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Objectives: This study aims to explore the treatment pattern of systemic lupus erythematosus (SLE) in Aotearoa/New Zealand., Methods: SLE patients were linked to the pharmaceutical dispensing data. The use of publicly funded anti-malarials, immunomodulators, biologics, glucocorticoids and bisphosphonates were compared by gender, ethnicity, age group, socioeconomic status and year of SLE identification. Adherence to hydroxychloroquine was examined using the medication possession ratio (MPR), with a MPR of ≥0.8 considered as high adherence., Results: Of the 2631 SLE patients, 73.8% used hydroxychloroquine, 64.1% used immunomodulators/biologics and 68.0% used 5 mg or more prednisone daily for at least 90 days. Women were more likely to use hydroxychloroquine than men. Asian patients had a different treatment pattern than other ethnic groups, and Māori were less likely to use hydroxychloroquine. The proportions of patients using different treatments decreased with age. Of the patients using hydroxychloroquine, 54.5% had high adherence. For patients over 40 years old and on long term prednisone, 47.3% had bisphosphonates and this figure was 17.8% for patients under the age of 40 years old. Patients with better socioeconomic status had a higher probability of using bisphosphonates than patients with lower socioeconomic status., Conclusions: Adherence to hydroxychloroquine in these patients varied and was lower in men and in Māori. Prednisone is commonly prescribed and used long term. Half of those over the age of 40 years old co-administered bisphosphonate. Further research is needed to identify the reasons for these discrepancies on SLE treatments by gender, ethnicity, age and socioeconomic status., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.)

Background: Validation of protective associations of the lupus low disease activity state (LLDAS) against flare, irreversible damage, health-related quality of life, and mortality has enabled the adoption of treat-to-target strategies in patients with systemic lupus erythematosus (SLE). Previous validation studies were of short duration, limiting the ability to detect longer term signals in flare rate and irreversible damage. In addition, previous studies have focused on percent time at target, rather than actual periods of time that are more useful in clinical practice and trials. We assessed long-term protective associations of LLDAS and remission, and specifically examined protective thresholds of sustained LLDAS and remission., Methods: Patients aged 18 years or older with SLE were followed up from May 1, 2013, to Dec 31, 2020 in a prospective, multinational, longitudinal cohort study. Patients were recruited from 25 centres in 12 countries. Multi-failure time-to-event analyses were used to assess the effect of sustained LLDAS on irreversible damage accrual (primary outcome; measured with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) and flare (key secondary outcome; measured with the SELENA Flare Index), with dose exposure and threshold effects studied. Sustained LLDAS or remission were defined as two or more consecutive visits over at least 3 months in the respective state. This study is registered with ClinicalTrials.gov, NCT03138941., Findings: 3449 patients were followed up for a median of 2·8 years (IQR 1·1-5·6), totalling 37 662 visits. 3180 (92·2%) patients were women, and 3031 (87·9%) were of Asian ethnicity. 2506 (72·7%) patients had sustained LLDAS at least once. Any duration of sustained LLDAS or remission longer than 3 months was associated with reduced damage accrual (LLDAS: hazard ratio 0·60 [95% CI 0·51-0·71], p<0·0001; remission: 0·66 [0·57-0·76], p<0·0001) and flare (LLDAS: 0·56 [0·51-0·63], p<0·0001; remission: 0·66 [0·60-0·73], p<0·0001), and increasing durations of sustained LLDAS corresponded to increased protective associations. Sustained DORIS remission or steroid-free remission were less attainable than LLDAS., Interpretation: We observed significant protective associations of LLDAS and remission against damage accrual and flare, establish a threshold of 3 months sustained LLDAS or remission as