Maria Dall'Era’s research while affiliated with University of California, San Francisco and other places

Objective Recent research has explored frailty in systemic lupus erythematosus using multiple measures. We examined the agreement among frailty measures and the association of each with cross‐sectional and longitudinal health outcomes. Methods We used data from the California Lupus Epidemiology Study to examine the following measures of frailty: Systemic Lupus International Collaborating Clinics (SLICC) Frailty Index (SLICC‐FI), Short Physical Performance Battery (SPPB), and Fatigue, Resistance, Ambulation, Illness, and Loss of Weight (FRAIL) scale questionnaire. Patient‐Reported Outcomes Measurement Information System Physical Function 10a (PF) was tested as a proxy measure of frailty. Agreement between frailty classifications by each measure was assessed. Cross‐sectional associations of frailty classifications with hospitalization, valued life activities disability, cognitive impairment, six‐minute walk test distance, self‐reported disease damage, fatigue, and depressive symptoms were assessed with logistic and linear regression analyses. Associations with hospitalization, disease damage increase, and disability increase over the subsequent three years were assessed by Cox proportional hazards analyses. Results Percentages of participants identified as frail varied among the measures, from 10.8% to 45.9%. Agreement among classifications ranged from slight to substantial (k from 0.17 to 0.63). Most of the frailty measures were associated with both cross‐sectional and longitudinal health outcomes, with the notable exception of the SPPB. SLICC‐FI had the most consistent association with outcomes, followed by FRAIL and PF. Conclusion Multiple measures of frailty appear to identify the risk of poor health outcomes. The intended use, as well as the simplicity and practicality of implementing the measure, may be the most important considerations in choosing a frailty measure.

Background Systemic lupus erythematosus (SLE) has numerous symptoms across organs and an unpredictable flare-remittance pattern. This has made it challenging to understand drivers of long-term SLE outcomes. Our objective was to identify whether changes in DNA methylation over time, in an actively flaring SLE cohort, were associated with remission and whether these changes meaningfully subtype SLE patients. Methods Fifty-nine multi-ethnic SLE patients had clinical visits and DNA methylation profiles at a flare and approximately 3 months later. Methylation was measured using the Illumina EPIC array. We identified sites where methylation change between visits was associated with remission at the follow-up visit using limma package and a time x remission interaction term. Models adjusted for batch, age at diagnosis, time between visits, age at flare, sex, medications, and cell-type proportions. Separately, a paired T-test identified Bonferroni significant methylation sites with ≥ 3% change between visits (n = 546). Methylation changes at these sites were used for unsupervised consensus hierarchical clustering. Associations between clusters and patient features were assessed. Results Nineteen patients fully remitted at the follow-up visit. For 1,953 CpG sites, methylation changed differently for remitters vs. non-remitters (Bonferroni p < 0.05). Nearly half were within genes regulated by interferon. The largest effect was at cg22873177; on average, remitters had 23% decreased methylation between visits while non-remitters had no change. Three SLE patient clusters were identified using methylation differences agnostic of clinical outcomes. All Cluster 1 subjects (n = 12) experienced complete flare remission, despite similar baseline disease activity scores, medications, and demographics as other clusters. Methylation changes at six CpG sites, including within immune-related CD45 and IFI genes, were particularly distinct for each cluster, suggesting these may be good candidates for stratifying patients in the future. Conclusions Changes in DNA methylation during active SLE were associated with remission status and identified subgroups of SLE patients with several distinct clinical and biological characteristics. DNA methylation patterns might help inform SLE subtypes, leading to targeted therapies based on relevant underlying biological pathways.

