Lupus Low Disease Activity State Research Articles

Serum IFNα2 levels are associated with disease activity and outperform IFN-I gene signature in a longitudinal childhood-onset SLE cohort.

To study the association of serum IFNα2 levels measured by ultrasensitive single-molecule array (Simoa) and the IFN-I gene signature (IGS) with disease activity and determine whether these assays can mark disease activity states in a longitudinal cohort of childhood-onset SLE (cSLE) patients. Serum IFNα2 levels were measured in 338 samples from 48 cSLE patients and 67 healthy controls using an IFNα Simoa assay. Five-gene IGS was measured by RT-PCR in paired whole blood samples. Disease activity was measured by clinical SELENA-SLEDAI and BILAG-2004. Low disease activity was defined by Low Lupus Disease Activity State (LLDAS) and flares were characterized by SELENA-SLEDAI flare index. Analysis was performed using linear mixed models. A clear positive correlation was present between serum IFNα2 levels and the IGS (r = 0.78, P < 0.0001). Serum IFNα2 levels and IGS showed the same significant negative trend in the first 3 years after diagnosis. In this timeframe, mean baseline serum IFNα2 levels decreased by 55.1% (Δ 201 fg/ml, P < 0.001) to a mean value of 164 fg/ml, which was below the calculated threshold of 219.4 fg/ml that discriminated between patients and healthy controls. In the linear mixed model, serum IFNα2 levels were significantly associated with both cSELENA-SLEDAI and BILAG-2004, while the IGS did not show this association. Both IFN-I assays were able to characterize LLDAS and disease flare in receiver operating characteristic analysis. Serum IFNα2 levels measured by Simoa technology are associated with disease activity scores and characterize disease activity states in cSLE.

Lupus low disease activity state and remission and risk of mortality in patients with systemic lupus erythematosus: a prospective, multinational, longitudinal cohort study.

Treat-to-target goals for patients with systemic lupus erythematosus (SLE) have been validated to protect against organ damage and to improve quality of life. We aimed to investigate the association between lupus low disease activity state (LLDAS) and remission and risk of mortality in patients with SLE. We hypothesised that LLDAS has a protective association with mortality risk. In this prospective, multinational, longitudinal cohort study, we used data from patients with SLE in the Asia Pacific Lupus Collaboration cohort collected between May 1, 2013, and Dec 31, 2020. Eligible patients were adults (aged ≥18 years) who met either the 1997 American College of Rheumatology modified classification criteria for SLE or the 2012 Systemic Lupus International Collaborating Clinics classification criteria. The primary outcome was all-cause mortality, and LLDAS, remission, and variations of remission with lower glucocorticoid thresholds were the primary exposure variables. Survival analyses were used to examine longitudinal associations between these endpoints and risk of mortality. This study is registered with ClinicalTrials.gov, NCT03138941. Among a total of 4106 patients in the cohort, 3811 (92·8%) patients were included in the final analysis (median follow-up 2·8 years [IQR 1·0-5·3]; 3509 [92·1%] women and 302 [7·9%] men), of whom 80 died during the observation period (crude mortality rate 6·4 deaths per 1000 person-years). LLDAS was attained at least once in 43 (53·8%) of 80 participants who died and in 3035 (81·3%) of 3731 participants who were alive at the end of the study (p<0·0001); 22 (27·5%) participants who died versus 1966 (52·7%) who were alive at the end of the study attained LLDAS for at least 50% of observed time (p<0·0001). Remission was attained by 32 (40·0%) of 80 who died and in 2403 (64·4%) of 3731 participants who were alive at the end of the study (p<0·0001); 14 (17·5%) participants who died versus 1389 (37·2%) who were alive at the end of the study attained remission for at least 50% of observed time (p<0·0001). LLDAS for at least 50% of observed time (adjusted hazard ratio 0·51 [95% CI 0·31-0·85]; p=0·010) and remission for at least 50% of observed time (0·52 [0·29-0·93]; p=0·027) were associated with reduced risk of mortality. Modifying the remission glucocorticoid threshold (<5·0 mg/day prednisolone) was more protective against mortality than current remission definitions (0·31 [0·12-0·77]; p=0·012), and glucocorticoid-free remission was the most protective (0·13 [0·02-0·96]; p=0·046). LLDAS significantly reduced the risk of mortality in patients with SLE. Remission did not further reduce the risk of mortality compared with LLDAS, unless lower glucocorticoid thresholds were used. The Asia-Pacific Lupus Collaboration received funding from Janssen, Bristol Myers Squibb, Eli Lilly, and UCB for this study.

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.

Associations of improvement in laboratory tests with clinical outcomes in patients with active systemic lupus erythematosus: a multinational longitudinal cohort study.