protective, and demonstrate deepening protection with longer durations of sustained LLDAS or remission., Funding: The Asia Pacific Lupus Collaboration receives project support grants from AstraZeneca, Bristol Myers Squibb, EMD Sereno, GSK, Janssen, Eli Lilly, and UCB., Competing Interests: Declaration of interests RK-R received grants from GSK and Novartis. SVN received consulting fees from Biogen, Boehringer Ingelheim, Astra Zeneca, Idorsia; payment for lectures from AstraZeneca, Boehringer Ingelheim, GSK, and Roche; participation in advisory board for Biogen; and leadership of societies, unpaid (CEO of Rheumatology Educational Trust Foundation, and Head of the SLE Special Interest Group at the Philippine Rheumatology Association). ZL received consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, and UCB, and has royalties with Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, and UCB. SS received consulting fees from Pfizer, AstraZeneca, and ZP Therapeutics. YK received payment or honoraria from GlaxoSmithKline, AstraZeneca, Sanofi, Pfizer Japan, Janssen Pharmaceutical, Chugai Pharmaceutical, Asahi Kasei Pharma, Astellas Pharma, and Mitsubishi Tanabe Pharma Corporation. MH received institutional research grants from GSK and Novartis; and honoraria for lectures from AstraZeneca and Astellas Pharma. ZZ received payment or honoraria from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Novartis, Pfizer, Roche, Sanofi, Janssen, and UCB; and participation in advisory board for Beigene. JK received speaker fees from GSK and Asahi Kasei. TT received grants from Astellas, Asahi Kasei, Chugai, and Mitsubishi Tanabe, and consulting fees from Astellas and Chugai. FG is Director of the Board of the Australian Rheumatology Association. KN received Advisory Board participation fees from AbbVie. YT received research grants from Boehringer Ingelheim, Taisho, and Chugai; and speaker fees or honoraria from AbbVie, Eisai, Chugai, Eli Lilly, Boehringer Ingelheim, GSK, Taisho, AstraZeneca, Daiichi-Sankyo, Gilead, Pfizer, UCB, Asahi-kasei, and Astellas. AH received a research grant from AstraZeneca; consulting fees from EUSA Pharma (UK); and speaker fees or honoraria from Limbic, Novartis, Moose Republic, AbbVie, and Eli Lilly. MN received an Investigator Grant from the National Health and Medical Research Council of Australia (NHMRC GNT1176538); research grants from Janssen and Boehringer Ingelheim; consulting fees from AstraZeneca and GSK; honoraria for presentations from AstraZeneca, GSK, and Boehringer Ingelheim; and support for conference attendance from Boehringer Ingelheim. EFM received consulting fees from AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Genetech, Janssen, Novartis, Servier, and EMD Serono. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objective: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE)., Methods: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare., Results: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up., Conclusion: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941)., (Copyright © 2024 by the Journal of Rheumatology.)

Objectives: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE)., Methods: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred., Results: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day., Conclusions: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients., Competing Interests: Competing interests: YK received honoraria from Asahi Kasei Pharma, Astellas Pharma, AstraZeneca K.K., Chugai Pharmaceutical, GlaxoSmithKline KK, Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma Corporation, Pfizer Japan, Sanofi KK. EI received honoraria from Bristol-Myers Squibb KK, Eisai and consulting fees from Nippontect Systems. MH received honoraria from AbbVie GK, Ayumi Pharmaceutical, Bristol-Myers Squibb K.K., Chugai Pharmaceutical, Eisai, Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical, Nippon Boehringer Ingelheim, Pfizer Japan, Takeda Pharmaceutical, Teijin Pharma, consulting fees from AbbVie GK, Bristol-Myers Squibb K.K., Kissei Pharmaceutical, Nippon Boehringer Ingelheim, Teijin Pharma, grant/research support from AbbVie GK, Asahi Kasei