Background Physical activity is an adjunctive therapy that improves symptoms in people living with systemic lupus erythematosus (SLE), yet the mechanisms underlying this benefit remain unclear. Methods We carried out a cohort study of 123 patients with SLE enrolled in the California Lupus Epidemiology Study (CLUES). The primary predictor variable was self-reported physical activity, which was measured using a previously validated instrument. We analyzed peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) data available from the cohort. From the scRNA-seq data, we compared immune cell frequencies, cell-specific gene expression, biological signalling pathways, and upstream cytokine activation states between physically active and inactive patients, adjusting for age, sex and race. Findings We found that physical activity influenced immune cell frequencies, with sedentary patients most notably demonstrating greater CD4+ T cell lymphopenia (Padj = 0.028). Differential gene expression analysis identified a transcriptional signature of physical inactivity across five cell types. In CD4+ and CD8+ T cells, this signature was characterized by 686 and 445 differentially expressed genes (Padj < 0.1). Gene set enrichment analysis demonstrated enrichment of proinflammatory genes in the TNF-α signalling through NF-kB, interferon-γ (IFN-γ), IL2/STAT5, and IL6/JAK/STAT3 signalling pathways. Computational prediction of upstream cytokine activation states suggested CD4+ T cells from physically inactive patients exhibited increased activation of TNF-α, IFN-γ, IL1Β, and other proinflammatory cytokines. Network analysis demonstrated interconnectivity of genes driving the proinflammatory state of sedentary patients. Findings were consistent in sensitivity analyses adjusting for corticosteroid treatment and physical function. Interpretation Taken together, our findings suggest a mechanistic explanation for the observed benefits of physical activity in patients with SLE. Specifically, we find that physical inactivity is associated with altered frequencies and transcriptional profiles of immune cell populations and may exacerbate pathologic inflammatory signalling via CD4+ and CD8+ T cells. Funding This work was supported by the US 10.13039/100000002National Institutes of Health (NIH) (R01 AR069616, K23HL138461-01A1, K23AT011768) the US 10.13039/100000030CDC (U01DP0670), and the CZ Biohub.

Introduction High-dose glucocorticoid (GC)-based dual immunosuppressive treatment regimens are still frequently used in active lupus nephritis (LN) despite their known association with dose-dependent toxicities and incomplete efficacy. We hypothesised that the addition of voclosporin to low-dose GCs and mycophenolate mofetil (MMF) would reduce exposure to the toxicities of high-dose GC-based dual immunosuppressive therapy regimens, resulting in an improved safety profile without compromising efficacy. Methods Propensity score matching generated two groups of matched participants from the voclosporin arms (in combination with MMF (2 g/day) and low-dose GCs) of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies and the MMF (3 g/day) and intravenous cyclophosphamide (IVC) arms (both in combination with high-dose GCs) of the Aspreva Lupus Management Study (ALMS) induction study. Safety and efficacy outcomes were assessed over 6 months. Results There were 179 matched participants identified between the AURA-LV/AURORA 1 studies and ALMS. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS; more voclosporin-treated participants reported AEs by preferred term of glomerular filtration rate decreased, hypertension and anaemia. The incidence of serious AEs was similar across treatments. There were four (2.2%) deaths in IVC- and MMF-treated participants of ALMS compared with seven (3.9%) deaths in voclosporin-treated participants. Significantly more voclosporin-treated participants achieved a ≥25% reduction in urine protein creatinine ratio (UPCR) from baseline at 3 months and ≥50% reduction in UPCR from baseline at 6 months. Conclusions Compared with the high-dose GC-based regimens used in ALMS, voclosporin-based triple immunosuppressive therapy resulted in fewer AEs overall and greater and earlier reductions in proteinuria over the first 6 months of treatment. These data reinforce the feasibility of using low doses of GCs and MMF to treat LN when combined with voclosporin as a third agent.

Objective There is an established yet unexplained link between interferon (IFN) and systemic lupus erythematosus (SLE). The expression of sequences derived from transposable elements (TEs) may contribute to SLE phenotypes, specifically production of type I IFNs and generation of autoantibodies. Methods We profiled cell‐sorted RNA‐sequencing data (CD4⁺ T cells, CD14⁺ monocytes, CD19⁺ B cells, and natural killer cells) from peripheral blood mononuclear cells of 120 patients with SLE and quantified TE expression identifying 27,135 TEs. We tested for differential TE expression across 10 SLE phenotypes, including autoantibody production and disease activity. Results We found 731 differentially expressed (DE) TEs across all SLE phenotypes that were mostly cell specific and phenotype specific. DE TEs were enriched for specific families and open reading frames of viral genes encoded in TE sequences. Increased expression of DE TEs was associated with genes involved in antiviral activity, such as LY6E, ISG15, and TRIM22, and pathways such as IFN signaling. Conclusion These findings suggest that expression of TEs contributes to activation of SLE‐related mechanisms in a cell‐specific manner, which can impact disease diagnostics and therapeutics.