The selection and categorisation of laboratory tests in disease activity measures used within systemic lupus erythematosus (SLE) trial endpoints lack strong evidence. We aimed to determine whether longitudinal improvements in routinely measured laboratory tests are associated with measures of clinical improvement in patients with baseline active SLE. We included patients from a multicentre longitudinal cohort (recruited between May 1, 2013, and Dec 31, 2019) with active SLE (SLEDAI-2K ≥6) coinciding with an abnormality in at least one of 13 routine laboratory tests, at a visit designated as baseline. At 12 months, we analysed associations between thresholds of improvement in individual laboratory test results, measured as continuous variables, and five clinical outcomes using logistic regression. Primary outcomes were damage accrual and lupus low disease activity state (LLDAS), and secondary outcomes were modified SLE responder index (mSRI), physician global assessment (PGA) improvement of at least 0·3, and flare. We included 1525 patients (1415 [93%] women and 110 [7%] men, 1328 [87%] Asian ethnicity) in separate subsets for each laboratory test. The strongest associations with LLDAS and damage protection were seen with improvements in proteinuria (complete response: adjusted odds ratio [OR] 62·48, 95% CI 18·79-208·31 for LLDAS, OR 0·22, 95% CI 0·10-0·49 for damage accrual), albumin (complete response: adjusted OR 6·46, 95% CI 2·20-18·98 for LLDAS, OR 0·42, 95% CI 0·20-1·22 for damage accrual), haemoglobin (complete response: adjusted OR 1·97, 95% CI 1·09-3·53 for LLDAS, OR 0·33, 95% CI 0·15-0·71 for damage accrual), erythrocyte sedimentation rate (complete response: adjusted OR 1·71, 95% CI 1·10-2·67 for LLDAS, OR 0·53, 95% CI 0·30-0·94 for damage accrual), and platelets (complete response: adjusted OR 4·82, 95% CI 1·54-15·07 for LLDAS, OR 0·49, 95% CI 0·20-1·19 for damage accrual). Improvement in serological tests were mainly associated with PGA and mSRI. White cell and lymphocyte count improvements were least predictive. Improvements in several routine laboratory tests correspond with clinical outcomes in SLE over 12 months. Tests with the strongest associations were discrepant with laboratory tests included in current trial endpoints, and associations were observed across a range of improvement thresholds including incomplete resolution. These findings suggest the need to revise the use of laboratory test results in SLE trial endpoints. Abbvie.

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.

Grit personality of physicians and achievement of treatment goals in patients with system lupus erythematosus.

Although personality characteristics of patients with SLE affect their disease activity and damage, it is unclear whether those of attending physicians affect the outcomes of patients with SLE. Grit is a personality trait for achieving long-term goals that may influence the decision-making for continuing treatment plans for patients. We aimed to evaluate the relationship between the grit of attending physicians and achievement of treatment goals in patients with SLE. This cross-sectional study was conducted at five referral hospitals. The main exposure was 'consistency of interest' and 'perseverance of effort' of the attending physicians, measured by the Short Grit Scale. The primary outcome was achievement of a lupus low disease activity state (LLDAS). The association between physicians' grit score and LLDAS was analysed by generalized estimating equation (GEE) logistic regression with cluster robust variance estimation, with adjustment for confounders. The median (interquartile range) total, consistency and perseverance scores of 37 physicians were 3.1 (2.9-3.6), 3.3 (2.8-3.8) and 3.3 (3.0-3.5), respectively. Among the 386 patients, 154 (40%) had achieved LLDAS. Low consistency score (≤2.75) in physicians was related to LLDAS achievement independently using GEE logistic regression. The score of the question 'I often set a goal but later choose to pursue a different one' was significantly higher in patients achieving LLDAS. Difficulty of attending physicians to change treatment goals might be related to lower LLDAS achievement in patients with SLE.

Lupus low disease activity state as a treatment target for pediatric patients with lupus nephritis.

Lupus low disease activity state (LLDAS) is a treatment target for patients with SLE and is associated with decreased risk for severe flare and new damage. We investigated the utility of the achievement of LLDAS in children with lupus nephritis and whether attainment of LLDAS is associated with more favorable outcomes. Data of children, diagnosed with biopsy-proven lupus nephritis between January 2012 and December 2020, were retrospectively analyzed. For patients who did not achieve LLDAS after initial treatment (first 6months), presence of autoimmune hemolytic anemia (62% vs. 18%, p = 0.047), anti-Sm (85% vs. 18%, p = 0.003) and anti-dsDNA (77% vs. 27%, p = 0.038) antibodies, proliferative lupus nephritis (77% vs. 27%, p = 0.038), and hypertension (69% vs. 9%, p = 0.005) at onset were more frequently encountered. Also, a lower rate of complete kidney response (43% vs. 100%, p = 0.005) and a higher rate of hypertension (86% vs. 13%, p = 0.002) were observed in patients who did not achieve LLDAS-50, defined as being in LLDAS at least 50% of the observation time. Attainment of both LLDAS after initial treatment and LLDAS-50 were associated with lower rates of kidney flare (p = 0.001 and p = 0.002, respectively) and damage accrual (p = 0.007 and p = 0.02, respectively) through the observation period. LLDAS is an attainable treatment target for children with lupus nephritis and associated with lower rates of kidney flare and damage. Presence of hematologic involvement, hypertension, and proliferative lupus nephritis at onset adversely influenced the early achievement of LLDAS. A higher resolution version of the Graphical abstract is available as Supplementary information.

