British Isles Lupus Assessment Group Research Articles

Evaluation of RNase therapy in systemic lupus erythematosus: a randomised phase 2a clinical trial of RSLV-132

BackgroundCirculating, extracellular RNA is the primary trigger of type I interferon in systemic lupus erythematosus (SLE), and interferon is known to play a central pathogenic role in the disease. RSLV-132...

Usefulness of Belimumab in Adult Patients With Systemic Lupus Erythematosus Evaluated Using Single Indexes: A Meta-Analysis and Systematic Review

BackgroundBelimumab is the first antibody drug approved for systemic lupus erythematosus (SLE), and is a fully human monoclonal antibody that inhibits soluble B lymphocyte stimulator protein. In clinical trials, a composite index was used to assess efficacy of belimumab. However, clinical guidelines on SLE treatment currently use single efficacy indexes. ObjectiveThe main objective of this study was to perform a meta-analysis to evaluate the efficacy of belimumab utilizing single indexes used in routine clinical practice, rather than the composite efficacy index used in clinical trials during the development phase. As a secondary endpoint, safety was also evaluated. MethodsSeveral databases were searched to identify reports published up to December 1, 2021 on randomized controlled trials examining the efficacy of belimumab in adult patients with SLE. From the clinical trial data, efficacy was evaluated using single indexes including the SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index, and Physician Global Assessment. Safety was also assessed. Data were synthesized and analyzed using Review Manager 5.4. This study protocol was registered in the UMIN Clinical Trials Registry (Registration number: UMIN000052846). ResultsThe search identified 12 reports that met the inclusion criteria. Five reports were included in efficacy evaluation and 9 in safety evaluation. The primary endpoint was SLEDAI. Significantly more belimumab-treated patients achieved a ≥4-point reduction in SLEDAI (relative risk 1.28; 95% confidence interval, 1.16–1.40; P < 0.00001) compared with placebo. Other efficacy endpoints were also improved significantly in the belimumab group. No difference in safety was found between belimumab and placebo. ConclusionsThe present meta-analysis evaluating clinical trial data using various single indexes recommended by clinical guidelines for SLE verifies that addition of belimumab to standard of care is efficacious for moderate-to-severe SLE.

Efficacy and safety of intravenous belimumab in a subgroup of South Korean patients with systemic lupus erythematosus enrolled into a Phase 3, randomized, placebo-controlled trial in North East Asia.

This post hoc analysis evaluated the efficacy and safety of intravenous belimumab 10 mg/kg in the South Korean subgroup of patients with systemic lupus erythematosus (SLE) enrolled in the North East Asia (NEA) study (GSK Study BEL113750; NCT01345253). NEA was a double-blind, placebo-controlled, randomized Phase 3 trial. Patients with active, autoantibody-positive SLE were randomized 2:1 to belimumab or placebo plus standard therapy administered on Days 0, 14, and 28, and then every 28 days up to Week 48. The primary efficacy endpoint in this analysis was SLE Responder Index 4 (SRI-4) response rate at Week 52, defined as the proportion of patients achieving a ≥4-point reduction in Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score, no worsening (<0.3 increase from baseline) in Physician Global Assessment, no new British Isles Lupus Assessment Group (BILAG) A domain and <2 new BILAG B domain scores. Among 100 South Korean patients enrolled in NEA, 54/66 (81.8%) belimumab- and 24/34 (70.6%) placebo-treated patients completed the double-blind phase. Significantly more belimumab- than placebo-treated patients achieved SRI-4 response at Week 52 (n = 35/66, 53.0% vs. n = 8/34, 23.5%; odds ratio [OR; 95% confidence interval (CI)]: 3.67 [1.45, 9.28]; p = .0061). The proportion of patients experiencing ≥1 adverse event was similar between groups (belimumab: n = 60/66, 90.9% vs. placebo: n = 31/34, 91.2%). No new safety signals emerged in this subgroup analysis. Belimumab was efficacious for the treatment of SLE and well tolerated among the South Korean subgroup of patients from the NEA study.

