Introduction: Current dietary therapies for epilepsy have side effects and are low in nutrients, which would make an alternative dietary treatment, which addresses these issues, advantageous. One potential option is the low glutamate diet (LGD). Glutamate is implicated in seizure activity. Blood brain barrier permeability in epilepsy could enable dietary glutamate to reach the brain and contribute to ictogenesis.Objective: to assess the LGD as an adjunct treatment for pediatric epilepsy.Methods: This study was a nonblinded, parallel, randomized clinical trial. The study was conducted virtually due to COVID-19 and registered on clinicaltrials.gov (NCT04545346). Participants were eligible if they were between the ages of 2 and 21 with >= 4 seizures per month. Baseline seizures were assessed for 1-month, then participants were allocated via block randomization to the intervention month (N=18), or a wait-listed control month fol-lowed by the intervention month (N=15). Outcome measures included seizure frequency, caregiver global impression of change (CGIC), non-seizure improvements, nutrient intake, and adverse events.Results: Nutrient intake significantly increased during the intervention. No significant differences in seizure frequency were observed between intervention and control groups. However, efficacy was assessed at 1-month compared to the standard 3-months in diet research. Additionally, 21% of participants were observed to be clinical responders to the diet. Overall health (CGIC) significantly improved in 31%, 63% experienced >= 1 non -seizure improvements, and 53% experienced adverse events. Clinical response likelihood decreased with increasing age (0.71 [0.50-0.99], p=0.04), as did the likelihood of overall health improvement (0.71 [0.54-0.92], p=0.01).Discussion: This study provides preliminary support for the LGD as an adjunct treatment before epilepsy becomes drug resistant, which is in contrast to the role of current dietary therapies in drug resistant epilepsy.

What is this summary about? This summary explains the findings from a recent investigation that combined the results of over 1000 people from three clinical studies to understand the safety of evobrutinib. Evobrutinib is an oral medication (taken by mouth), being researched as a potential treatment for multiple sclerosis (MS). This medication was also investigated in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Over 1000 people have taken evobrutinib as part of three separate phase 2 clinical studies. These studies looked at how much of the drug should be taken, how safe the drug is, and how well it might work for treating a certain medical condition. What were the results? Evobrutinib was well-tolerated by participants in all three studies. The number of side effects reported by participants taking the medication was very similar to those reported by participants taking the placebo (a ‘dummy’ treatment without a real drug). The most common side effects in clinical studies were urinary tract infections, headache, swelling of the nose and throat, diarrhoea and blood markers of potential liver damage (these returned to normal once the treatment was stopped). What do the results mean? The safety data from all three clinical studies are encouraging and can be used to inform further research into using evobrutinib in MS. Clinical Trial Registration: NCT02975349 (multiple sclerosis), NCT03233230 (rheumatoid arthritis), NCT02975336 (systemic lupus erythematosus) ( ClinicalTrials.gov )

Objective To use cell‐based gene signatures to identify patients with systemic lupus erythematous (SLE) in the phase II/III APRIL–SLE and phase IIb ADDRESS II trials most likely to respond to atacicept. Methods A published immune cell deconvolution algorithm based on Affymetrix gene array data was applied to whole blood gene expression from patients entering APRIL‐SLE. Five distinct patient clusters were identified. Patient characteristics, biomarkers, and clinical response to atacicept were assessed per cluster. A modified immune cell deconvolution algorithm was developed based on RNA sequencing data and applied to ADDRESS II data to identify similar patient clusters and their responses. Results Patients in APRIL‐SLE (N = 105) were segregated into the following five clusters (P1‐5) characterized by dominant cell subset signatures: high neutrophils, T helper cells and natural killer (NK) cells (P1), high plasma cells and activated NK cells (P2), high B cells and neutrophils (P3), high B cells and low neutrophils (P4), or high activated dendritic cells, activated NK cells, and neutrophils (P5). Placebo‐ and atacicept‐treated patients in clusters P2,4,5 had markedly higher British Isles Lupus Assessment Group (BILAG) A/B flare rates than those in clusters P1,3, with a greater treatment effect of atacicept on lowering flares in clusters P2,4,5. In ADDRESS II, placebo‐treated patients from P2,4,5 were less likely to be SLE Responder Index (SRI)‐4, SRI‐6, and BILAG‐Based Combined Lupus Assessment responders than those in P1,3; the response proportions again suggested lower placebo effect and a greater treatment differential for atacicept in P2,4,5. Conclusion This exploratory analysis indicates larger differences between placebo‐ and atacicept‐treated patients with SLE in a molecularly defined patient subset.