Predictors of infection requiring hospitalization in patients with systemic lupus erythematosus: a time-to-event analysis

ObjectivesTo evaluate the predictors of serious infection in patients with systemic lupus erythematosus (SLE). MethodsSerious infections were identified in SLE patients in a prospectively-followed single centre cohort. Associations of serious infection with disease-related variables and medication use were analysed using Cox and related regression models. Results346 patients were followed for a mean (SD) of 6.6 (3.7) years. 86 episodes of serious infection were observed, with an incidence rate of 3.8 episodes per 100 person-years. Patients who had serious infection had higher baseline SLE Damage Index (SDI) and Charlston Comorbidity Index (CCI); they were also more likely to have high disease activity status (HDAS), and higher disease activity in multiple clinical domains, higher flare rates, higher time-adjusted prednisolone dose exposure, and less time in lupus low disease activity state (LLDAS). Patients who have received cyclophosphamide, rituximab and mycophenolate were more likely to have experienced serious infection. After multivariable adjustment in Cox regression analysis, cyclophosphamide, higher SDI score, and higher disease activity were associated with an increased hazard of first serious infection. History of previous serious infection conferred the highest risk. Lymphopenia was also a modest but statistically significant predictor of serious infection. ConclusionHistory of previous serious infection was the strongest predictor of serious infection in our SLE cohort. This study also suggests that clinical factors such as damage accrual, disease activity, and choice of immunosuppressant, can each have an independent risk in predicting serious infection particularly the first episode.

The association of psychosocial stressors and psychiatric disorders with fatigue in systemic lupus erythematosus patients.

In systemic lupus erythematosus (SLE), fatigue is the most common and aggravating symptom which has been reported to be influenced by several factors, such as disease activity, psychosocial stressors, and psychiatric disorders. Therefore, this study aims to determine the association between disease activity, psychosocial stressors, and psychiatric disorders with fatigue in SLE patients. In this cross-sectional study, 73 female SLE patients were accepted to participate by filling out the informed consent. Besides, disease activity was divided into Lupus Low Disease Activity State (LLDAS) and non-LLDAS. The Holmes-Rahe Stress Scale and Fatigue Severity Scale (FSS) were employed to assess psychosocial stress and fatigue severity. The Mini-International Neuropsychiatric Interview (MINI) ICD-10 was used to examine psychiatric disorders. The Chi-square test was conducted to determine the association between dependent variables (fatigue) and independent variables (psychosocial stress, psychosocial stress severity, and psychiatric disorders). Out of the participants, 49 (67.1%) suffered from fatigue, and the LLDAS group contained fewer individuals than non-LLDAS, 46.6% versus 53.4%. The majority (86.3%) also experienced psychosocial stress, ranging from mild to severe, and 56 (76.7%) patients had psychiatric disorders. No significant association was discovered between SLE disease activity and fatigue. However, fatigue had significant associations with psychiatric disorders in both LLDAS (p = 0.02) and non-LLDAS groups (p = 0.04), as well as with psychosocial stress severity (p = 0.02). Histories of major personal illness (p = 0.01) and changes in eating habits (p = 0.02) were associated with fatigue among the LLDAS participants. Psychosocial stressors and psychiatric disorders were significantly associated with fatigue in SLE. Histories of major personal disease and changes in eating habits were also significantly associated with fatigue in the LLDAS participants. Therefore, early recognition of these factors is necessary to manage and prevent fatigue in SLE patients.

Immunosuppressant exposure confounds gene expression analysis in systemic lupus erythematosus.

ObjectivesThe analysis of gene module expression in SLE is emerging as a tool to identify active biological pathways, with the aim of developing targeted therapies for subsets of patients. Detailed information on the effect of immunosuppressants on gene module expression is lacking. We aimed to examine the impact of medication exposure on gene module expression.MethodsA set of commercially available disease-relevant gene modules were measured in 730 whole blood samples from a dedicated lupus clinic on whom prospectively collected, contemporaneous clinical data including medication exposure were available.ResultsCompared to heathy controls, SLE patients showed over-expression of IFN and under-expression of B cell, T cell and pDC modules. Neutrophil module over-expression and under-expression of B and T cell modules were observed in patients with active lupus nephritis or highly active disease (SLEDAI-2K > 8), while Lupus Low Disease Activity State (LLDAS) had inverse associations. Disease activity in other organ domains was not associated with specific gene modules. In contrast, medications were associated with multiple effects. Glucocorticoid use was associated with under-expression of T cell, B cell and plasmablast modules, and over-expression of neutrophil modules. Mycophenolate and azathioprine exposure were associated with plasmablast module and B cell module under-expression respectively. Disease activity associations with neutrophil over-expression and lymphocyte module under-expression were attenuated by multivariable adjustment for medication exposure.ConclusionMedications have significant effect on gene module expression in SLE patients. These findings emphasize the need to control for medications in studies of gene expression in SLE.

