regression analysis showed that compared with non-LLDAS, all three subsets of LLDAS had a protective association with flares in the ensuing 6 months and damage accrual in the ensuing 36 months. LLDAS with no clinical or serological activity had a significantly stronger protective association with severe flares in the ensuing 6 months compared with LLDAS with clinical activity (HR 0.47, 95% CI (0.27 to 0.82), p=0.007)., Conclusions: LLDAS without any clinical activity accounted for almost 80% of LLDAS visits. This study confirms that all subsets of LLDAS are associated with reduced flare and damage accrual. However, LLDAS without any clinical or serological activity has the strongest protective association with severe flares., Competing Interests: Competing interests: SO'N received consulting fees from AstraZeneca, Biogen, Boehringer Ingelheim; lecture/speaker fees from AstraZeneca, Biogen, Boehringer Ingelheim, Pfizer and GSK and research grants from Aurania, Biogen, Idorsia, Novartis. ZL received consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol-Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB and have royalties with Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol-Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB. SS received consulting fees from Pfizer, AstraZeneca, ZP Therapeutics. YK received payment/Honoria from Asahi Kasei, Astellas, AstraZeneca, Chugai, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Pfizer Japan and Sanofi. MH received speaker’s fee from AbbVie Japan, Ayumi, Boehringer Ingelheim Japan, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly Japan, GlaxoSmithKline, Kissei Pharmaceutical, Pfizer Japan, Takeda and Teijin; consultant fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Kissei Pharmaceutical and Teijin and research grants from AbbVie Japan GK, Asahi Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo. Eisai, KisseiPharmaceutical, Mitsubishi Tanabe, Nippon Kayaku, Sekisui Medical, Shionogi, Taisho, Takeda and Teijin. TT received grants from Astellas, Asahi Kasei, Chugai, Mitsubishi Tanabe, and consulting fees from Astellas, Chugai. KN received Advisory Board participation fees from AbbVie. YT has received research grants from Eli Lilly, AstraZeneca, AbbVie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer and Taiho. AH received research grants from AstraZeneca, and consulting fees from EUSA Pharma (UK), and Speaker/Honoraria from Limbic, Novartis, Moose Republic, AbbVie, Eli Lilly. RK-R received research grants from Novartis and GlaxoSmithKline. EM received research grants and/or consulting fees from AbbVie, AstraZeneca, Biogen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Genentech, GlaxoSmithKline, Genentech, Janssen, Novartis, Servier, EMD Serono, Takeda and UCB. MN received research grants and honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Janssen., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Cognitive dysfunction in SLE is common, but clinical risk factors are poorly understood. This study aims to explore the associations of cognitive dysfunction in SLE with disease activity, organ damage, biomarkers and medications., Methods: We performed cross-sectional cognitive assessment using a conventional neuropsychological test battery, with normative values derived from demographically matched healthy subjects. Endpoints included two binary definitions of cognitive dysfunction and seven individual cognitive domain scores. Clinical parameters included disease activity (SLEDAI-2K) and organ damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We performed regression analyses to determine associations between clinical parameters and cognitive endpoints., Results: 89 patients with SLE were studied, with median age of 45 and disease duration of 15 years. Organ damage was significantly associated with severe cognitive dysfunction (OR 1.49, CI 1.01-2.22) and worse cognitive test performance in three of the seven individual cognitive domains. In contrast, no significant associations were found between SLEDAI-2K at the time of cognitive assessment and any cognitive endpoints on multivariate analysis. Higher time-adjusted mean SLEDAI-2K was associated with better verbal memory scores but had no significant associations with other cognitive endpoints. The presence of anti-dsDNA antibodies and high IFN gene signature were negatively associated with severe cognitive dysfunction; there were no significant associations with the other autoantibodies studied or any