Selection of indicators reporting response rate in pharmaceutical trials for systemic lupus erythematosus: preference and relative sensitivity

ObjectiveSLE is a common multisystem autoimmune disease with chronic inflammation. Many efficacy evaluation indicators of randomised clinical trials (RCTs) for SLE have been proposed but the comparability remains unknown. We...

Identifying lupus Patient Subsets Through Immune Cell Deconvolution of Gene Expression Data in Two Atacicept Phase II Studies.

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. 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. 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. This exploratory analysis indicates larger differences between placebo- and atacicept-treated patients with SLE in a molecularly defined patient subset.

A Practical Overview of the Articular Manifestations of Systemic Lupus Erythematosus.

Although it is widely known that joint involvement is the most frequent and prevalent manifestation of systemic lupus erythematosus (SLE), not having a validated organ-specific index for this domain in order to guide its treatment has been a major limitation. In addition, its clinical importance had been underestimated since it was not a vital risk domain; it was never the center of treatment, under the premise that in most cases its progression was slow and did not lead to significant functional disability.However, this concept has been changing due to the greater description of erosions both in ultrasonography and in osteoarticular magnetic resonance, so their identification can establish a more appropriate treatment time and thus avoid joint deformities, which in some cases can become irreversible.Recently, anifrolumab and belimumab have been able to significantly reduce the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG) index scores, along with improvement in quality of life indices and a significant decrease in the required dose of glucocorticoids. Despite this, the ideal moment to consider biological therapy in this domain is not clear, since the clinical examination can sometimes be biased by the pain associated with fibromyalgia or the fatigue associated with SLE.For this reason, perhaps ultrasonography or magnetic resonance imaging, apart from differentiating the joint phenotype, can identify patients in time to define the onset of disease-modifying antirheumatic drugs and rationalize the use of glucocorticoids.The objective of this review is to characterize in detail the joint manifestations of SLE to offer the clinician a practical view of its diagnosis and treatment.

Proteomic analysis identifies subgroups of patients with active systemic lupus erythematosus

ObjectiveSystemic lupus erythematosus (SLE) is a clinically and biologically heterogenous autoimmune disease. We aimed to investigate the plasma proteome of patients with active SLE to identify novel subgroups, or endotypes, of patients.MethodPlasma was collected from patients with active SLE who were enrolled in the British Isles Lupus Assessment Group Biologics Registry (BILAG-BR). The plasma proteome was analysed using a data-independent acquisition method, Sequential Window Acquisition of All theoretical mass spectra mass spectrometry (SWATH-MS). Unsupervised, data-driven clustering algorithms were used to delineate groups of patients with a shared proteomic profile.ResultsIn 223 patients, six clusters were identified based on quantification of 581 proteins. Between the clusters, there were significant differences in age (p = 0.012) and ethnicity (p = 0.003). There was increased musculoskeletal disease activity in cluster 1 (C1), 19/27 (70.4%) (p = 0.002) and renal activity in cluster 6 (C6) 15/24 (62.5%) (p = 0.051). Anti-SSa/Ro was the only autoantibody that significantly differed between clusters (p = 0.017). C1 was associated with p21-activated kinases (PAK) and Phospholipase C (PLC) signalling. Within C1 there were two sub-clusters (C1A and C1B) defined by 49 proteins related to cytoskeletal protein binding. C2 and C6 demonstrated opposite Rho family GTPase and Rho GDI signalling. Three proteins (MZB1, SND1 and AGL) identified in C6 increased the classification of active renal disease although this did not reach statistical significance (p = 0.0617).ConclusionsUnsupervised proteomic analysis identifies clusters of patients with active SLE, that are associated with clinical and serological features, which may facilitate biomarker discovery. The observed proteomic heterogeneity further supports the need for a personalised approach to treatment in SLE.

Validation and the associated factors of the Malay version of systemic lupus erythematosus-specific health-related quality of life questionnaires (SLEQoL and LupusQoL).