Effect and safety profile of belimumab and tacrolimus combination therapy in thirty-three patients with systemic lupus erythematosus.

Belimumab combined with mycophenolate mofetil has been proven to be effective for treating systemic lupus erythematosus (SLE) in several randomized controlled trials. Calcineurin inhibitors are also useful in controlling the activity of SLE. However, the safety and effectiveness of belimumab-calcineurin inhibitor combination therapy have not been addressed. Therefore, the current single-center retrospective study aimed to analyze the safety/efficacy profile of belimumab-tacrolimus (B-T) combination therapy in patients with SLE. Patients with SLE administered tacrolimus and belimumab during treatment were included in the study. Samples were analyzed for the drug retention rate, SLE flare rate, infection incidence rate, and glucocorticoid-sparing effect of the B-T combination therapy. Thirty-three patients with SLE were treated with B-T combination therapy at our institution. Four patients discontinued treatment due to insufficient response or adverse events. The drug retention rate was over 90% at week 52 and approximately 80% at day 1000. Only one patient developed serious infection. The lupus low disease activity state (LLDAS) achievement ratio was 9.1% on the day of initiation and improved to 64.0% at 52weeks after initiation. SLE flares were observed in three patients (9.1%) in the first 52weeks after initiation, and in five patients (15.2%) throughout the study period. A glucocorticoid-reducing effect was also observed in patients treated with B-T combination therapy. In most patients with SLE, B-T combination therapy is well tolerated with a good efficacy profile and glucocorticoid-reducing effect. Thus, B-T combination therapy represents a feasible option for patients with refractory lupus. Key Points • The safety and effectiveness of belimumab-calcineurin inhibitor combination therapy have not been addressed. • The drug retention rate of belimumab-tacrolimus combination therapy was over 90% at week 52 and around 80% on day 1000 • Almost none of the patients suffered from severe infection after the initiation of belimumab-tacrolimus combination therapy. • Belimumab-tacrolimus combination therapy is efficacious in suppressing lupus activity and achieving LLDAS.

Predictors and prognostic stratification for lupus low disease activity state: results from a prospective clinical trial.

To identify predictors for lupus low disease activity state (LLDAS), early-achieved LLDAS and long-term disease activity, and to refine a prognostic stratification tool for use in active SLE patients. A total of 245 active SLE patients were enrolled, followed up quarterly from 2014 to 2016. LLDAS-50 was defined as the maintenance of LLDAS for ≥50% of the observed time. LLDAS at 3 months after cohort entry (LLDAS-3mo) was considered an early-achieved LLDAS. Multivariate analysis was performed to identify predictors for LLDAS, early-achieved LLDAS and long-term disease activity. Based on the factors associated with LLDAS, a prognostic stratification tool for LLDAS was established. The 2-year probability of achieving LLDAS was 62.9% (154/245). Multivariate analysis-determined renal involvement, haematological involvement and hypocomplementaemia were negative predictors for achieving LLDAS and LLDAS-50. In multivariate logistic analysis, antiphospholipid antibodies positivity, hypocomplementaemia, renal involvement and haematological involvement were identified as negative predictors for achieving LLDAS-3mo. LLDAS-3mo (P < 0.0001; risk ratio: 47.694; 95% CI: 13.776, 165.127) was a strong predictor for LLDAS-50. The probability of achieving LLDAS, LLDAS-50 and LLDAS-3mo were 88.9% (32/36), 69.4% (25/36) and 41.7% (15/36) in the low-risk group, 65% (65/100), 51.0% (51/100) and 32.0% (32/100) in intermediate-risk group, and 52.8% (57/108), 27.8% (30/108) and 13.0% (14/108) in high-risk group respectively. Significant differences (P < 0.0001) were observed in the LLDAS Kaplan-Meier estimates for the three risk groups based on the identified risk factors. Renal involvement, haematological involvement and hypocomplementaemia were negative predictors of LLDAS achievement and maintenance. LLDAS-3mo was a positive predictor for the long-term sustainment of LLDAS.

Supplemental hydroxychloroquine therapy regulates adipokines in patients with systemic lupus erythematosus with stable disease.