Objective Our objective was to evaluate the effect of glucocorticoid regimens on renal response, infections, and mortality among patients with lupus nephritis (LN). Methods We performed a systematic review and meta‐analysis of the control arms of randomized clinical trials (RCTs). We included RCTs of biopsy‐proven LN that used a protocolized regimen of glucocorticoids in combination with mycophenolic acid analogs or cyclophosphamide and reported the outcomes of complete response (CR), serious infections, and death. The starting dosage of glucocorticoids, tapering method, and administration of glucocorticoid pulses were abstracted. Meta‐analysis of proportions, meta‐regression, and subgroup meta‐analysis were performed at 6 and 12 months for all outcomes. Results Fifty RCT arms (3,231 patients with LN) were included. The predicted rates of CR, serious infections, and death when starting on oral prednisone at 25 mg/day without pulses were 19.5% (95% confidence interval [CI] 7.3–31.5), 3.2% (95% CI 2.4–4.0), and 0.2% (95% CI 0.0–0.4), respectively. Starting on prednisone at 60 mg/day (without pulses) increased the rates to 34.6% (95% CI 16.9–52.3), 12.1% (95% CI 9.3–14.9), and 2.7% (95% CI 0.0–5.3), respectively. Adding glucocorticoid pulses increased the rates of CR and death but not serious infections. We observed a dose–response gradient between the initial glucocorticoid dosage and all the outcomes at six months after accounting for the administration of glucocorticoid pulses, underlying immunosuppressant, and baseline proteinuria. Conclusion A higher exposure to glucocorticoids during the initial therapy of LN was associated with better renal outcomes at the cost of increased infections and death.

Background Systemic Lupus Erythematosus Responder Index 4 (SRI-4) and British Isles Lupus Assessment Group (BILAG)–based Composite Lupus Assessment (BICLA) responses are the most common primary endpoints in systemic lupus erythematosus (SLE) randomized controlled trials (RCTs). Discordance between SRI-4 and BICLA effect sizes in RCTs has engendered skepticism about the utility of these composite indices. Objectives In this post hoc analysis of 2 SLE RCTs, we examined concordance in SRI-4 and BICLA outcome measures among participants receiving placebo and standard of care (SOC) and explored reasons for SRI-4 and BICLA discordance. Methods This analysis included data from participants on SOC with evaluable BICLA and SRI-4 response enrolled in the placebo arms of the EXPLORER (n=87; NCT00137969)1 and ATHOS (n=80; NCT02908100)2 RCTs. SRI-4 and BICLA data from Weeks 24 and 52 in EXPLORER and Weeks 24 and 48 in ATHOS were analyzed. Both RCTs had the entry criterion of an SLE Disease Activity Index (SLEDAI) score of ≥6. The trials applied 2 different corticosteroid taper protocols: EXPLORER had an oral corticosteroid target dose of prednisone (or equivalent) of ≤10 mg/d by Week 12 and ≤5 mg/d by Week 52, and ATHOS had a target of <10 mg/d by Weeks 12 and 36. Disease activity was measured using BILAG and SELENA-SLEDAI in EXPLORER and BILAG-2004 and SLEDAI-2K in ATHOS. For this analysis, participants were classified as either responders or nonresponders based on the SRI-4 and BICLA composite indices, as well as the presence of an intercurrent event, and