Pharma, Astellas Pharma, Ayumi Pharmaceutical, Bristol-Myers Squibb K.K., Chugai Pharmaceutical, Daiichi-Sankyo, Eisai, Kissei Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Kayaku, Sekisui Medical, Shionogi, Taisho Pharmaceutical, Takeda Pharmaceutical, Teijin Pharma. AH received honoraria from UCB, Janssen, Sandoz, Eli Lilly, consulting fees from AbbVie, GSK and grant/research support from AstraZeneca, GSK, Bristol Myers Squibb, Janssen, Merck Serono. CSL received honoraria from AstraZeneca UK and consulting fee from AstraZeneca Pharmaceuticals LP. ZL received honoraria from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB Pharma and consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB Pharma. SS received consulting fees from Pfizer, AstraZeneca, ZP Therapeutics and grant/research support from Pfizer, AstraZeneca, ZP Therapeutics. SVN received consulting fees from Biogen, Boehringer Ingelheim, AstraZeneca, grant/research support from Jannsen, Novartis, Pfizer, GSK and support for attending meetings from Biogen. SOon received royalty from Venetoclax. KN is on the advisory board for AbbVie. TT received honoraria from AbbVie GK, Chugai Pharmaceutical, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma, consulting fees from AbbVie GK, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma and grant/research support from AbbVie GK, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma. YT received honoraria from AbbVie GK, Asahi Kasei Pharma, AstraZeneca K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical, Eisai, Eli Lilly Japan K.K., Gilead Sciences, GlaxoSmithKline K.K., Nippon Boehringer Ingelheim, Pfizer Japan, Taiho Pharmaceutical, Taisho Pharmaceutical and grant/research support from Asahi Kasei Pharma, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Taisho Pharmaceutical. MN received honoraria from Actelion, GSK, Janssen, Pfizer, UCB, consulting fees from Boehringer Ingelheim, Certa Therapeutics, Eli Lilly, GSK, Janssen, Pfizer, UCB and grant/research support from Actelion, AstraZeneca, Bristol Myers Squibb, GSK, Janssen, UCB. EFM received honoraria from AstraZeneca, EMD Serono, Gilead, consulting fees from AstraZeneca, Bristol Myers Squibb, Biogen, Eli Lilly, EMD Serono, Novartis and grant/research support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Biogen, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, UCB. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: Disease activity monitoring in SLE includes serial measurement of anti-double stranded-DNA (dsDNA) antibodies, but in patients who are persistently anti-dsDNA positive, the utility of repeated measurement is unclear. We investigated the usefulness of serial anti-dsDNA testing in predicting flare in SLE patients who are persistently anti-dsDNA positive., Methods: Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorized based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare., Results: Data from 37 582 visits of 3484 patients were analysed. Of the patients 1029 (29.5%) had persistently positive anti-dsDNA and 1195 (34.3%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio [HR] 1.56; 95% CI: 1.30, 1.87; P < 0.001) and fluctuating cohort (adjusted HR 1.46; 95% CI: 1.28, 1.66), both for a ratio >3. Both increases and decreases in anti-dsDNA more than 2-fold compared with the previous visit were associated with increased risk of flare in the fluctuating cohort (adjusted HR 1.33; 95% CI: 1.08, 1.65; P = 0.008) and the persistently positive cohort (adjusted HR 1.36; 95% CI: 1.08, 1.71; P = 0.009)., Conclusion: Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Targets of treatment for systemic lupus erythematosus (SLE) include the Lupus Low Disease Activity State (LLDAS), remission, and complete remission. Whether treatment can be tapered after attaining these targets and whether tapering is safer in patients in complete remission compared with LLDAS are unknown. We aimed to assess the odds of disease flares after treatment tapering in stable disease, versus continuing the same therapy. We also aimed to examine whether tapering in complete remission resulted in fewer flares or longer time to flare compared with tapering in