In patients with systemic lupus erythematosus (SLE), a higher frequency of atherosclerotic lesions is associated with poor prognosis. Hydroxychloroquine (HCQ) has been reported to improve the lifespan and the prognosis of dyslipidaemia in patients with SLE, but the mechanism is unclear. We investigated the effect of supplemental HCQ treatment on the levels of serum cytokines associated with atherosclerosis in patients with stable SLE. Patients with SLE who received supplemental HCQ and maintained low disease activity between January 2016 and September 2020 were included in this study. Disease activity was assessed using Safety of Estrogens in Lupus National Assessment-SLE Disease Activity Index, Cutaneous Lupus Erythematous Disease Area and Severity Index, and Lupus Low Disease Activity State. Serum complement titres, anti-dsDNA antibodies, and serum cytokines (adiponectin, resistin, and leptin) were analyzed before and after HCQ treatment. Forty-one patients (4 males and 37 females, mean age 41.3 ± 13.2years) were included. Serum adiponectin levels were significantly increased after 3months of HCQ treatment compared to baseline, and serum resistin levels were significantly reduced. The change in serum resistin level after HCQ administration was correlated with a significant reduction in serum TNF-α, interleukin (IL)-6, IL-8, and IL-1RA levels. Supplemental HCQ treatment in patients with SLE improved adipokine levels. HCQ may improve prognosis by controlling disease activity in SLE and reducing risk factors for atherosclerosis. Key Points • Hydroxychloroquine has been reported to improve the prognosis of dyslipidaemia in patients with SLE, but the underlying mechanism is unclear. • In this study, hydroxychloroquine improved adipokine levels in patients with SLE, implicating adipokines as a potential mechanism underlying the benefit of hydroxychloroquine on dyslipidaemia. • Supplemental hydroxychloroquine should be considered in patients with SLE harboring lipid abnormalities and risk factors for atherosclerosis.

Long-Term Clinical Outcome in Systemic Lupus Erythematosus Patients Followed for More Than 20 Years: The Milan Systemic Lupus Erythematosus Consortium (SMiLE) Cohort.

Tackling active disease to prevent damage accrual constitutes a major goal in the management of patients with systemic lupus erythematosus (SLE). Patients with early onset disease or in the early phase of the disease course are at increased risk of developing severe manifestations and subsequent damage accrual, while less is known about the course of the disease in the long term. To address this issue, we performed a multicentre retrospective observational study focused on patients living with SLE for at least 20 years and determined their disease status at 15 and 20 years after onset and at their last clinical evaluation. Disease activity was measured through the British Isles Lupus Assessment Group (BILAG) tool and late flares were defined as worsening in one or more BILAG domains after 20 years of disease. Remission was classified according to attainment of lupus low-disease-activity state (LLDAS) criteria or the Definitions Of Remission In SLE (DORIS) parameters. Damage was quantitated through the Systemic Lupus Erythematosus International Collaborating Clinics/American College of Rheumatology damage index (SLICC/ACR-DI). LLAS/DORIS remission prevalence steadily increased over time. In total, 84 patients had a late flare and 88 had late damage accrual. Lack of LLDAS/DORIS remission status at the 20 year timepoint (p = 0.0026 and p = 0.0337, respectively), prednisone dose ≥ 7.5 mg (p = 9.17 × 10−5) or active serology (either dsDNA binding, low complement or both; p = 0.001) were all associated with increased late flare risk. Late flares, in turn, heralded the development of late damage (p = 2.7 × 10−5). These data suggest that patients with longstanding SLE are frequently in remission but still at risk of disease flares and eventual damage accrual, suggesting the need for tailored monitoring and therapeutic approaches aiming at effective immunomodulation besides immunosuppression, at least by means of steroids.

POS0190 EFFICACY AND SAFETY OF BARICITINIB IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS FROM TWO RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, PHASE 3 STUDIES