To assess the reliability and validity of two disease-specific questionnaires that assess the quality of life (QoL) among patients with Systemic Lupus Erythematosus (SLE); SLEQoL and LupusQoL in Malay language. This study also identified the factors affecting each domain of the questionnaires. This cross-sectional study was conducted from June 2021 until April 2022, and SLE patients were recruited to complete the SLEQoL, LupusQoL and Short Form Health Survey (SF-36) in Malay language. Disease activity were recorded using the modified SLE Disease Activity Index (M- SLEDAI) and British Isles Lupus Assessment Group 2004 (BILAG-2004) index. Presence of organ damage was determined using the SLICC Damage index. Cronbach's alpha was calculated to determine internal consistency while exploratory factor analysis was done to determine the construct validity. Concurrent validity was evaluated using correlation with SF-36. Multiple linear regression analysis was deployed to determine the factors affecting each domain of SLEQoL and LupusQoL. A total of 125 subjects were recruited. The Cronbach's α value for the Malay-SLEQoL (M-SLEQoL) and Malay-LupusQOL (M-LupusQoL) was 0.890 and 0.944 respectively. Exploratory factor analysis found formation of similar number of components with the original version of questionnaires and all items have good factor loading of >0.4. Both instruments also had good concurrent validity with SF-36. M-SLEQoL had good correlations with BILAG-2004 and M-SLEDAI scores. Musculoskeletal (MSK) involvement was independently associated with lower M-SLEQoL in physical function, activity and symptom domains. Meanwhile, MSK and NPSLE were associated with fatigue in M-LupusQoL. Both M-SLEQoL and M-LupusQoL are reliable and valid as disease -specific QoL instruments for Malaysian patients. The M-Lupus QoL has better discriminative validity compared to the M-SLEQoL. SLE patients with MSK involvement are at risk of poor QoL in multiple domains including physical function, activity, symptoms and fatigue.

Early infection risk in patients with systemic lupus erythematosus treated with rituximab or belimumab from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR): a prospective longitudinal study.

Patients with systemic lupus erythematosus (SLE) are at an increased risk of infection relative to the general population. We aimed to describe the frequency and risk factors for serious infections in patients with moderate-to-severe SLE treated with rituximab, belimumab, and standard of care therapies in a large national observational cohort. The British Isles Lupus Assessment Group Biologics Register (BILAG-BR) is a UK-based prospective register of patients with SLE. Patients were recruited by their treating physician as part of their scheduled care from 64 centres across the UK by use of a standardised case report form. Inclusion criteria for the BILAG-BR included age older than 5 years, ability to provide informed consent, a diagnosis of SLE, and starting a new biological therapy within the last 12 months or a new standard of care drug within the last month. The primary outcome for this study was the rate of serious infections within the first 12 months of therapy. Serious infections were defined as those requiring intravenous antibiotic treatment, hospital admission, or resulting in morbidity or death. Infection and mortality data were collected from study centres and further mortality data were collected from the UK Office for National Statistics. The relationship between serious infection and drug type was analysed using a multiple-failure Cox proportional hazards model. Between July 1, 2010, and Feb 23, 2021, 1383 individuals were recruited to the BILAG-BR. 335 patients were excluded from this analysis. The remaining 1048 participants contributed 1002·7 person-years of follow-up and included 746 (71%) participants on rituximab, 119 (11%) participants on belimumab, and 183 (17%) participants on standard of care. The median age of the cohort was 39 years (IQR 30-50), 942 (90%) of 1048 patients were women and 106 (10%) were men. Of the patients with available ethnicity data, 514 (56%) of 911 were White, 169 (19%) were Asian, 161 (18%) were Black, and 67 (7%) were of multiple-mixed or other ethnic backgrounds. 118 serious infections occurred in 76 individuals during the 12-month study period, which included 92 serious infections in 58 individuals on rituximab, eight serious infections in five individuals receiving belimumab, and 18 serious infections in 13 individuals on standard of care. The overall crude incidence rate of serious infection was 117·7 (95% CI 98·3-141·0) per 1000 person-years. Compared with standard of care, the serious infection risk was similar in the rituximab (adjusted hazard ratio [HR] 1·68 [0·60-4·68]) and belimumab groups (1·01 [0·21-4·80]). Across the whole cohort in multivariate analysis, serious infection risk was associated with prednisolone dose (>10 mg; 2·38 [95%CI 1·47-3·84]), hypogammaglobulinaemia (<6 g/L; 2·16 [1·38-3·37]), and multimorbidity (1·45 [1·17-1·80]). Additional concomitant immunosuppressive use appeared to be associated with a reduced risk (0·60 [0·41-0·90]). We found no significant safety signals regarding atypical infections. Six infection-related deaths occurred at a median of 121 days (IQR 60-151) days from cohort entry. In patients with moderate-to-severe SLE, rituximab, belimumab, and standard immunosuppressive therapy have similar serious infection risks. Key risk factors for serious infections included multimorbidity, hypogammaglobulinaemia, and increased glucocorticoid doses. When considering the risk of serious infection, we propose that immunosupppressives, rituximab, and belimumab should be prioritised as mainstay therapies to optimise SLE management and support proactive minimisation of glucocorticoid use. None.