Abstract Enpatoran is a selective inhibitor of toll‐like receptors 7 and 8 (TLR7/8) that potentially targets pro‐inflammatory pathways induced by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). A phase II study conducted in Brazil, the Philippines, and the USA during the early pandemic phase assessed the safety and efficacy of enpatoran in patients hospitalized with COVID‐19 pneumonia (NCT04448756). A total of 149 patients, who scored 4 on the World Health Organization's (WHO) 9‐point ordinal severity scale, were randomized 1:1:1 and received enpatoran 50 mg (n = 54) or 100 mg (n = 46), or placebo (n = 49) twice daily (b.i.d.) for 14 days plus standard of care. The primary objectives were safety and time to recovery (WHO 9‐point scale ≤3). Clinical deterioration (WHO 9‐point scale ≥ 5) was a key secondary objective. Treatment‐emergent adverse events (TEAEs) were comparable across groups (56.5%–63.0%). Treatment‐related TEAEs were numerically higher with enpatoran 50 mg (14.8%) than 100 mg (10.9%) or placebo (8.2%). Serious TEAEs were numerically lower with enpatoran (50 mg 9.3%, 100 mg 2.2%) than placebo (18.4%). The primary efficacy objective was not met; median time to recovery was 3.4–3.9 days across groups, with placebo‐treated patients recovering on average faster than anticipated. Clinical deterioration event‐free rates up to Day 7 were 90.6%, 95.6%, and 81.6% with enpatoran 50 mg, 100 mg, and placebo, respectively. Enpatoran was well tolerated by patients acutely ill and hospitalized with COVID‐19 pneumonia. Positive signals in some secondary end points suggested potential beneficial effects, supporting further evaluation of enpatoran in patients with hyperinflammation due to infection or autoimmunity.

Objective Analyse the integrated safety profile of evobrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), using pooled data from multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) trials. Methods Phase II, randomised, double-blind, placebo-controlled trial data were analysed (N=1083; MS: n=213, 48 weeks (W); RA: n=390, 12W; SLE: n=480, 52W). The analysis included all patients who received ≥1 dose of evobrutinib (25 mg or 75 mg once daily, or 50 mg or 75 mgtwice daily) or placebo. Descriptive statistics and exposure-adjusted incidence rates (EAIR) were used to report treatment-emergent adverse events (TEAEs). Results Data from 1083 patients were pooled: evobrutinib, n=861; placebo, n=271 (sum >1083 due to MS trial design: n=49 received both placebo (W0–24) and evobrutinib 25 mg (W25–48)); median follow-up time (pt-years): evobrutinib, 0.501; placebo, 0.463. Across indications, the proportion of patients with TEAEs and the EAIR were similar for evobrutinib and placebo (66.2% (247.6 events/100 pt-years) vs 62.4% (261.4 events/100 pt-years)). By indication, the EAIR (events/100 pt-years) of TEAEs for evobrutinib versus placebo were: MS: 119.7 vs 148.3; RA: 331.8 vs 306.8; SLE: 343.0 vs 302.1. Two fatal events occurred (in SLE). The serious infections EAIR was 2.7 and 2.1 events/100 pt-years for evobrutinib and placebo. For previously reported BTKi-class effects, the EAIR of transient elevated alanine aminotransferase/aspartate aminotransferase TEAEs (events/100 pt-years) with evobrutinib versus placebo was 4.8 vs 2.8/3.5 vs 0.7, respectively. IgG levels were similar in evobrutinib/placebo-treated patients. Conclusions This is the first BTKi-integrated safety analysis that includes patients with MS. Overall, evobrutinib treatment (all doses) was generally well tolerated across indications. Trial registration numbers NCT02975349, NCT03233230, NCT02975336.

