Systemic Lupus Erythematosus Responder Index Response Research Articles

Type I interferon-stimulated genes predict clinical response to belimumab in systemic lupus erythematosus.

The type I interferon (IFN-I) response is crucial in systemic lupus erythematosus (SLE). The mRNA level of interferon-stimulated genes (ISGs) is widely used for evaluating the activity of IFN in SLE. However, the character of ISGs in belimumab-treated SLE patients has not be reported. In this study, we enrolled 53 SLE patients undergoing belimumab treatment and assessed their clinical responses at 3, 6, and 12 months. The expression levels of 25 ISGs in Peripheral blood mononuclear cells (PBMCs) were quantified at baseline and at 3 months using quantitative real-time PCR. Using Least absolute shrinkage and selection operator (LASSO)-logistic regression, five genes (CXCL10, EPSTI1, HECR6, IFI27, IFIH1) were identified to predict belimumab efficacy. The IFN signature score, a multivariate logistic regression model based on the change rates of these genes, positively predicted the SLE responder index (SRI) at 12 months, with an area under curve of 0.940 in receiver operating characteristic and favorable outcomes in decision curve analysis. Patients with an IFN signature score ≥0 had higher SRI response rates, better clinical markers (including SLE disease activity index 2000 scores, anti-dsDNA, IgG levels, daily doses of prednisone, and higher complement C3 and C4 levels), and faster B cell decline than those with scores <0. In conclusion, after 3 months of belimumab treatment, the expression levels of IFN-I-inducible genes varied, and the IFN signature score reliably forecasted the SRI response at 6 and 12 months.

Safety and Efficacy of Belimumab Plus Standard Therapy for Up to Thirteen Years in Patients With Systemic Lupus Erythematosus.

ObjectiveTo investigate the long‐term safety and efficacy of intravenous (IV) belimumab plus standard of care (SOC) therapy for systemic lupus erythematosus (SLE) in patients with active, autoantibody‐positive SLE.MethodsThe study was designed as a multicenter, open‐label, continuation study of IV belimumab given every 4 weeks in conjunction with SOC therapy in patients with SLE who completed a phase II, double‐blind study. Adverse events (AEs) and laboratory data were monitored from the first belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments included SLE Responder Index (SRI) and flare index scores (each assessed at 16‐week intervals) and glucocorticoid use (assessed at 4‐week intervals).ResultsOf the 476 patients in the parent study, 298 (62.6%) entered the continuation study, of whom 96 (32.2%) remained in the study. Patients received belimumab for up to 13 years (median duration of exposure 3,334.0 days [range 260–4,332 days], total belimumab exposure 2,294 patient‐years, median number of infusions 115.5 [range 7–155]). The percentage of patients with AEs each year remained stable or decreased. Normal serum IgG levels were maintained in the majority of patients over the study, and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (year 1) to 75.6% of those remaining on treatment at year 12. The glucocorticoid dose was decreased in patients who had been receiving >7.5 mg/day at baseline.ConclusionThis study is the longest to date to assess belimumab treatment in patients with SLE in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially exhibited a satisfactory response to belimumab, the treatment continues to be well tolerated and provides long‐term disease control.

Clinical response beyond the Systemic Lupus Erythematosus Responder Index: post-hoc analysis of the BLISS-SC study

ObjectiveThe Systemic Lupus Erythematosus (SLE) Responder Index (SRI), developed as a primary outcome measure for use in clinical trials, captures improvement in SLE disease activity without concomitant worsening in disease...

Smoking and pre-existing organ damage reduce the efficacy of belimumab in systemic lupus erythematosus.