OA27 Mortality in patients with moderate-to-severe SLE: results from the British Isles Lupus Assessment Group Biologics Registry (BILAG-BR)

Abstract Background/Aims Individuals with systemic lupus erythematosus (SLE) have an increased rate of mortality compared to the general population. We aimed to assess the cause of death and characteristics of these patients in a large national biologics register. Methods Patients receiving biological or standard of care (SoC) treatment recruited to the UK national SLE biologics registry (2010-21) were included. Demographic, clinical and laboratory data were recorded at recruitment. Information relating to date and cause of death were collected from study centres and the UK Office for National Statistics. The relationship between mortality and patient variables was analysed using a Cox proportional hazards model. Results There were 54 deaths in 1,477 patients over 6,162 patient years of follow up. The mortality rate was 5.97 (6.92-11.80) per 1000 person years (py). The cause of death was identifiable in 52 (96.2%) patients and included infection (21, 38.9%), active SLE (10, 18.5%), malignancy (6, 11.1%), cardiovascular disease (6, 11%), thrombosis (3, 5.6%), opiate toxicity (1, 1.9%) and cerebral haemorrhage (1, 1.9%). The characteristics of patients who died are described in Table 1. The median time between BILAG-BR registration and death was 679 (251-1,227) days. The mortality rate was 11.34 (8.54-15.04) per 1,000 py in patients on rituximab, 2.52 (0.36-17.90) per 1,000 py in belimumab and 3.32 (1.25-8.86) per 1,000 py in patients on SOC medicines. Factors independently associated with mortality included age at recruitment (HR 1.07 [1.05-1.09]), previous myocardial infarction (HR 5.35 [2.27-12.59]), diabetes mellitus (HR 3.87 [1.81-8.29]), previous cancer (HR 3.30 [1.59-6.86]) and hypertension (HR 1.81 [1.00-3.27]). In multivariate models adjusted for age, gender and presence of co-morbidities at baseline, risk of death was not significantly different between rituximab and belimumab (HR 0.36 [0.05-2.65) or SOC (HR 0.40 [0.12-1.32]) groups. Conclusion Risk of mortality was not different between treatment groups after accounting for differences in baseline demographics and co-morbidities. Co-morbidities were independently associated with high risk of death for patients with moderate-to-severe SLE; these should be actively assessed and managed to improve mortality outcomes. Disclosure S. Dyball: Grants/research support; MRC. Other; GSK, UCB. M. Rodziewicz: Grants/research support; MRC. Other; UCB. E. Sutton: None. A. Aksoy: None. S. McDonald: None. B. Parker: Honoraria; Fresenius-Kabi, AbbVie. Grants/research support; Genzyme/Sanofi, GSK. Other; Eli Lilly, Roche. I. Bruce: Consultancies; AstraZeneca, Eli Lilly, UCB, ILTOO, Merck Serono, GSK. Grants/research support; UCB, Roche, GSK, Genzyme/Sanofi. Other; AstraZeneca, GSK, UCB.