LLDAS or remission., Methods: This multinational cohort study was conducted at 25 sites across 13 Asia-Pacific countries. We included adult patients aged 18 years or older with stable SLE who were receiving routine clinical care, had two or more visits and had attained stable disease at one or more visits. We categorised stable disease into: LLDAS (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] score ≤4, Physician Global Assessment [PGA] ≤1, and prednisolone ≤7·5 mg/day); Definitions of Remission in SLE (DORIS) remission (clinical SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day); or complete remission on therapy (SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day). Stable disease categories were mutually exclusive. Tapering was defined as any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate). Using multivariable generalised estimating equations, we compared flares (SELENA-SLEDAI Flare Index) at the subsequent visit after drug tapering. We used generalised estimating equations and Cox proportional hazard models to compare tapering attempts that had begun in LLDAS, remission, and complete remission., Findings: Between May 1, 2013, and Dec 31, 2020, 4106 patients were recruited to the cohort, 3002 (73·1%) of whom were included in our analysis. 2769 (92·2%) participants were female, 233 (7·8%) were male, and 2636 (88·1%) of 2993 with ethnicity data available were Asian. The median age was 39·5 years (IQR 29·0-50·0). There were 14 808 patient visits for patients in LLDAS, or remission or complete remission, of which 13 140 (88·7%) entered the final multivariable model after excluding missing data. Among the 9863 visits at which patients continued the same therapy, 1121 (11·4%) flared at the next visit, of which 221 (19·7%) were severe flares. Of the 3277 visits at which a patient received a tapering of therapy, 557 (17·0%) flared at the next visit, of which 120 (21·5%) were severe flares. Tapering was associated with higher odds of flare compared with continuing the same therapy (odds ratio [OR] 1·24 [95% CI 1·10-1·39]; p=0·0005). Of 2095 continuous tapering attempts, 860 (41·1%) were initiated in LLDAS, 596 (28·4%) in remission, and 639 (30·5%) in complete remission. Tapering initiated in LLDAS (OR 1·37 [95% CI 1·03-1·81]; p=0·029) or remission (1·45 [1·08-1·94]; p=0·013) had higher odds of flare in 1 year compared with complete remission. Tapering in LLDAS (hazard ratio 1·24 [95% CI 1·04-1·48]; p=0·016) or remission (1·30 [1·08-1·56]; p=0·0054) had a significantly shorter time to first flare than tapering initiated in complete remission. Attaining sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit, flares in 1 year, and longer time to flare., Interpretation: Tapering of corticosteroids or immunosuppressive therapy in patients with stable SLE was associated with excess flares. Our findings suggest that drug tapering should be carefully considered, weighing the risks and benefits, and is best exercised in complete (clinical and serological) remission and after maintaining stable disease for at least 6 months., Funding: AstraZeneca, BMS, Eli Lily, Janssen, Merck Serono, GSK, and UCB., Competing Interests: Declaration of interests YK received honoraria from GSK, AstraZeneca, Sanofi, Pfizer Japan, Janssen Pharmaceutical, Chugai Pharmaceutical, Asahi Kasei Pharma, Astellas Pharma, and Mitsubishi Tanabe Pharma Corporation. MHa received payment for post-marketing surveillance from GSK; research grants from Novartis; and honoraria from GSK, AstraZeneca, and Astella Pharma. TT received research grants from Astellas Pharma, Asahi Kasei, Chugai, and Mitsubishi Tanabe, as well as consulting fees from Astellas Pharma and Chugai. KPKN is on the advisory board for AbbVie. SVN received consulting fees from Biogen and Boehringer Ingelheim; honoraria from Janssen, Novartis, Pfizer, and GSK; support for attending meetings from Pfizer; and is on the advisory board for Biogen. EFM received consulting fees from AstraZeneca, Biogen, Bristol Myers Squibb, Genentech, Janssen, Novartis, Servier, EMD, Serono, and Eli Lily. MN received research grants from Janssen; consulting fees from AstraZeneca, Boehringer Ingelheim, GSK, and