concordance and discordance frequencies between SRI-4 and BICLA were determined. Overall concordance between SRI-4 and BICLA was estimated by the Cohen κ score. Results In EXPLORER, SRI-4 placebo response rates were greater than BICLA response rates, whereas in ATHOS, SRI-4 and BICLA placebo response rates were similar (Figure 1). Across both trials, SRI-4 and BICLA placebo responses ranged from 40.2% to 45.0% and 29.9% to 47.5%, respectively. At Weeks 24 and 48/52, SRI-4 and BICLA concordance was 0.43 and 0.46 in EXPLORER and 0.60 and 0.54 in ATHOS, respectively (Figure 2). Discordance between SRI-4 and BICLA varied by trial (range, 25.3%-26.4% in EXPLORER and 20.0%-22.5% in ATHOS). In EXPLORER, SRI-4+/BICLA− discordance was high at 18.4% at Week 52. In ATHOS, the low SRI-4+/BICLA− discordance of 12.5% was in line with the similar SRI-4 and BICLA responses at Week 48. Conclusion Discordance between SRI-4 and BICLA in the EXPLORER and ATHOS trials varied, with the largest difference found in SRI-4 and BICLA placebo responders at Week 52 in EXPLORER; however, the trials cannot be directly compared due to differences in the use of rescue therapies and variants of instruments used. Potential reasons for discordance within studies warranting further evaluation include differences in how domain-specific changes are captured in the SLEDAI and BILAG instruments, especially with regard to the musculoskeletal, mucocutaneous and serologic domains. While BILAG does not capture any immunologic changes (eg, low complement or elevated anti–double-stranded DNA antibody), it does enable capture of partial improvement in each domain, whereas the SLEDAI instruments only permit a binary (present or absent) response for each disease manifestation. As such, BICLA has the advantage over SRI-4 in better detecting partial—but clinically meaningful—changes in SLE disease activity. Evaluating patient-level data inclusive of patient-reported outcomes may also provide insights into the reasons for the SRI-4+/BICLA− discordance. REFERENCES [1] Merril JT, et al. Arthritis Rheumatol. 2010;62(1):222-233.[2] Isenberg D, et al. Arthritis Rheumatol. 2021;73(10):1835-1846. • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint Acknowledgements Funded by F. Hoffmann-La Roche Ltd. Editorial assistance was provided by Nucleus Global and funded by F. Hoffmann-La Roche Ltd. Disclosure of Interests Anca Askanase has been an investigator and/or consultant for AbbVie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly and Company, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer and UCB, Edward M. Vital has received consulting fees from Roche/Genentech, AstraZeneca, Otsuka, Novartis, Eli Lilly and Company, Pfizer, Merck, AbbVie and UCB., Oliver Meier is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Armando Turchetta is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Huiyan (Ashley) Mao is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of F. Hoffmann-La Roche Ltd, Justine Maller is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of Genentech, Inc, Jorge A. Ross Terres is a shareholder of F. Hoffmann-La Roche Ltd, and an employee of Genentech, Inc, Maria Dall’Era reports professional services for Genentech, Aurinia, GSK, AstraZeneca and Eli Lilly and Company.