P165 The incidence of cancer in SLE patients receiving biologic therapy: Results from the British Isles Lupus Assessment Group Biologics Registry (BILAG-BR)

Abstract Background/Aims Patients with systemic lupus erythematosus (SLE) are known to have an increased risk of certain cancers, such as lymphoma, compared to the general population. We aimed to characterise the incidence of cancers in patients with moderate-severe SLE receiving biologic and standard of care (SoC) therapies. Methods The BILAG Biologics Registry (BILAG-BR) is a large prospective observational register of patients with SLE. Participants receiving rituximab, belimumab and SoC therapies from 2010-2021 were included. Data relating to malignancy were collected from study centres and the UK national cancer register. Overall cancer risk was assessed using a Cox proportional hazards model in Stata V14. Results There were 114 previous cancer diagnoses in 108 patients recorded. The most common cancer sites were cervical (43/114), non-melanoma skin cancer (20), breast (15) and lymphoma (13). All cervical neoplasms were carcinoma in situ. Five patients had more than one cancer diagnosis recorded; three had &amp;gt;1 non-melanoma skin cancer and two individuals had unrelated malignancies. During follow-up, (1437 patients with 5,738 person years [pys]), 33 incident cancers occurred in 32 individuals at a median of 477 (IQR 218-1265) days after registration. Incidence rates were 5.9 (95% CI 3.9-8.8) in rituximab, 7.8 (2.5-24.2) in belimumab and 4.16 (1.7-10.0) per 1,000 pys in the SoC group. Using rituximab as the comparator, the age and gender adjusted hazard ratio (HR) was 1.62 (0.48-5.52) for belimumab and 0.63 (0.24-1.65) for the SoC group. Patients who developed an incident cancer were older at registration (HR 1.07 [1.04-1.09] per year) and more likely to be of male sex (HR 2.95 [1.31-6.57]). Caucasian ethnicity was associated with increased risk in univariate analysis (HR 4.25 [1.46-12.32]), but not after adjusting for age and sex (HR 2.60 [0.86-7.83]). There were 6 cancer-related deaths which all occurred in the rituximab group a median of 2.3 (IQR 1.4-3.2) years from registration. Conclusion Although overall cancer numbers are low, the findings of this study are reassuring. The incidence of cancer in this cohort of SLE patients with moderate-to-severe disease appears to be broadly similar between those on biologic and standard of care therapies. Disclosure M. Rodziewicz: Grants/research support; North West England MRC Fellowship Scheme in Clinical Pharmacology and Therapeutics. Award Ref. MR/N025989/1, UCB. S. Dyball: Grants/research support; North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics. Award Ref. MR/N025989/1, UCB, Eli Lilly. E. Sutton: None. B. Parker: Honoraria; Fresenius-Kabi, AbbVie. Member of speakers’ bureau; Eli Lilly, Roche. Grants/research support; Genzyme/Sanofi, GSK. I.N. Bruce: Consultancies; AstraZeneca, Eli Lilly, ILTOO, GSK, Aurinia. Member of speakers’ bureau; GSK, UCB, AstraZeneca. Grants/research support; GSK, Roche, Janssen.

Evaluation of the LFA-REAL clinician-reported outcome (ClinRO) and patient-reported outcome (PRO): prespecified analysis of the phase III ustekinumab trial in patients with SLE

ObjectiveThe Lupus Foundation of America Rapid Evaluation of Activity in Lupus (LFA-REAL) system is a novel and simple SLE disease activity instrument, consisting of a tandem clinician-reported (ClinRO) and patient-reported...

Gene Expression and Autoantibody Analysis Revealing Distinct Ancestry-Specific Profiles Associated With Response to Rituximab in Refractory Systemic Lupus Erythematosus.