BackgroundIn a 24-week, phase 2 clinical study (NCT02708095) in patients with systemic lupus erythematosus (SLE), baricitinib (BARI), an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis and atopic dermatitis, inhibited the type l interferon gene signature, multiple other cytokine pathways, and improved disease activity (1) (2).ObjectivesTo further evaluate the efficacy and safety of BARI in patients with SLE.MethodsPatients with active SLE receiving stable background therapy were randomised 1:1:1 to BARI 2-mg, 4-mg, or placebo (PBO) once daily in two identically designed, 52-week, phase 3 randomised, PBO-controlled studies. In SLE-BRAVE-I (NCT03616912) and -II (NCT03616964), 760 and 775 patients, respectively were enrolled in a balanced manner across regions, although different countries per region participated in each study. The primary endpoint for both studies was the proportion of patients achieving an SLE Responder Index-4 (SRI-4) response at week 52. Glucocorticoid tapering was encouraged but not required per protocol.ResultsThe mean Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) at baseline was 10.1 for both SLE-BRAVE-I and -II participants; musculoskeletal and mucocutaneous domains were the most common domains involved at baseline. In SLE-BRAVE-I, the proportion of SRI-4 responders at week 52 among patients treated with BARI 4-mg (56.7%), but not BARI 2-mg (49.8%), was significantly greater than in patients treated with PBO (45.9%, p = 0.016) (Table 1). No difference was seen in SLE-BRAVE-II (47.1%, 46.3%, and 45.6%, BARI 4-mg, 2-mg, and PBO, respectively). None of the key secondary endpoints, including glucocorticoid tapering or time to first severe flare (SFI), were met in either study. The proportions of patients with serious adverse events (SAEs) were 7.1% and 8.6% for PBO, 9.4% and 13.4% for BARI 2-mg and 10.3% and 11.2% for BARI 4-mg in SLE-BRAVE-I and II, respectively.Table 1.Efficacy and safety of baricitinib in patients with SLE-BRAVE-I and -IISLE-BRAVE-ISLE-BRAVE-IIEfficacy measurePBO (N=253)BARI 2-mg (N=255)BARI 4-mg (N=252)PBO (N=256)BARI 2-mg (N=261)BARI 4-mg (N=258)SRI-4 (W52)116 (45.9)126 (49.8)142 (56.7)*116 (45.6)120 (46.3)121 (47.1)SRI-4 (W24)99 (39.1)114 (44.8)117 (46.5)98 (38.6)104 (40.0)108 (42.1)Severe Flares (n, events)38 (15.0)34 (13.3)26 (10.3)26 (10.2)29 (11.1)29 (11.2)HR for time to first severe flare (SFI) HR [CI]NA0.8 [0.52, 1.32]0.65 [0.40, 1.08]NA1.1 [0.65, 1.89]1.1 [0.67, 1.94]Glucocorticoid sparing36 (30.8)31 (29.2)36 (34.0)33 (31.7)34 (29.8)36 (34.3)LLDAS (W52)66 (26.2)65 (25.7)74 (29.7)59 (23.2)62 (24.0)65 (25.4)Safety measureTEAE210 (83.0)210 (82.4)208 (82.5)198 (77.3)199 (76.2)200 (77.5)SAE18 (7.1)24 (9.4)26 (10.3)22 (8.6)35 (13.4)29 (11.2)Data are n (%) patients, unless otherwise indicated. BARI=baricitinib; CI=confidence interval; HR=hazard ratio compared with PBO; LLDAS=lupus low disease activity state; N=number of patients in the analysis population; n=number of patients in the specified category; PBO=placebo; TEAE=treatment-emergent adverse event; SAE=serious adverse event; W=week. *p≤0.05 vs PBO.ConclusionAlthough phase 2 data suggested BARI as a potential treatment for patients with SLE (2), the SLE-BRAVE-I and -II phase 3 study results were discordant for the primary outcome measure, with only SLE-BRAVE-I positive, making it difficult to elucidate benefit. Additional analyses are being performed to understand this discordance. No new safety signals were observed.

OP0279 CAR-T CELL TREATMENT OF REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS- SAFETY AND PRELIMINARY EFFICACY DATA FROM THE FIRST FOUR PATIENTS

BackgroundWhile treatment of Systemic lupus erythematosus (SLE) has substantially improved, a subset of patients experiences severe progressive disease despite T- and B cell targeted therapy. Furthermore, drug-free remission and seroconversion is difficult to achieve in SLE to dateObjectivesTo study the safety, tolerability, and preliminary efficacy of deep B cell depletion using autologous CD19 chimeric antigen receptor (CAR) T cells in patients with severe and treatment-refractory SLEMethodsThe CAR product was manufactured by CliniMACS Prodigy system (Miltenyi Biotec, Bergisch Gladbach, Germany). T-cells were enriched from the patients’ peripheral blood apheresis product and 1x108 cells were used as starting cell population. The cells were transfected with a lentiviral vector encoding an anti-CD19 CAR is composed of the FMC63 scFv, a CD8- derived hinge region, TNFRSF19-derived transmembrane domain, CD3ζ intracellular domain, and 4-1BB co-stimulatory domain (Miltenyi Biotec) and expanded for 12 days. After conditioning with cyclophosphamide/ fludarabine patients received 1x106 CD19-CAR-T cells/kg body weight as a single infusion. All SLE treatments with the exception of low dose prednisolone were stopped before CAR-T cell administration. After CAR-T cell treatment, also prednisolone was stopped. Tolerability was assessed by monitoring for Cytokine-release syndrome (CRS), immune-related effector cell neurotoxicity syndrome (ICANS) and infections. Preliminary efficacy was assessed by reaching a Lupus Low Disease Activity State (LLDAS), seroconversion in dsDNA antibodies and ANA and cessation of all SLE-specific treatmentsResultsAs of January 22, 2022, our 4 SLE patients had been treated with CD19 CAR-T cells with a follow up of 10 months (patient 1, female aged 20, SLEDAI-2K: 16), 7 months (patient 2, male aged 22; SLEDAI-2K:8), 2 months (patient 3, female aged 22; SLEDAI 2K: 6), and 1 month (patient 4; female aged 24; SLEDAI-2K: 6), respectively. All patients had active severe SLE with failure of standard treatment including pulsed steroids, hydroxychloroquine, mycophenolate, cyclophosphamide, intravenous immunoglobulins, rituximab and belimumab before CD19 CAR-T cell administration. All patients had active kidney disease. No infections occurred. All four patients experienced fever without proof of infectious disease (CRS °I); only one patient was treated with a single dose of tocilizumab. No ICANS and no CRS of other organs occurred. In vivo, CAR-T cells rapidly expanded to a maximum of 27,6% (day 9, patient 1), 41,2% (day 9, patient 2), 11,5% (day 9, patient 3) and 59,1% (day 9, patient 4) of total circulating T cells followed by a typical decline, with circulating CAR-T cells being continuously detectable during the next months. Expansion of CAR T cells preceded the complete and sustained depletion of circulating B cells. Patient 1 experienced sustained drug-free remission (SLEDAI-2K=0) with complete loss of ANA and dsDNA antibodies despite reappearance of B cells at 6 months. Patient 2 also experienced complete loss of ANA and dsDNA antibodies with B cells not yet returned. Low-level proteinuria remained most likely due to previously accrued damage in glomerular filter function (SLEDAI-2K: 2). Patient 3 and patient 4 had a shorter observation period to date but also achieved clinical remission (both SLEDAI-2K 0). All patients met LLDAS and could successfully stop all SLE-specific medication, including glucocorticoids. No SLE flare occurred so far.ConclusionTaken together, these data show that CD19 CAR T-cell therapy is well tolerated and may induce rapid remission of severe refractory SLE.