Janssen; and honoraria from Janssen, Boehringer Ingelheim, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: In trials of systemic lupus erythematosus (SLE), the SLE Responder Index (SRI) is the most commonly used primary efficacy end point but has limited validation against long-term outcomes. We aimed to investigate associations of attainment of a modified version of the SRI (mSRI) with key clinical outcomes in SLE patients with up to 5 years of follow-up., Methods: We used data from a large multicenter, longitudinal SLE cohort in which patients received standard of care. The first visit with active disease (defined as SLE Disease Activity Index 2000 [SLEDAI-2K] score ≥6) was designated as baseline, and mSRI attainment (defined as a reduction in SLEDAI-2K ≥4 points with no worsening in physician global assessment ≥0.3 points) was determined at annual intervals from baseline up to 5 years. Associations between mSRI attainment and outcomes including disease activity, glucocorticoid dose, flare, damage accrual, Lupus Low Disease Activity State (LLDAS), and remission were studied., Results: We included 2,060 patients, with a median baseline SLEDAI-2K score of 8. An mSRI response was attained by 56% of patients at 1 year, with similar responder rates seen at subsequent annual time points. Compared to nonresponders, mSRI responders had significantly lower disease activity and prednisolone dose and higher proportions of LLDAS and remission attainment at each year, and less damage accrual at years 2 and 3. Furthermore, mSRI responder status at 1 year predicted clinical benefit at subsequent years across most outcomes, including damage accrual (odds ratio [OR] range 0.58-0.69, P < 0.05 for damage accrual ORs at all time points)., Conclusion: In SLE patients with active disease receiving standard of care, mSRI attainment predicts favorable outcomes over long-term follow-up, supporting the clinical meaningfulness of SRI attainment as an SLE trial end point., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: The selection and categorisation of laboratory tests in disease activity measures used within systemic lupus erythematosus (SLE) trial endpoints lack strong evidence. We aimed to determine whether longitudinal improvements in routinely measured laboratory tests are associated with measures of clinical improvement in patients with baseline active SLE., Methods: We included patients from a multicentre longitudinal cohort (recruited between May 1, 2013, and Dec 31, 2019) with active SLE (SLEDAI-2K ≥6) coinciding with an abnormality in at least one of 13 routine laboratory tests, at a visit designated as baseline. At 12 months, we analysed associations between thresholds of improvement in individual laboratory test results, measured as continuous variables, and five clinical outcomes using logistic regression. Primary outcomes were damage accrual and lupus low disease activity state (LLDAS), and secondary outcomes were modified SLE responder index (mSRI), physician global assessment (PGA) improvement of at least 0·3, and flare., Findings: We included 1525 patients (1415 [93%] women and 110 [7%] men, 1328 [87%] Asian ethnicity) in separate subsets for each laboratory test. The strongest associations with LLDAS and damage protection were seen with improvements in proteinuria (complete response: adjusted odds ratio [OR] 62·48, 95% CI 18·79-208·31 for LLDAS, OR 0·22, 95% CI 0·10-0·49 for damage accrual), albumin (complete response: adjusted OR 6·46, 95% CI 2·20-18·98 for LLDAS, OR 0·42, 95% CI 0·20-1·22 for damage accrual), haemoglobin (complete response: adjusted OR 1·97, 95% CI 1·09-3·53 for LLDAS, OR 0·33, 95% CI 0·15-0·71 for damage accrual), erythrocyte sedimentation rate (complete response: adjusted OR 1·71, 95% CI 1·10-2·67 for LLDAS, OR 0·53, 95% CI 0·30-0·94 for damage accrual), and platelets (complete response: adjusted OR 4·82, 95% CI 1·54-15·07 for LLDAS, OR 0·49, 95% CI 0·20-1·19 for damage accrual). Improvement in serological tests were mainly associated with PGA and mSRI. White cell and lymphocyte count improvements were least predictive., Interpretation: Improvements in several routine laboratory tests correspond with