Belimumab is the first biologic drug approved for Systemic Lupus Erythematosus (SLE). Here, we aimed to investigate the effects of belimumab on clinical and serologic outcomes, and sought to identify predictors of treatment response in three Swedish real-life settings. Fifty-eight patients were enrolled at initiation of belimumab and followed longitudinally for up to 53months. Surveillance outcomes included the SLE Disease Activity Index 2000 (SLEDAI-2K), 100mm Visual Analogue Scales for Physician's Global Assessment (PGA), fatigue, pain and general health, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Assessment of treatment response included the SLE responder index (SRI). B lymphocyte stimulator (BLyS) levels were determined using ELISA. SLEDAI-2K (median baseline score: 8.0; IQR: 4.0-13.8), PGA and corticosteroid use decreased during therapy, and patients reported improvements on fatigue, pain, and general health (p<0.0001 for all). SDI scores remained stable (p=0.08). Patients with baseline SDI scores >1 showed decreased probability and prolonged time to attain SRI response (HR: 0.449; 95% CI: 0.208-0.967), as did current smokers compared with non-smokers (HR: 0.103; 95% CI: 0.025-0.427). In contrast, baseline BLyS levels ≥1.2ng/mL predicted increased probability and shorter time to attain SRI response (HR: 2.566; 95% CI: 1.222-5.387). Disease activity and corticosteroid usage decreased, patient-reported outcomes improved, and no significant organ damage was accrued during follow-up. Smoking and organ damage predicted reduced treatment efficacy. These findings might contribute to a better selection of patients who are likely to benefit from belimumab.

Clinical, laboratory and health-related quality of life correlates of Systemic Lupus Erythematosus Responder Index response: a post hoc analysis of the phase 3 belimumab trials

ObjectiveCorrelates of systemic lupus erythematosus (SLE) Responder Index (SRI) response with clinical trial end points were examined using pooled data from the Study of Belimumab in Subjects with SLE (BLISS)...

Disease Control and Safety of Belimumab Plus Standard Therapy Over 7 Years in Patients with Systemic Lupus Erythematosus

To evaluate the efficacy/safety of belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing). Patients (n = 345) who completed a double-blind, placebo-controlled, 52-week study of belimumab 1, 4, or 10 mg/kg and 24-week extension of belimumab (placebo switched to 10 mg/kg; belimumab same dose or switched to 10 mg/kg) could receive belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study. Total belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with belimumab during the first year, with the annual rate declining to 2%-9% during years 2-7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%-60% from baseline over 2-7 years with belimumab. Corticosteroid use decreased over time with ≥ 50-55% reduction in median dose during years 5-7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment. Disease control and safety profile were maintained in patients with active SLE taking belimumab plus standard therapy for up to 7 years. [ClinicalTrials.gov numbers: NCT00071487 and NCT00583362].

A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus

To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE). In a phase III, multicenter, randomized, placebo-controlled trial, 819 antinuclear antibody-positive or anti-double-stranded DNA-positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks. The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4-point reduction in SELENA-SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline). Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (43.2% versus 33.5%; P = 0.017). The rate with 1 mg/kg belimumab was 40.6% (P = 0.089). Response rates at week 76 were 32.4%, 39.1%, and 38.5% with placebo, 1 mg/kg belimumab, and 10 mg/kg belimumab, respectively. In post hoc sensitivity analyses evaluating higher SELENA-SLEDAI score thresholds, 10 mg/kg belimumab achieved better discrimination at weeks 52 and 76. Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg belimumab (34%) (P = 0.023) and 10 mg/kg belimumab (23%) (P = 0.13). Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups. Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.

Novel evidence-based systemic lupus erythematosus responder index.

To describe a new systemic lupus erythematosus (SLE) responder index (SRI) based on a belimumab phase II SLE trial and demonstrate its potential utility in SLE clinical trials. Data from a randomized, double-blind, placebo-controlled study in 449 patients of 3 doses of belimumab (1, 4, 10 mg/kg) or placebo plus standard of care therapy (SOC) over a 56-week period were analyzed. The Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG) SLE disease activity instruments, the Short Form 36 health survey, and biomarker analyses were used to create a novel SRI. Response to treatment in a subset of 321 serologically active SLE patients (antinuclear antibodies >/=1:80 and/or anti-double-stranded DNA antibodies >/=30 IU/ml) at baseline was retrospectively evaluated using the SRI. SRI response is defined as 1) a >/=4-point reduction in SELENA-SLEDAI score, 2) no new BILAG A or no more than 1 new BILAG B domain score, and 3) no deterioration from baseline in the physician's global assessment by >/=0.3 points. In serologically active patients, the addition of belimumab to SOC resulted in a response in 46% of patients at week 52 compared with 29% of the placebo patients (P = 0.006). SRI responses were independent of baseline autoantibody subtype. This evidence-based evaluation of a large randomized, placebo-controlled trial in SLE resulted in the ability to define a robust responder index based on improvement in disease activity without worsening the overall condition or the development of significant disease activity in new organ systems.