2022 Systemic lupus erythematosus remission in clinical practice. Message for Polish rheumatologists.

Systemic lupus erythematosus (SLE) is a complicated multiorgan disease and can lead to organ damage and increased risk of morbidity and mortality. The strategy of management while avoiding complications, especially caused by chronic glucocorticoid therapy, improves outcomes. Different definitions of the treatment goal in different configurations of lupus activity indexes have appeared over the years. In 2021 the definition of remission and recommendations for its achievement were published and it become a way to implement a treat-to-target strategy. The main goal of treatment has become DORIS (definition of remission in SLE) remission and the alternative LLDAS (low lupus disease activity state).Prolonging remission with clinical and immunological lupus activity restrictions and minimizing or stopping steroid doses reduced flares and damage accrual. The analysis and neutralization of poor prognosis predictive factors in lupus could be the most beneficial for less morbidity and mortality and better quality of life.

P241 Efficacy of obinutuzumab in systemic lupus erythematosus patients with secondary non response to rituximab

Abstract Background/Aims Rituximab is a chimeric type-1 anti-CD20 monoclonal antibody approved by NHS England for refractory SLE. Secondary inefficacy with infusion reactions and anti-rituximab-antibodies occurs in 14% of re-treated patients. Obinutuzumab is a next-generation humanised type-2 anti-CD20 antibody licensed for the treatment of haematological malignancies. Methods We collated data from nine SLE patients receiving off-label obinutuzumab for secondary non-response to rituximab with infusion reactions across six centres (Leeds, Bradford, York, UCL, Birmingham and Nottingham). Disease activity was assessed using BILAG-2004 and SLEDAI-2K and serology in local diagnostic laboratories before, and 6 months after, obinutuzumab 2x1000mg infusions 2 weeks apart alongside methylprednisolone 100mg. Results All patients received concomitant oral immunosuppression and prednisolone. 6/9 received hydroxychloroquine. The median number of rituximab cycles before obinutuzumab therapy was 2.5. Before obinutuzumab 6/9 patients had BILAG A/B mucocutaneous, 6/9 had BILAG A/B musculoskeletal and 4/9 had BILAG A/B renal. 6 months after obinutuzumab 1/9 patients had BILAG B mucocutaneous, no patients had BILAG A/B musculoskeletal and 2/9 patients had BILAG A/B renal. Median dsDNA reduced from 118 to 83 IU/mL, C3 increased from 0.53 to 1.02g/L and C4 increased from 0.095 to 0.23g/L. Prednisolone dose was reduced in 5/9 patients; before obinutuzumab all patients received 10mg or more. After obinutuzumab, 4/9 patients received 5mg and were in Lupus Low Disease Activity State (LLDAS). Patient 5 did not respond and required further methylprednisolone and cyclophosphamide at 4 months. Patient 6 had a partial renal response but required renal transplantation, which was successful. Patient 8 responded well to obinutuzumab but died from severe COVID-19 infection (unvaccinated). After obinutuzumab 6 patients with B-cell data all achieved complete depletion including 4/4 assessed with highly sensitive assays. Conclusion These results demonstrate obinutuzumab’s efficacy in patients with secondary non-response to rituximab. These patients have severe disease with few treatment options, but previous responsiveness to B-cell depletion. Therefore, switching to another therapy in this class is mechanistically logical. Obinutuzumab appeared effective in renal and non-renal SLE as well as steroid-sparing. Immunological markers also improved. Obinutuzumab was generally well tolerated and will be further investigated for treatment-refractory lupus in the REGENCY and ALLEGORY trials. Disclosure J.E. Arnold: None. S. Dass: Consultancies; Received consultancy fees from Roche, Abbvie, UCB &amp; Chugai. Honoraria; Received honoraria from Roche, Abbvie, UCB &amp; Chugai. S. Twigg: None. C.H. Jones: None. B. Rhodes: None. P. Hewins: None. M. Chakravorty: None. P. Courtney: None. M. Ehrenstein: Honoraria; Received honoraria from GSK. Grants/research support; Received funding from GSK. M. Md Yusof: None. E. Vital: Consultancies; Received consulting fees from Roche, GSK, Eli Lilly and AstraZeneca. Honoraria; Received honoraria from Roche, GSK, Eli Lilly and AstraZenec. Grants/research support; Received research support from Roche and AstraZeneca (Paid to the University of Leeds).