BackgroundEnpatoran is a selective and potent dual toll-like receptor (TLR) 7/8 inhibitor in development for the treatment of cutaneous and systemic lupus erythematosus (CLE/SLE). Enpatoran inhibits TLR7/8 activation in vitro and suppresses disease activity in lupus mouse models.1 Enpatoran was well tolerated and had linear pharmacokinetic (PK) parameters in healthy volunteers.2 As TLR7/8 mediate immune responses to single-stranded RNA viruses, including SARS-CoV-2, it was postulated that enpatoran may prevent hyperinflammation and cytokine storm in COVID-19.ObjectivesIn response to the COVID-19 pandemic, we conducted an exploratory Phase II trial to assess safety and determine whether enpatoran prevents clinical deterioration in patients (pts) hospitalized with COVID-19 pneumonia. PK and pharmacodynamics (PD) of enpatoran were also evaluated.MethodsANEMONE was a randomized, double-blind, placebo (PBO)-controlled study conducted in Brazil, the Philippines, and the USA (NCT04448756). Pts aged 18–75 years, hospitalized with COVID-19 pneumonia (WHO 9-point scale score =4) but not mechanically ventilated, with SpO2 <94% and PaO2/FiO2 ≥150 (FiO2 maximum 0.4) were eligible. Those with a history of uncontrolled illness, active/unstable cardiovascular disease and SARS-CoV-2 vaccination were excluded. Pts received PBO or enpatoran (50 or 100 mg twice daily [BID]) for 14 days, with monitoring to Day 28 and safety follow-up to Day 60. Primary outcomes were safety and time to recovery (WHO 9-point scale ≤3). Clinical deterioration (time to clinical status >4, WHO 9-point scale) was a secondary outcome. Exploratory endpoints were enpatoran and biomarker concentrations (cytokines, C-reactive protein [CRP], D-dimer and interferon gene signature [IFN-GS] scores) assessed over time.Results149 pts received either PBO (n=49), or enpatoran 50 mg (n=54) or 100 mg (n=46) BID; 88% completed treatment and 86% received concomitant steroids. Median age was 50 years (77% <60 years old), 66% were male, and 50% had ≥1 comorbidity (40% hypertension, 24% diabetes). Overall, 59% pts reported a treatment-emergent adverse event (TEAE) with three non-treatment-related deaths; 11% reported a treatment-related TEAE. The proportion of pts in the enpatoran group reporting serious TEAEs was low (50 mg BID 9%; 100 mg BID 2%) vs PBO (18%). Gastrointestinal disorders were most common (PBO 8%; 50 mg BID 28%; 100 mg BID 9%). The primary outcome of time to recovery with enpatoran vs PBO was not met; medians were 3.4–3.9 days. A positive signal in time to clinical deterioration from Day 1 through Day 28 was observed; hazard ratios [95% CI] for enpatoran vs PBO were 0.39 [0.13, 1.15] (50 mg BID) and 0.30 [0.08, 1.08] (100 mg BID). Mean enpatoran exposure was dose-proportional, and PK properties were within expectations. The median (quartile [Q]1– Q3) interleukin 6 (IL-6), CRP and D-dimer baseline concentration across the groups were 5.7 (4.0–13.5) pg/mL, 30.04 (11.40–98.02) and 0.62 (0.39–1.01) mg/L, respectively. Baseline IFN-GS scores were similar across groups.ConclusionThe ANEMONE trial was the first to evaluate the safety and efficacy of a TLR7/8 inhibitor in an infectious disease for preventing cytokine storm. Enpatoran up to 100 mg BID for 14 days was well tolerated by patients acutely ill with COVID-19 pneumonia. Time to recovery was not improved with enpatoran, perhaps due to the younger age of patients who had fewer comorbidities compared to those in similar COVID-19 trials. However, there was less likelihood for clinical deterioration with enpatoran than placebo. This trial provides important safety, tolerability, PK and PD data supporting continued development of enpatoran in SLE and CLE (NCT04647708, NCT05162586).References[1]Vlach, et al. J Pharmacol Exp Ther 2021;376:397–409;[2]Port, et al. Pharmacol Res Perspect 2021;9:e00842.AcknowledgementsWe would like to thank those who took part in the the ANEMONE trial. This study was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945), who funded medical writing support by Bioscript Stirling Ltd.Disclosure of InterestsJohn E. McKinnon Consultant of: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Joel Santiaguel Speakers bureau: Merck Healthcare KGaA, Claudia Murta Speakers bureau: Pfizer/Wyeth, Dongzi Yu Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Mukhy Khursheed Employee of: Merck Serono Ltd (an affiliate of Merck KGaA), Flavie Moreau Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Lena Klopp-Schulze Employee of: Merck Healthcare KGaA, Jamie Shaw Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA), Sanjeev Roy Employee of: Ares Trading SA (an affiliate of Merck KGaA), Amy Kao Employee of: EMD Serono Research & Development institute (an affiliate of Merck KGaA)