medications. Substance use was significantly associated with lower psychomotor speed. Only 8% of patients who had cognitive dysfunction on testing had been recognised by clinicians on their SDI score., Conclusions: In SLE, cognitive dysfunction was positively associated with organ damage, but not associated with disease activity, and serological activity and high IFN signature were negatively associated. Cognitive dysfunction was poorly captured by clinicians. These findings have implications for preventative strategies addressing cognitive dysfunction in SLE., Competing Interests: Competing interests: SR reports a research grant from Lupus Victoria and postgraduate scholarships from the National Health and Medical Research Council (NHMRC), Arthritis Australia and the Australian Rheumatology Association. YG-J, VG, RK-R and JCS have nothing to disclose. EFM reports grants from Abbvie, Amgen, AstraZeneca, Biogen, BristolMyersSquibb, Eli Lilly, EMD Serano, Genentech, GlaxoSmithKline, Janssen and UCB, as well as consulting fees from AstraZeneca, Biogen, BristolMyersSquibb, Eli Lily, EMD Serano, Novartis, Servier and Zenas, all of which were outside the submitted work. EFM also reports payment or honoraria for educational events from AstraZeneca, Gilead and ONO, meeting support from AstraZeneca, patents with Monash University and AstraZeneca and director role for Rare Voices Australia. AH reports grants from AstraZeneca and Merck Serono outside the submitted work, Sponsorship of the Australian Lupus Registry and Biobank which is chaired by AH is received from Janssen, BMS, AstraZeneca and UCB. AH also reports meeting support from Janssen and consulting fees from Abbvie, Janssen and GSK. AH is honorary treasurer and board member for the Australian Rheumatology Association., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Type 1 interferon (IFN) is key to the pathogenesis of SLE, evidenced by the expression of IFN-stimulated genes (ISGs) in most patients, but the clinical utility of serial ISG assessment remains unknown. With the emergence of IFN-blocking drugs, we aimed to examine IFN status in relation to clinical findings longitudinally to provide insights into the value of testing ISG levels over time., Methods: Clinical data and whole blood were collected prospectively on adult patients with SLE from a single tertiary lupus centre. IFN status was measured using a panel of ISGs., Findings: 729 samples were analysed from 205 patients. At baseline, 62.9% of patients were IFN high, 30.2% IFN low and 6.8% borderline. 142 patients had multiple samples collected, and 87.3% of these demonstrated stable ISG status over time. In longitudinal follow-up, IFN high patients had higher activity in multiple organ domains and spent less time in Lupus Low Disease Activity State, but IFN score did not correlate with SLE Disease Activity Index in individual patients. In the small subset of patients who had large fluctuations in ISG across the observation period, most had high-dose glucocorticoids that correlated with ISG suppression. However, low-moderate-dose glucocorticoids did not suppress ISG expression., Conclusion: Although IFN high status is associated with indicators of more severe SLE, in the majority of patients, ISGs are stable across time and do not correlate with disease activity. Changes in ISG expression may be seen with high-dose, but not routine dose, glucocorticoid exposure. These findings suggest baseline but not serial ISG measurement may be of value in the management of SLE., Competing Interests: Competing interests: Outside the scope of this work, EM has received consulting fees from AbbVie, AstraZeneca, Amgen, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genetech, Janssen, Servier and UCB, and research grants from AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, EMD Serono and Janssen. AH has received research grants from AstraZeneca, Merck and BMS., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Fas/Fas ligand (FasL) and B cell-activating factor (BAFF) signalling have pivotal roles in SLE pathogenesis. We investigated the clinical associations of serum concentrations of soluble Fas (sFas) and soluble FasL (sFasL) in SLE and their relationship with BAFF., Methods: Serum sFas and sFasL were quantified by multiplex assay, and BAFF by ELISA, in 118 patients with SLE and 17 healthy controls (HC). SLE disease activity and organ damage were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics Damage Index., Results: sFas, sFasL and