clinical outcomes in SLE over 12 months. Tests with the strongest associations were discrepant with laboratory tests included in current trial endpoints, and associations were observed across a range of improvement thresholds including incomplete resolution. These findings suggest the need to revise the use of laboratory test results in SLE trial endpoints., Funding: Abbvie., Competing Interests: Declaration of interests KC reports grants from the National Health and Medical Research Council and Royal Australian College of Physicians, personal fees from AstraZeneca, and sponsorship from Janssen and Pfizer. AH reports grants from Merck Serono, AstraZeneca, Janssen, Bristol Myers Squibb and UCB, personal fees from Abbvie, Janssen, and GlaxoSmithKline, sponsorship from Janssen, and honorary treasurer and board participation for Australia Rheumatology Association. SN reports personal fees from Biogen, Boehringer Ingelheim, Janssen, Novartis, Pfizer, and GlaxoSmithKline, sponsorship from Pfizer, and advisory board participation for Biogen. YK reports personal fees from GlaxoSmithKline, AstraZeneca, Sanofi, Pfizer Japan, Janssen, Chugai, Asahi-Kasei, Astellas, and Mitsubishi Tanabe Pharma. MH reports grants from Chugai, and personal fees from GlaxoSmithKline, Chugai, and AstraZeneca. KPLN reports advisory board participation for Abbvie. TT reports grants from Astellas, Asahi-Kasei, Chugai, and Mitsubishe-Tanabe, and personal fees from Astellas and Chugai. YT reports grants from Asahi-Kasei, Abbvie, Chugai, Eisai, Takeda, Daiichi-Sankyo, and Boehringer-Ingelheim, and personal fees from Behringer-Ingelheim, Eli Lilly, Abbvie, Gilead, AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, and GlaxoSmithKline. MN reports grants from Janssen, and personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen and Pfizer. EFM reports grants from Janssen, Astra-Zeneca, Bristol Myers Squibb, Eli Lilly, EMD Serono, GlaxoSmithKline, Genentech, UCB, Amgen, Abbvie, and Biogen; personal fees from Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Capella, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen, Neovacs, Novartis, Sanofi, Servier, UCB, Wolf, and Zenas; sponsorship from AstraZeneca; a patent application with Monash University; and a not-for-profit participation in Rare Voices of Australia. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Treat-to-target goals for patients with systemic lupus erythematosus (SLE) have been validated to protect against organ damage and to improve quality of life. We aimed to investigate the association between lupus low disease activity state (LLDAS) and remission and risk of mortality in patients with SLE. We hypothesised that LLDAS has a protective association with mortality risk., Methods: In this prospective, multinational, longitudinal cohort study, we used data from patients with SLE in the Asia Pacific Lupus Collaboration cohort collected between May 1, 2013, and Dec 31, 2020. Eligible patients were adults (aged ≥18 years) who met either the 1997 American College of Rheumatology modified classification criteria for SLE or the 2012 Systemic Lupus International Collaborating Clinics classification criteria. The primary outcome was all-cause mortality, and LLDAS, remission, and variations of remission with lower glucocorticoid thresholds were the primary exposure variables. Survival analyses were used to examine longitudinal associations between these endpoints and risk of mortality. This study is registered with ClinicalTrials.gov, NCT03138941., Findings: Among a total of 4106 patients in the cohort, 3811 (92·8%) patients were included in the final analysis (median follow-up 2·8 years [IQR 1·0-5·3]; 3509 [92·1%] women and 302 [7·9%] men), of whom 80 died during the observation period (crude mortality rate 6·4 deaths per 1000 person-years). LLDAS was attained at least once in 43 (53·8%) of 80 participants who died and in 3035 (81·3%) of 3731 participants who were alive at the end of the study (p<0·0001); 22 (27·5%) participants who died versus 1966 (52·7%) who were alive at the end of the study attained LLDAS for at least 50% of observed time (p<0·0001). Remission was attained by 32 (40·0%) of 80 who