Background The Treatment Response Measure for Systemic Lupus Erythematosus (TRM-SLE) is a novel clinical outcome assessment (COA) to define meaningful improvement in disease activity for the purpose of SLE randomised clinical trials (RCTs), being developed by an international taskforce of clinicians, patient partners and industry representatives. To support regulatory approval of new treatments, contemporary guidelines require that clinical trials must demonstrate treatment benefit relevant to how patients “feel, function or survive”, as measured by COAs specific for the RCT context of use [1]. Objectives The aim of this study was to establish consensus on the outcome domains with which to define meaningful improvement in disease activity in the novel TRM-SLE instrument, considering both patient and clinician perspectives as well as clinical trial utility. Methods Candidate domains identified by surveying TRM-SLE Taskforce members were rated in a two-stage modified Delphi study. Each stage comprised two online survey rounds, separated by a structured discussion meeting. In Stage 1 clinicians and patient partners rated domain “importance” (impact on SLE symptoms, function or survival). In Stage 2, clinicians rated “important” domains on three further characteristics relevant to RCT utility: “appropriateness” for evaluating disease activity, “representation” among patients with active SLE, and “measurability” in an RCT context. Ratings of “importance” and “representation” were supported by the results of targeted literature reviews. The prespecified consensus threshold for each Delphi round was a rating of 7 or more (0-9) by at least 70% of participants, with consensus on all four characteristics rated across the two Delphi stages required for inclusion in TRM-SLE. Results The domain generation survey completed by 36/59 (61%) TRM-SLE Taskforce members yielded 34 candidate outcome domains. Of 118 invitees to the modified Delphi study, 87/102 (85%) clinicians with a median (IQR) of 21 (11, 30) years’ experience and 13/16 (81%) patient partners with median (IQR) disease duration 19 (16,33) years completed at least one Delphi round, with representation from six continents. In Stage 1, 14 domains met consensus on “importance” in both clinician and patient groups, and 11 domains met consensus on “importance” amongst patients only (Table 1). These 25 “important” domains were rated in Stage 2, after which eight domains (alopecia, arthritis, haemolytic anaemia, mucosal ulcers, nephritis, rash, serositis and thrombocytopenia) also reached consensus on all of “appropriateness”, “representation” and “measurability” (Table 2). Notably, two domains ultimately meeting consensus for inclusion in TRM-SLE were rated “important” in Stage 1 by patients only, highlighting the vital contribution of the patient perspective. Conclusion We reached consensus on eight domains (alopecia, arthritis, haemolytic anaemia, mucosal ulcers, nephritis, rash, serositis and thrombocytopenia) which will define meaningful change in disease activity in TRM-SLE, considering patient and clinician perspectives on importance, and utility in an RCT context. In the next stage of the TRM-SLE project working groups will reach consensus on the measurement, scoring and thresholds defining response for each of these domains. REFERENCES [1] FDA Patient Focused Drug Development Guidance: Selecting, Developing or Modifying Fit-for-Purpose Clinical Outcome Assessments. https://www.fda.gov/media/159500/download Table 1 Proportion of participants rating domains highly based on “importance”, defined as being associated with how a patient feels, functions or survives when assessing treatment effect in an SLE clinical trial, after two Delphi voting rounds. • Download figure • Open in new tab • Download powerpoint Table 2 Proportion of participants rating “important” domains highly on “appropriateness”, “representation” and “measurability” when assessing treatment effect in an SLE clinical trial, after two Delphi voting rounds. • Download figure • Open in new tab • Download powerpoint