BAFF were detectable in all samples. Serum sFas and sFasL were significantly higher in SLE compared with HC. In univariable regression analyses, patients with active renal disease and those with flare had significantly higher levels of sFas compared with those without. High serum BAFF in patients with SLE was associated with increased sFas but not sFasL. The association between sFas and renal disease remained significant after adjusting for BAFF, but the association with flare attenuated. High sFas levels were associated with increased time-adjusted mean SLEDAI-2K, even after adjusting for BAFF, and with higher odds of flare over time. In contrast, high sFasL was associated with reduced organ damage over time. Serum sFasL/sFas ratio was negatively associated with active overall disease, flare and organ damage., Conclusions: Serum sFas is associated with active renal SLE, and active disease and flare over time, while sFasL/sFas ratio is negatively associated with disease activity and organ damage accrual. Treatments correcting abnormal levels of sFas/FasL may be worthy of evaluation in SLE., Competing Interests: Competing interests: EM has been a consultant to GSK and Eli Lilly. Other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To characterise the clinical relevance of urinary macrophage migration inhibitory factor (uMIF) concentrations in patients with systemic lupus erythematosus (SLE)., Methods: MIF, adjusted for urine creatinine, was quantified by ELISA in urine samples from 64 prospectively recruited patients with SLE. Serum MIF and urinary monocyte chemoattractant protein 1 (uMCP-1) were quantified by ELISA in a subset of patients (n = 39). Disease activity was assessed using the SLE Disease Activity Index-2000 (SLEDAI-2K) score., Results: uMIF was detectable in all patients with SLE. uMIF was positively correlated with overall SLEDAI-2K, was significantly higher in patients with SLE with high disease activity (SLEDAI-2K≥10) compared with those with inactive disease (SLEDAI-2K<4), and this association remained significant after adjusting for ethnicity, flare and use of immunosuppressants. uMIF was also significantly higher in SLE patients with flare of disease, although not confirmed in multivariable analysis. No significant differences in uMIF levels were observed according to the presence of renal disease activity, as assessed by renal SLEDAI-2K or biopsy-confirmed lupus nephritis. In contrast, uMCP-1 was significantly higher in SLE patients with active renal disease. uMIF expression was not associated with irreversible organ damage accrual or glucocorticoid use., Conclusions: These data suggest uMIF as a potential overall but not renal-specific SLE biomarker, whereas uMCP-1 is a renal-specific SLE biomarker., Competing Interests: Competing interests: EFM has been consultants to GSK and Eli Lilly. The other authors have no conflict of interest to declare. This study had no external funding source.

Objectives: To determine factors associated with damage accrual in a prospective cohort of patients with SLE., Methods: Patients with SLE who attended the Lupus Clinic at Monash Health, Australia, between 2007 and 2013 were studied. Clinical variables included disease activity (Systemic Lupus Erythematosus Disease Activity Index-2K, SLEDAI-2K), time-adjusted mean SLEDAI, cumulative glucocorticoid dose and organ damage (Systemic Lupus International Collaborating Clinics Damage Index (SDI)). Multivariate logistic regression analyses were performed to identify factors associated with damage accrual., Results: A total of 162 patients were observed over a median (IQR) 3.6 (2.0-4.7) years. Seventy-five per cent (n=121) of patients received glucocorticoids. Damage accrual was significantly more frequent in glucocorticoid-exposed patients (42% vs 15%, p<0.01). Higher glucocorticoid exposure was independently associated with overall damage accrual after controlling for factors including ethnicity and disease activity and was significant at time-adjusted mean doses above 4.42 mg prednisolone/day; the OR of damage accrual in patients in the highest quartile of cumulative glucocorticoid exposure was over 10. Glucocorticoid exposure was independently associated with damage accrual in glucocorticoid-related and non-glucocorticoid related domains of the SDI., Conclusions: Glucocorticoid use is independently associated with the accrual of damage in SLE, including in non-glucocorticoid related domains., Competing Interests: Conflicts of Interest: None declared.