Gene expression profiles are associated with the clinical heterogeneity of systemic lupus erythematosus (SLE) but are not well studied as biomarkers for therapy. We studied gene expression and response to rituximab in a multiethnic UK cohort who were refractory to standard therapy. We evaluated baseline expression levels of transcripts known to associate with clinical features of SLE using a 96-probe TaqMan array and whole blood samples from 213 patients with active SLE who had been prospectively enrolled in the British Isles Lupus Assessment Group (BILAG) Biologics Register. We measured autoantibodies using immunoprecipitation and enzyme-linked immunosorbent assays. We determined responses to first-cycle rituximab at 6 months from treatment start in 110 SLE patients by assessing BILAG 2004 disease activity. Interferon gene expression scores were lower in patients of European ancestry than in all other ancestry groups. The relationship between blood interferon gene expression scores and scores annotated to plasmablasts, neutrophils, myeloid lineage, inflammation, and erythropoiesis differed between patients of European and non-European ancestries. Hierarchical clustering revealed 3 distinct non-European ancestry patient subsets with stratified responses to rituximab that were not explained by sociodemographic and clinical variables, with responses lowest in an interferon-low, neutrophil-high cluster and highest in a cluster with high expression levels across all signatures (P < 0.001). Clusters in European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon-high clusters were associated with U1 RNP/Sm antibodies. Ancestry appears central to the immunologic and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity, and transcriptional signatures could each assist in predicting the effectiveness of B cell depletion therapies.

Effects of N-acetylcysteine on systemic lupus erythematosus disease activity and its associated complications: a randomized double-blind clinical trial study

BackgroundsN-acetylcysteine (NAC) has broadly been used as an anti-oxidant agent in various types of diseases. This study aimed to assess the effect of NAC on the systemic lupus erythematosus (SLE) disease activity and outcome.MethodsIn this randomized, double-blind clinical trial study, 80 SLE patients were recruited that were classified into two groups: 40 patients received NAC (1800 mg/day; 3 times per day with 8-h intervals) for 3 months and 40 patients as the control group received normal therapies. Laboratory measurements and disease activity based on the British Isles Lupus Assessment Group (BILAG) and SLE Disease Activity Index (SLEDAI) were determined before the initiation of treatment and after the study time period.ResultsA statistically significant decrease in BILAG (P= 0.023) and SLEDAI (P= 0.034) scores after receiving NAC for a 3-month period was observed. BILAG (P= 0.021) and SLEDAI (P= 0.030) scores were significantly lower in NAC-receiving patients compared to the control group after 3 months. The disease activity in each organ based on BILAG score after treatment indicated a significant decrease in the NAC group compared to the baseline level in general (P=0.018), mucocutaneous (P=0.003), neurological (P=0.015), musculoskeletal (P=0.048), cardiorespiratory (P=0.047), renal (P=0.025), and vascular (P=0.048) complications. Analysis indicated a significant increase in CH50 level in the NAC group after treatment compared to the baseline level (P=0.049). No adverse event was reported by the study subjects.ConclusionsIt appears that the administration of 1800 mg/day NAC to SLE patients can decrease the SLE disease activity and its complications.

Risk of systemic lupus erythematosus flares according to autoantibody positivity at the time of diagnosis