Abstract BACKGROUND AND AIMS Atacicept is a dual BLyS/APRIL inhibitor. APRIL-SLE was a double-blind, placebo-controlled phase 2 study, which randomized moderate-to-severe systemic lupus erythematosus (SLE) patients to atacicept 75 mg, atacicept 150 mg or placebo. The primary endpoint was the proportion of subjects who experienced a new flare during the 52-week treatment period. In total, 111 patients in the placebo group, 112 patients in the atacicept 75 mg group and 62 patients in the atacicept 150 mg group completed 52 weeks of treatment. Patients with severe renal disease were excluded, while patients with proteinuria and mild–moderate chronic kidney disease, as assessed by KDIGO criteria, were eligible. The effect of atacicept on measures of renal function in these patients has not previously been reported. METHOD The study excluded moderate to severe glomerulonephritis, as defined by either of the following: urinary protein/creatinine ratio > 1 mg/mg and/or hematuria or a significant renal impairment as defined by glomerular filtration rate (GFR) < 50 mL/min/1.73 m2. Urine protein/creatinine ratio (UPCR) and GFR were measured at baseline, week 2, and then every 4 weeks until week 52. RESULTS In the APRIL-SLE study, the analysis for GFR and UPCR are of all patients (62–111 per group) with up to 15% of patients having a history of SLE-related renal disease. GFR time course showed stability for the atacicept groups compared to a 4.3% decline in the placebo group at week 52 from baseline (figure and table). Furthermore, reductions in UPCR from baseline at week 52 were observed in the atacicept groups compared to an increase in the placebo group. CONCLUSION In this phase 2 APRIL-SLE study, analysis of renal data suggests potential for improved renal function with atacicept treatment in SLE renal disease.

Introduction: Patients with IgA nephropathy (IgAN) and persistent proteinuria are at risk of progression to kidney failure. Atacicept is a novel B-cell-targeted immunomodulator, shown to reduce immunoglobulin levels in patients with autoimmune diseases. Methods: JANUS (NCT02808429) was a phase II study that assessed the safety, pharmacodynamic effects, and efficacy of atacicept in patients with IgAN and proteinuria >= 1 g/d or 0.75 mg/mg on 24-hour UPCR despite maximal standard of care therapy.Results: A total of 16 patients were randomized 1:1:1 to placebo (n = 5), atacicept 25 mg (n = 6), or ata-cicept 75 mg (n = 5) once weekly using subcutaneous injection. Twelve (75%) completed >= 48 weeks of treatment; 8 (50%) completed 72 weeks of treatment and the 24-week safety follow-up period. Fourteen patients reported treatment-emergent adverse events (TEAEs). Most TEAEs were mild or moderate in severity. Three patients (placebo n = 1; atacicept 25 mg n = 2) reported serious TEAEs, none of which were treatment related. Dose-dependent reductions in IgA, IgG, IgM, and galactose-deficient (Gd)-IgA1 with atacicept at week 24 were maintained to week 72. Early reduction in proteinuria was observed at week 24 with atacicept. Renal function progressively declined with placebo but remained stable under exposure to atacicept.Conclusion: Atacicept has an acceptable safety profile in patients with IgAN and is effective at reducing the levels of pathogenic factor Gd-IgA1, with potential improvements in proteinuria and renal function.