Acknowledgements We would like to acknowledge all members of the TRM-SLE Taskforce and those who generously contributed their time and expertise to our Delphi study. Disclosure of Interests Kathryn Connelly: None declared, Rachel Koelmeyer: None declared, Darshini Ayton: None declared, John May: None declared, Kate Gregory: None declared, Laura Eades: None declared, Raychel Barallon: None declared, Rangi Kandane-Rathnayake GSK, Novartis (Institutional research grants), Vera Golder: None declared, Afia Anzum: None declared, Maisarah Mydin: None declared, Munni Akther: None declared, Alan Friedman Abbvie, Anca Askanase Investigator/Consultant for Abbvie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer and UCB, Cynthia Aranow AstraZeneca, GSK, Kezar Inc, Bristl Myers Squibb, Kezar Inc., Edward M. Vital Novartis, AstraZeneca, UCB, Novartis, Roche, Pfizer, UCB, AstraZeneca, Novartis, Abbvie, Merck, Lilly, Otsuka, AstraZeneca, Sandoz, Guillermo Pons-Estel Boehringer Ingelheim, GSK, Janssen, Novartis and Pfizer, AstraZeneca, Boehringer Ingelheim, GSK, Janssen, Novartis, Pfizer and RemeGen, Janssen, Hermine Brunner AZ, BI, Novartis, Pfizer, UCB, BMS, TAKEDA, Kenneth C. Kalunian BMS, GSK, Artiva, Cabaletta Bio, Roche/Genentech, AstraZeneca, Artiva, Eli Lilly, Kezar, Aurinia, Abbvie, Khadija Dantata: None declared, Laurent Arnaud Alexion, Amgen, Astra-Zeneca, Abbvie, Biogen, BMS, Boehringer-Ingelheim, Cêmka, GSK, Grifols, Janssen, LFB, Lilly, Menarini France, Medac, Novartis, Oséus, Pfizer, Roche-Chugaï, Sêmeia, UCB, Laurie Burke Multiple across many different therapeutic areas; no active consulting in SLE., Lee Simon: None declared, Qing Zuraw: None declared, Sandra Garces Amgen, Amgen- Executive role, Victoria Werth Gilead, Lilly, BMS, Nektar, Abbvie, Akira, Viela, GSK, EMD Serona, Sanofi, Xencor, ONO, Cabaletta, Pfizer, Corbus, Amgen, Janssen, Biogen, Gilead, Viela, Ventus, Regeneron, Argenx, Ying Sun Yes, Merck KGaA, Darmstadt, Germany, Yoshiya Tanaka Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho, Mitsubishi-Tanabe, Eisai, Chugai, Taisho, Youmna Lahoud Biogen, Biogen, Alain Cornet: None declared, Alessandro Sorrentino: None declared, Anisur Rahman Lilly, Anna Stevens Multiple - Abbvie, Amgen, AstraZeneca, Aurinia, BMS, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Mallinckrodt, Pfizer and UCB, Catherine Barbey Biogen, Biogen, Dzifa Dey Pfizer, Roche, Elaine Karis Amgen Inc, Amgen Inc, Eloisa Bonfa: None declared, Erika Noss Johnson and Johnson Innovative Medicine, Eve MD Smith: None declared, George Stojan UCB, Jeanette Andersen: None declared, Joan Merrill UCB, GlaxoSmithKline, Abbvie, EMD Serono, Janssen, Lilly, Genentech, Aurinia, Provention, Remegen, Celgene/Bristo Myers Squibb, AstraZeneca, Amgen, Astellas, Alexion, Sanofi, Zenas, Joseph F. Merola Consultant and/or investigator for multiple complanies - Amgen, Astra-Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Abbvie, Dermavant, Eli Lilly, Incyte, Moonlake, Novartis, Janssen, UCB, Sanofi-Regeneron, Sun Pharma, Biogen, Pfizer and Leo Pharma, Jorge A. Ross Terres Genentech/Roche, Genentech/Roche, Joy Buie Novartis, Aurinia, Justine Maller Genentech/Roche, Genentech/Roche, Karen Costenbader BMS, GSK, Cabaletta Bio, Merck, Gilead, Marta Mosca GSK, Astra Zeneca, Janssen, ASTRA ZENECA, ABBVIE, UCB, GKS, OTSUKA, GSK, Maja Hojnik Eli Lilly and Company (Lilly), Maria Dall’Era Genentech, Aurinia, GSK, AstraZeneca, Janssen, Nikolay Delev BMS, Richard A. Furie AZ; GSK, BMS, GSK, Genentech, AZ, Biogen, GMS, GSK, Genentech, Biogen, Kyverna, Ronald F. van Vollenhoven AbbVie, AstraZeneca, BMS, Galapagos, GSK, Janssen, Pfizer, UCB, AbbVie, AstraZeneca, Biogen, BMS, Galapagos, GSK, Janssen, Pfizer, RemeGen, UCB, AstraZeneca, BMS, Galapagos, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, Subhashis Banerjee BMS, BMS, Eric Morand AstraZeneca, Merck, Gilead, Roche, EMD Serono, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Novartis, AbbVie, Galapagos, IgM, AbbVie, Amgen, AstraZeneca, Biogen, BMS, Eli Lilly, EMD Serono, Genetech, GSK, Janssen, UCB (all institutional).