To estimate the risk of systemic lupus erythematosus (SLE) flares based on the autoantibody positivity at the time of SLE diagnosis. This retrospective cohort study included 228 patients with newly diagnosed SLE. Clinical characteristics including autoantibody positivity at the time of diagnosis of SLE were reviewed. Flares were defined as a new British Isles Lupus Assessment Group (BILAG) A score or BILAG B score for at least one organ system. Multivariable Cox regression analyses were performed to estimate the risk of flares according to autoantibody positivity. Anti-dsDNA, anti-Sm, anti-U1RNP, anti-Ro, and anti-La antibodies (Abs) were positive in 50.0%, 30.7%, 42.5%, 54.8%, and 22.4% of the patients, respectively. The incidence rate of flares was 28.2/100 person-years. Multivariable Cox regression analysis, adjusted for potential confounders, revealed that anti-dsDNA Ab positivity (adjusted hazard ratio [HR]: 1.46, p = 0.037) and anti-Sm Ab positivity (adjusted HR: 1.81, p = 0.004) at the time of diagnosis of SLE were associated with higher risk of flares. To better delineate the flare risk, patients were categorized as double-negative, single-positive, double-positive for anti-dsDNA and anti-Sm Abs. Compared with double-negativity, double-positivity (adjusted HR: 3.34, p < 0.001) was associated with higher risk of flares, while anti-dsDNA Ab single-positivity (adjusted HR: 1.11, p = 0.620) or anti-Sm Ab single-positivity (adjusted HR: 1.32, p = 0.270) was not associated with higher risk of flares. Patients who are double-positive for anti-dsDNA and anti-Sm Abs at the time of the diagnosis of SLE are at higher risk of flares and may benefit from stringent monitoring and early preventive treatment.

Performance of systemic lupus erythematosus responder index for detecting clinician-rated responders in patients with active systemic lupus erythematosus.

Disease activity measures in systemic lupus erythematosus (SLE) are critical tools for trial endpoints. We aimed to evaluate the performance of current treatment outcome measures in SLE. Individuals with active SLE with a clinical SLE Disease Activity Index-2000 (SLEDAI-2K) score of at least 4 were followed up for two or more visits and classified as responders and non-responders based on a physician's judgment of improvement. The treatment outcome measures including SLEDAI-2K responder index-50 (SRI-50), SLE responder index-4 (SRI-4), substituting SLEDAI-2K with SRI-50 in SRI-4 (SRI-4(50)), SLE Disease Activity Score (SLE-DAS) responder index (Δ ≥ 1.72) and the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) were tested. The performance of those measures was shown by sensitivity, specificity, predictive value, positive likelihood ratio, accuracy, and agreement against a physician-rated improvement. Twenty-seven patients with active SLE were followed. The total cumulative pair of visits (baseline and follow up) was 48. The overall accuracies (95% confidence interval [CI]) of SRI-50, SRI-4, SRI-4(50), SLE-DAS, and BICLA for detecting responders in all patients were 72.9 (58.2-84.7), 75.0 (60.4-86.4), 72.9 (58.2-84.7), 75.0 (60.4-86.4), and 64.6 (49.5-77.8), respectively. Subgroup analyses of lupus nephritis (23 patients had a pair of visits) found the accuracies (95% CI) of SRI-50, SRI-4, SRI-4(50), SLE-DAS, and BICLA were 82.6 (61.2-95.0), 73.9 (51.6-89.8), 82.6 (61.2-95.0), 82.6 (61.2-95.0), and 78.3 (56.3-92.5), respectively. However, there were no significant differences between the groups (P > 0.05). SRI-4, SRI-50, SRI-4(50), SLE-DAS responder index, and BICLA demonstrated comparable abilities to identify clinician-rated responders in patients with active SLE and lupus nephritis.

Comprehensive genetic and functional analyses of Fc gamma receptors influence on response to rituximab therapy for autoimmunity.