ObjectiveEvobrutinib is a highly selective, orally administered Bruton's tyrosine kinase (BTK) inhibitor. The objective of this phase II, multicenter, randomized, double‐blind, placebo‐controlled trial was to evaluate the efficacy and safety of evobrutinib in patients with active autoantibody‐positive systemic lupus erythematosus (SLE).MethodsPatients were diagnosed with SLE by either the Systemic Lupus International Collaborating Clinics criteria or at least four American College of Rheumatology criteria 6 months or more prior to screening, had an SLE Disease Activity Index‐2000 score of 6 or more, were autoantibody‐positive and on standard‐of‐care therapy. Randomization was 1:1:1:1 to oral evobrutinib 25 mg once daily (QD), 75 mg QD, 50 mg twice daily, or placebo. Primary efficacy endpoints were SLE responder index (SRI)‐4 response at week 52 and SRI‐6 response at week 52 in the high disease activity subpopulation. Safety endpoints included treatment‐emergent adverse events (TEAEs).ResultsA total of 469 patients were randomized and received at least one dose of evobrutinib or placebo at the time of primary analysis. Mean (SD) age at baseline was 40.7 (±12.3) years; 94.9% of patients were female. Neither primary efficacy endpoint was met. All doses of evobrutinib were well tolerated, and there was no clear dose effect on the incidence of reported TEAEs, or serious TEAEs, including severe infections.ConclusionThis phase II, dose‐ranging trial in SLE failed to show a treatment effect of evobrutinib versus placebo at any dose. Evobrutinib was generally well tolerated, with no dose effect observed for TEAEs. These results suggest that BTK inhibition does not appear to be an effective therapeutic intervention for patients with SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple organ systems. Many investigational agents have failed or shown only modest effects when added to standard of care (SoC) therapy in placebo-controlled trials, and only two therapies have been approved for SLE in the last 60 years. Clinical trial outcomes have shown discordance in drug effects between clinical endpoints. Herein, we characterized longitudinal disease activity in the SLE population and the sources of variability by developing a latent disease trajectory model for SLE component endpoints (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI], Physician's Global Assessment [PGA], British Isles Lupus Assessment Group Index [BILAG]) and composite endpoints (Systemic Lupus Erythematosus Responder Index [SRI], BILAG-based Composite Lupus Assessment [BICLA], and Lupus Low Disease Activity State [LLDAS]) using patient-level historical SoC data from nine phase II and III studies. Across all endpoints, in predictions up to 52 weeks from the final disease trajectory model, the following baseline covariates were associated with a greater decrease in SLE disease activity and higher response to placebo + SoC: Hispanic ethnicity from Central/South America, absence of hypocomplementemia, recent SLE diagnosis, and high baseline disease activity score using SLEDAI and BILAG separately. No discernible differences were observed in the trajectory of response to placebo + SoC across different SoC medications (antimalarial and immunosuppressant such as mycophenolate, methotrexate, and azathioprine). Across all endpoints, disease trajectory showed no difference in Asian versus non-Asian patients, supporting Asia-inclusive global SLE drug development. These results describe the first population approach to support a model-informed drug development framework in SLE.