Self-Reported Anxiety and Depression in a Monocentric Cohort of Patients With Systemic Lupus Erythematosus: Analysis of Prevalence, Main Determinants, and Impact on Quality of Life.

Aims of the studyTo analyze the prevalence of self-reported anxiety and depression in a monocentric cohort of patients with Systemic Lupus Erythematosus (SLE); to study the main determinants and the impact on quality of life (QoL).MethodsA cross-sectional observational study including adult outpatients with SLE. Demographic and clinical data were analyzed: indices of disease activity (SELENA-SLEDAI); damage (SLICC-DI); comorbidities and concomitant therapies. The definitions for remission (DORIS) and “Lupus Low Disease Activity State” (LLDAS) were applied. At enrollment, each patient completed the following questionnaires: SF-36, FACIT-Fatigue, Lupus Impact Tracker (LIT), Systemic Lupus Activity Questionnaire (SLAQ), and the Hospital Anxiety and Depression Scale (HADS) in order to self-assess anxiety and depression symptoms. The Student t-test and Chi2 tests were conducted for univariate analysis. The Spearman test was used for linear correlation between continuous data. Multivariate analysis was performed by multiple linear and logistic regression.ResultsOne hundred fifty-four consecutive patients with SLE were enrolled, the majority female and Caucasian with a mean age = 43.3 ± 13.7 years. 79.9% were in LLDAS or remission. 36.4% had a SDI > 1. 13.7% of patients had concomitant fibromyalgia. 37.4% had symptoms indicating anxiety and 25% of depression according to the HADS questionnaire. In the multivariate analysis, patients with active disease were significantly more anxious and depressed (p < 0.01) compared to patients in LLDAS or remission. Fibromyalgia and older age were independently associated with anxiety and depression, respectively (p < 0.05). Active skin involvement was significantly linked to depression (p < 0.05). Higher scores on the HADS questionnaire (higher levels of anxiety and depression) were found to be significantly linked to patients’ perception of higher disease activity and worse quality of life, irrespective of disease activity, age and fibromyalgia.ConclusionSymptoms of anxiety and depression are frequent in SLE patients, including outpatients with mild/moderate disease. Such symptoms have a significant negative impact on QoL and perception of disease activity, regardless of other factors. Moreover, disease activity, advanced age and fibromyalgia appear to be significantly linked to mood disorders. Assessing symptoms of the anxious-depressive spectrum in patients with SLE could lead to improvement in patients’ perception of health status and quality of life.

Impact of remission and low disease activity on health-related quality of life in patients with systemic lupus erythematosus.

To investigate the impact of remission and lupus low disease activity state (LLDAS) on health-related quality of life (HRQoL) in systemic lupus erythematosus. Short-Form 36 (SF-36), three-level EQ-5D (EQ-5D-3L)and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatiguedata from the BLISS-52 (NCT00424476) and BLISS-76 (NCT00410384) trials were used. Duration in remission/LLDAS required to reach a HRQoL benefit ≥ minimal clinically important differences (MCIDs) during and post-treatment was determined using quantile regression and generalized estimating equations. Patients (n = 1684) were assessed every fourth week (15 visits). Four cumulative (β = 0.60) or four consecutive (β = 0.66) visits in remission were required to achieve a benefit ≥MCID in SF-36 physical component summary (PCS) scores, and six cumulative (β = 0.44) or five consecutive (β = 0.49) for a benefit ≥MCID in mental component summary (MCS) scores. Eight cumulative (β = 0.30 for both) or eight consecutive (β = 0.32 for both) visits in LLDAS were required for a benefit in PCS/MCS ≥MCID, respectively. For EQ-5D-3L index scores ≥MCID, six cumulative (β = 0.007) or five consecutive (β = 0.008) visits in remission were required, and eight cumulative (β = 0.005) or six consecutive (β = 0.006) visits in LLDAS. For FACIT-Fatigue scores ≥MCID, 12 cumulative (β = 0.34) or 10 consecutive (β = 0.39) visits in remission were required, and 17 cumulative (β = 0.24) or 16 consecutive (β = 0.25) visits in LLDAS. Remission and LLDAS contribute to a HRQoL benefit in a time-dependent manner. Shorter time in remission than in LLDAS was required for a clinically important benefit in HRQoL, and longer time in remission for a benefit in mental compared with physical HRQoL aspects. When remission/LLDAS was sustained, the same benefit was achieved in a shorter time.