Rituximab is widely used to treat autoimmunity but clinical response varies. Efficacy is determined by the efficiency of B-cell depletion, which may depend on various Fc gamma receptor (FcγR)-dependent mechanisms. Study of FcγR is challenging due to the complexity of the FCGR genetic locus. We sought to assess the effect of FCGR variants on clinical response, B-cell depletion and NK-cell-mediated killing in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). A longitudinal cohort study was conducted in 835 patients [RA=573; SLE=262]. Clinical outcome measures were two-component disease activity score in 28-joints (2C-DAS28CRP) for RA and British Isles Lupus Assessment Group (BILAG)-2004 major clinical response (MCR) for SLE at 6 months. B-cells were evaluated by highly-sensitive flow cytometry. Single nucleotide polymorphism and copy number variation for genes encoding five FcγRs were measured using multiplex ligation-dependent probe amplification. Exvivo studies assessed NK-cell antibody-dependent cellular cytotoxicity (ADCC) and FcγR expression. In RA, carriage of FCGR3A-158V and increased FCGR3A-158V copies were associated with greater 2C-DAS28CRP response (adjusted for baseline 2C-DAS28CRP). In SLE, MCR was associated with increased FCGR3A-158V, OR 1.64 (95% CI 1.12-2.41) and FCGR2C-ORF OR 1.93 (95% CI 1.09-3.40) copies. 236/413 (57%) patients with B-cell data achieved complete depletion. Homozygosity for FCGR3A-158V and increased FCGR3A-158V copies were associated with complete depletion in combined analyses. FCGR3A genotype was associated with rituximab-induced ADCC, and increased NK-cell FcγRIIIa expression was associated with improved clinical response and depletion invivo. Furthermore, disease status and concomitant therapies impacted both NK-cell FcγRIIIa expression and ADCC. FcγRIIIa is the major low affinity FcγR associated with rituximab response. Increased copies of the FCGR3A-158V allele (higher affinity for IgG1), influences clinical and biological responses to rituximab in autoimmunity. Enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping may stratify patients for optimal treatment protocols. Medical Research Council, National Institute for Health and Care Research, Versus Arthritis.

Can lupus low disease activity state predict mortality in patients with SLE?

Since 2000, our ability to measure systemic lupus erythematosus (SLE) from a diagnostic, assessment, and prognostic standpoint has advanced substantially. These advances include the incorporation of the SLE Disease Activity Index, the British Isles Lupus Assessment Group, and their composite indices in clinical trials. Additional benchmarks, such as the Definition of Remission in SLE (DORIS) framework and lupus low disease activity state (LLDAS), have been used to evaluate disease activity and attainment of remission.

Disease trajectory of SLE clinical endpoints and covariates affecting disease severity and probability of response: Analysis of pooled patient-level placebo (Standard-of-Care) data to enable model-informed drug development.

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.

Cost-Effectiveness of Acthar Gel Versus Standard of Care for the Treatment of Exacerbations in Moderate-to-Severe Systemic Lupus Erythematosus.

Despite current standard of care (SoC), there is an unmet need for the treatment of active systemic lupus erythematosus (SLE). The study assessed the cost-effectiveness of Acthar® Gel (repository corticotropin injection) versus SoC treatment in patients with active, moderate-to-severe SLE from the US payer and societal perspectives over 2 and 3 years. Cost-effectiveness model was developed using a probabilistic cohort-level state-transition approach. Patients received Acthar Gel in an exacerbation state, and the outcomes were assessed at the end of a 3-month cycle for response achievement based on the probability of treatment success with Acthar Gel. Patients may sustain the response or experience an exacerbation. For the base case scenario, moderate-to-severe SLE was defined as British Isles Lupus Assessment Group (BILAG)-2004 ≥ 20 or SLE Disease Activity Index 2000 (SLEDAI-2K) ≥ 10 and clinical response was based on SLE responder index (SRI)-4. Clinical response, productivity loss, and utility were derived from a phase 4 SLE trial; cost and disutility estimates were sourced from the literature. From a payer perspective, Acthar Gel versus SoC resulted in an incremental cost-effectiveness ratio (ICER) of $133,110 per quality-adjusted life-year (QALY) and $94,818 per QALY over 2 and 3 years, respectively. From a societal perspective, Acthar Gel versus SoC results in an ICER of $70,827 per QALY and $32,525 per QALY over 2 and 3 years, respectively. Results from the sensitivity and scenario analyses are consistent with those of the base case model. Acthar Gel is a cost-effective, value-based treatment option for appropriate patients with moderate-to-severe SLE at a willingness-to-pay threshold of $150,000 over 2-3 years from the US payer and societal perspectives. Acthar Gel results in the reduction of direct medical and indirect costs.