BackgroundAtacicept is a fusion protein that blocks B-lymphocyte stimulator and a proliferation-inducing ligand, which are increased in patients with SLE. APRIL-SLE was a double-blind, placebo-controlled, Phase 2 study that randomized patients with moderate-to-severe systemic lupus erythematosus (SLE) to atacicept 75 mg, atacicept 150 mg, or placebo twice-weekly for 4 weeks, then weekly for 48 weeks.ObjectivesThe primary results of the APRIL-SLE study – the effect of atacicept compared to placebo in preventing new flares in patients with moderate-to-severe SLE – have been reported (Isenberg et al., 2013). We performed a post hoc analysis to describe the effect of atacicept compared to placebo on measures of renal function in patients with SLE; this effect has not been reported previously.MethodsThe APRIL-SLE study excluded patients with moderate to severe glomerulonephritis, as defined by either of the following: urinary protein/creatinine ratio (UPCR)>1 mg/mg and/or hematuria or a significant renal impairment as defined by estimated glomerular filtration rate (eGFR)<50 mL/min/1.73 m2. Patients with proteinuria and mild to moderate chronic kidney disease, as assessed by KDIGO criteria were eligible. UPCR and eGFR were measured at baseline, week 2, and then every 4 weeks until week 52. The median change from baseline to each of these timepoints was calculated for eGFR and UPCR using the Safety Analysis Set, comprised of all randomized patients who received at least 1 dose of study medication. Enrollment in the atacicept 150 mg group was discontinued prematurely due to 2 deaths from pneumonias. When treatment was discontinued, 62 of 144 patients in this group had completed 52 weeks of treatment; 27 other patients had already been withdrawn for various reasons; and, in the remaining 55 patients, treatment was stopped early as a safety precaution. Patients in the other two groups completed the protocol.ResultsIn total, 111 patients in the placebo group, 112 patients in the atacicept 75 mg group, and 62 patients in the atacicept 150 mg group completed 52 weeks of treatment. The eGFR time course was stable for the atacicept groups compared to a 4.4% decline in the placebo group from baseline at week 52 (Figure 1 and Table 1). UPCR from baseline at week 52 declined in the atacicept groups and increased in the placebo group.Table 1.Median Percent Change from Baseline of Estimated Glomerular Filtration Rate (eGFR) and Proteinuria at Week 52 – Safety Analysis SetVariablePlaceboAtacicept 75 mgAtacicept 150 mgeGFR (mL/min)n=110n=111n=62 bmedian-4.35-1.490.57UPCR (mg/mg)n=108n=108n=63median6.29-6.27-12.72UPCR (mg/mg) an=12n=15n=8median26.11-54.42-12.15eGFR=estimated glomerular filtration rate; UPCR=urinary protein/creatinine ratio.aAmong patients with screening UPCR ≥0.2 mg/mg.bEnrollment in the atacicept 150 mg arm was discontinued prematurely (described in Isenberg et al., 2015).Figure 1.Median Change from Baseline in eGFR.eGFR= estimated glomerular filtration rate; IQR=interquartile rangeConclusionResults from this double-blind, placebo-controlled, Phase 2 study suggest a potential for improved renal function with atacicept treatment of patients with moderate-to-severe SLE.References[1]Isenberg D, Gordon C, Licu D, Copt S, Rossi CP, Wofsy D. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann Rheum Dis. 2015;74(11):2006-15. Erratum in: Ann Rheum Dis. 2016 May;75(5):946.Disclosure of InterestsDavid Isenberg Consultant of: Professor Isenberg has consulted for Veratx, Servier, Astro-Zeneca, Idorsia, Merck Serono, and Amgen. His honoraria are passed onto a local arthritis charity., Celia J. F. Lin Shareholder of: Dr. Lin is an employee of Vera Therapeutics, Inc., Employee of: Dr. Lin is an employee of Vera Therapeutics, Inc., Amy Kao Shareholder of: Dr. Kao own stocks of Merck KGaA, Darmstadt, Germany, Employee of: Dr. Kao is an employee of EMD Serono Research & Development Institute, Inc (a business of Merck KGaA), Aida Arselan Aydemir Employee of: Ms. Aydemir is an employee of EMD Serono Research & Development Institute, Inc (a business of Merck KGaA), Caroline Gordon Speakers bureau: Dr. Gordon reports personal fees for speakers bureau from UCB, Consultant of: Dr. Gordon reports personal fees for honoraria from consultancy work from the Center for Disease Control and Prevention, Amgen, Astra-Zeneca, AbbVie, EMD Serono, MGP, Sanofi, and UCB, Grant/research support from: Dr. Gordon reports an educational grant from UCB to Sandwell and West Birmingham Hospitals NHS Trust that supported previous research work unrelated to any specific drug (last payment July 2019).