Background Lupus nephritis (LN) is characterized by proteinuria, which is not only a marker of active kidney inflammation, but also a driver of progressive kidney injury. Early reduction in proteinuria following treatment initiation has been shown to be a predictor of long-term kidney survival and overall mortality. The AURA-LV and AURORA 1 clinical trials have shown that voclosporin-based triple therapy with lower-dose MMF, and low-dose glucocorticoids (GCs) led to early and significant reductions in proteinuria with an acceptable safety profile. However, dual-immunosuppressive regimens containing high-dose glucocorticoids (GCs) and higher doses (>2 g/day) of mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) are still frequently used for the management of active LN in the belief that they may be more efficacious and safer. Objectives To compare the safety and efficacy of a voclosporin-based, triple immunosuppressive regimen to a dual-immunosuppressive regimen for the treatment of active LN, we analyzed outcomes in propensity-matched participants from the ALMS, AURA-LV, and AURORA 1 studies. We hypothesized that a voclosporin-based, triple therapy approach would reduce exposure to the toxicities associated with higher doses of GCs, MMF, and IVC, resulting in an improved safety profile without compromising efficacy. Methods All three studies enrolled participants with active LN. In AURA-LV and AURORA 1, participants received voclosporin 23.7 mg BID in combination with MMF (target 2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (target 3 g/day) or IVC (0.5 to 1.0 g/m²/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS [MMF and IVC] vs. AURA-LV/AURORA 1 [voclosporin]) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months. Results Propensity matching identified 179 participant pairs with similar demographics and baseline disease characteristics. Mean cumulative exposure to GCs was more than 2-fold higher in the IVC and MMF cohorts of ALMS than AURA-LV/AURORA 1 participants over both 3 and 6 months. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants in ALMS over the 6-month period. More participants in AURA-LV and AURORA 1 reported hypertension and anemia. Due to the known hemodynamic effects of calcineurin inhibition, there was a small decrease in mean eGFR in the AURA-LV/AURORA 1 participants in the first few weeks of treatment after which mean eGFR remained stable; a greater number of events of GFR decreased were reported by AURA-LV/AURORA 1 participants. The incidence of serious AEs was similar across groups. UPCR ≤0.5 mg/mg was achieved by 52% of voclosporin-treated participants compared to 41.1% of IVC- or MMF-treated participants of ALMS; the median time to this endpoint for the voclosporin group was 142 days; a median time was not determinable for ALMS participants as less than 50% achieved the endpoint within the study period (hazard ratio [HR] 1.41; 95% confidence interval [CI] 1.03, 1.94; p=0.0324; Table 1, Figure 1). More voclosporin-treated participants achieved a 50% reduction in UPCR from baseline at any point during the study; this endpoint was met significantly earlier by voclosporin-treated patients as well (29 vs. 84 days; HR 1.88, 95% CI 1.48, 2.39; p<0.0001). Conclusion Participants treated with voclosporin in combination with low-dose GCs and MMF 2g/day demonstrated an improved safety profile and earlier reductions in proteinuria compared to participants treated with high-dose GCs and MMF up to 3 g/day or IVC. These findings support the recommendation that a voclosporin-based, triple-immunosuppressive regimen should be considered as an initial therapy in patients with active LN. REFERENCES NIL • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint Acknowledgements NIL Disclosure of Interests Anca Askanase Consultant for Aurinia Pharmaceuticals Inc., AstraZeneca, GSK plc., Eli Lilly, Kenneth C. Kalunian: None declared, Maria Dall’Era Consultant for Annexon Biosciences, AstraZeneca, Aurinia Pharmaceuticals Inc., Biogen, GSK plc., and Pfizer, Grant/research support from Annexon Biosciences, GSK plc., Neil Solomons Shareholder of Aurinia Pharmaceuticals Inc., Former employee of Aurinia Pharmaceuticals Inc., Lucy Hodge Shareholder of Aurinia Pharmaceuticals, Inc., Employee of Aurinia Pharmaceuticals, Inc., Matt Truman Consultant for Aurinia Pharmaceuticals, Inc., Ernie Yap Shareholder of Aurinia Pharmaceuticals Inc., Employee of Aurinia Pharmaceuticals Inc.