died and in 2403 (64·4%) of 3731 participants who were alive at the end of the study (p<0·0001); 14 (17·5%) participants who died versus 1389 (37·2%) who were alive at the end of the study attained remission for at least 50% of observed time (p<0·0001). LLDAS for at least 50% of observed time (adjusted hazard ratio 0·51 [95% CI 0·31-0·85]; p=0·010) and remission for at least 50% of observed time (0·52 [0·29-0·93]; p=0·027) were associated with reduced risk of mortality. Modifying the remission glucocorticoid threshold (<5·0 mg/day prednisolone) was more protective against mortality than current remission definitions (0·31 [0·12-0·77]; p=0·012), and glucocorticoid-free remission was the most protective (0·13 [0·02-0·96]; p=0·046)., Interpretation: LLDAS significantly reduced the risk of mortality in patients with SLE. Remission did not further reduce the risk of mortality compared with LLDAS, unless lower glucocorticoid thresholds were used., Funding: The Asia-Pacific Lupus Collaboration received funding from Janssen, Bristol Myers Squibb, Eli Lilly, and UCB for this study., Competing Interests: Declaration of interests SVN has received consulting fees from Biogen and Boehringer Ingelheim; lecture or speaker fees from Janssen, Novartis, Pfizer, and GlaxoSmithKline; conference registration fees from Pfizer; and payment from Biogen for participation on an advisory board. YK has received payment or honouria from GlaxoSmithKline, AstraZeneca, Sanofi, Pfizer Japan, Janssen Pharmaceutical, Chugai Pharmaceutical, Asahi Kasei Pharma, Astellas Pharma, and Mitsubishi Tanabe Pharma Corporation. MH has received payment for post-marketing surveillance from GlaxoSmithKline; research grants from Novartis Pharma; and honoraria for lectures for GlaxoSmithKline, AstraZeneca, and Astellas Pharma. TT has received grants from Astellas, Asahi Kasei, Chugai, and Mitsubishi Tanabe; and consulting fees from Astellas and Chugai. KPLN has received advisory board participation fees from AbbVie. DYY is an employee of Janssen. CSK is a stock owner and an employee of Janssen. MN has received research grants from Janssen; and consulting fees from AstraZeneca, Boehringer & Ingelheim, GlaxoSmithKline, and Janssen. EFM has received consulting fees from AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Genetech, Janssen, Novartis, Servier, and EMD Serono. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes., Methods: Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI)., Results: A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI] = 4.98 [2.07, 12.0], p<0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI] = 5.45 [2.75, 10.8], p<0.001) patients., Conclusion: Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality., (© 2022. The Author(s).)

Genetic and environmental factors appear to contribute to the pathogenesis of systemic lupus erythematosus (SLE). Viral infections have been reported to be associated with the disease. A number of exogenous viruses have been linked to the pathogenesis of SLE, of which Epstein-Barr virus (EBV) has the most evidence of an aetiological candidate. In addition, human endogenous retroviruses (HERV), HRES-1, ERV-3, HERV-E 4-1, HERV-K10 and HERV-K18 have also been implicated in SLE. HERVs are incorporated into human DNA, and thus can be inherited. HERVs may trigger an autoimmune reaction through molecular mimicry, since homology of amino acid sequences between HERV proteins and SLE autoantigens has been demonstrated. These viruses can also be influenced by oestrogen, DNA hypomethylation, and ultraviolet light (UVB) exposure which have been shown to enhance HERV activation or expression. Viral infection, or other environmental factors, could induce defective apoptosis, resulting in loss of immune tolerance. Further studies in SLE and other autoimmune diseases are needed to elucidate the contribution of both exogenous and endogenous viruses in the development of autoimmunity. If key peptide sequences could be identified as molecular mimics between viruses and autoantigens, then this might offer the possibility of the development of blocking peptides or antibodies as therapeutic agents in SLE and other autoimmune conditions.