Background We sought to examine the disease course of High Disease Activity Status (HDAS) patients and their different disease patterns in a real-world longitudinal cohort. Disease resolution till Lupus Low Disease Activity State (LLDAS) has been a general treatment goal, but there is limited information on this subset of patients who achieve this. Methods All consenting patients of the Monash Lupus Cohort who had at least 12 months of observation were included. HDAS was defined as SLEDAI-2K ≥ 10 ever, and HDAS episode as the period from the first HDAS clinic visit until attainment of LLDAS. We examined the associations of different HDAS patterns with the likelihood of damage accrual. Results Of 342 SLE patients, 151 experienced HDAS at least once, accounting for 298 HDAS episodes. The majority of HDAS patients (76.2%) experienced Recurrent HDAS (> 1 HDAS visit), and a smaller subset (47.7%) had Persistent HDAS (consecutive HDAS visits for longer than 2 months). Recurrent or Persistent HDAS patients were younger at diagnosis and more likely to experience renal or serositis manifestations; persistent HDAS patients were also more likely to experience neurological manifestations. Baseline SLEDAI greater than 10 was associated with longer HDAS episodes. Recurrent and Persistent HDAS were both associated with an increased likelihood of damage accrual. The total duration of HDAS episode greater than 2 years and experiencing multiple HDAS episodes (≥4) was also associated with an increased likelihood of damage accrual (OR 1.80, 95% CI 1.08–2.97, p = 0.02, and OR 3.31, 95% CI 1.66–13.26, p = 0.01, respectively). Conclusion HDAS episodes have a highly variable course. Recurrent and Persistent HDAS, and longer duration of HDAS episodes, increased the risk of damage accrual. In addition to a major signifier of severity in SLE, its resolution to LLDAS can determine the subsequent outcome in SLE patients.

The Addressing Lupus Pillars for Health Advancement (ALPHA) Project is a global consensus effort to identify, prioritise and address top barriers in lupus impacting diagnosis, care, treatment and research. To conduct this process, the ALPHA Project convened a multistakeholder Global Advisory Committee (GAC) of lupus experts and collected input from global audiences, including patients. In phase I, the ALPHA Project used expert interviews and a global survey of lupus experts to identify and categorise barriers into three overarching pillars: drug development, clinical care and access to care. In phase II, reported here, the GAC developed recommended actionable solutions to address these previously identified barriers through an in-person stakeholder meeting, followed by a two-round scoring process. Recommendations were assessed for feasibility, impact and timeline for implementation (FIT), where potential FIT component values were between 1 and 3 and total scores were between 3 and 9. Higher scores represented higher achievability based on the composite of the three criteria. Simplifying and standardising outcomes measures, including steroid sparing as an outcome (drug development) and defining the lupus spectrum (clinical care) ranked as the highest two priority solutions during the GAC meeting and received high FIT scores (7.67 and 7.44, respectively). Leveraging social media (access to care) received the highest FIT score across all pillars (7.86). Cross-cutting themes of many solutions include leveraging digital technology and applying specific considerations for special populations, including paediatrics. Implementing the recommendations to address key barriers to drug development, clinical care and access to care is essential to improving the quality of life of adults and children with lupus. Multistakeholder collaboration and guidance across existing efforts globally is warranted.

OBJECTIVES:Atacicept reduced SLE disease activity in the phase 2b ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II.METHODS:In the 24-week, randomized, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary endpoint. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares.RESULTS:In total, 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4-93.2%), and 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo.CONCLUSION:Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy.TRIAL REGISTRATION:ClinicalTrials.gov, http://clinicaltrials.gov, NCT02070978.

BACKGROUND The ability to identify lupus patients in High Disease Activity Status (HDAS) without knowledge of the SLEDAI could have application in selection of patients for treatment escalation or enrolment in trials. We sought to generate an algorithm that could calculate via model fitting the presence of HDAS using simple demographic and laboratory values. METHODS We examined the association of High Disease Activity (HDA) with demographic and laboratory parameters using prospectively collected data. An HDA visit is recorded when SLEDAI-2K ≥10. We utilised the use of combinatorial search to find algorithms to build a mathematical model predictive of HDA. Performance of each algorithm was evaluated using multi-class area under receiver operating characteristics (mAUROC) and the final model was compared with the Naïve Bayes Classifier, and analysed using the confusion matrix for accuracy and misclassification rate. RESULTS Data on 286 patients, followed for a median of 5.1 years were studied for a total of 5,680 visits. Sixteen laboratory parameters were found to be significantly associated with HDA. A total of 216 algorithms were evaluated and final algorithm chosen was based on 7 pathology measures and 3 demographic variables. It has an accuracy of 88.6% and misclassification rate of 11.4%. When compared with the Naïve Bayes Classifier (AUC = 0.663), our algorithm has a better accuracy with AUC = 0.829. CONCLUSION This study shows that building an accurate model to calculate HDA using routinely available clinical parameters is feasible. Future studies to independently validate the algorithm will be needed to confirm its predictive performance.

OBJECTIVE:Focal Cortical Dysplasias (CD) are a common etiology of refractory pediatric epilepsy and are amenable to epilepsy surgery. We investigated the association of lesion volume and location to age of seizure onset among children with CD who underwent epilepsy surgery. METHODS:A retrospective study of epilepsy surgery patients with pathologically-confirmed CD. Regions of interest (ROI) determined preoperative lesion volumes on 1.5 T and 3 T T2 and SPGR MRIs, and location in 7 distributed neural networks. Descriptive and inferential statistics were used. RESULTS:Fifty-five patients were identified: 35 girls (56.5 %). Median age of seizure onset: 19.0 months (range 0.02 months - 16.0 years). Median age of surgery: 7.8 years (range 2.89 months - 24.45 years). CD were frontal (n = 21, 38 %); temporal (n = 15, 27 %); parietal (n = 10, 18 %); occipital (n = 3, 5%); multilobar (n = 6, 11 %). Frontal FCD had seizure onset < 1-year-old (P = 0.10); temporal lobe CD seizure onset was more likely > 5-years-old (P= 0.06). Median lesion volume for CD was 23.23 cm3 (range: 1.87-591.73 cm3). Larger CD lesions were associated with earlier epilepsy (P = 0.01, r = -0.16). We did not find that lesions proximal to early maturing cortical regions were associated with earlier seizure onset. We found an association with CD location in the default mode network (DMN) and age onset < 5years old (P = 0.03). Age of seizure onset was negatively correlated with percent of CD overlapping motor cortex (P = 0.001, r =-0.794) but not with CD overlap of the visual cortex (P = 0.35). There was no effect of CD type on age of epilepsy onset. SIGNIFICANCE:Larger CD lesions are associated with earlier onset epilepsy. CD most commonly occurs within the DMN and Limbic network, and DMN is associated with seizure onset before 5-years-old. Percent of CD overlapping motor cortex correlates with earlier seizure onset. These observations may reflect patterns of brain maturation or regional differences in clinical expression of seizures.

Objective Disease severity in SLE is an important concept related to disease activity, treatment burden and prognosis. We set out to evaluate if high disease activity status (HDAS), based on ever attainment of a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) disease activity score of ≥10, is an indicator for disease severity in SLE. Methods Using prospectively collected data, we assessed the association of HDAS with sociodemographic and disease characteristics and adverse clinical outcomes using logistic regression or generalised estimating equations. Results Of 286 patients with SLE, who were observed for a median (range) of 5.1 years (1–10.8 years), 43.7% experienced HDAS at least once during the observational period. Autoantibody positivity, particularly anti-dsDNA and anti-Sm positivity, were associated with increased likelihood of HDAS. Age ≥45 years at diagnosis was associated with reduced likelihood of HDAS (p=0.002). Patients with HDAS had higher Physician Global Assessment score (>1: OR 8.1, p<0.001) and were more likely to meet criteria for flare (mild/moderate flare: OR 4.4, p<0.001; severe flare: OR 17.2, p<0.001) at the time of experiencing HDAS. They were also more likely to have overall higher disease activity, as defined by time-adjusted mean SLEDAI-2K score in the highest quartile (OR 11.7, 95% CI 5.1 to 26.6; p>0.001), higher corticosteroid exposure (corticosteroid dose in highest quartile: OR 7.7, 95% CI 3.9 to 15.3; p<0.001) and damage accrual (OR 2.3, 95% CI 1.3 to 3.9; p=0.003) when compared with non-HDAS patients. Conclusions HDAS is associated with more severe disease, as measured by higher disease activity across time, corticosteroid exposure and damage accrual. The occurrence of HDAS may be a useful prognostic marker in the management of SLE.