Elevated BLyS levels in patients with systemic lupus erythematosus: Associated factors and responses to belimumab

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)...

Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial

ObjectiveTo assess the efficacy and safety of belimumab in paediatric versus adult patients with systemic lupus erythematosus (SLE).MethodsWe performed across-study comparisons of patients with active SLE who received belimumab or...

BackgroundTelitacicept, a new dual inhibitor of the cytokines B-lymphocyte stimulator (BLyS) and APRIL (a proliferation-inducing ligand), showed efficacy in adults with active systemic lupus erythematosus (SLE) in a phase 2b trial when added to standard therapy.MethodsWe conducted a phase 3 trial in China in which participants with active SLE were randomly assigned (in a 1:1 ratio) to receive telitacicept (160 mg) or placebo subcutaneously once weekly for 52 weeks, in addition to standard therapy. The primary end point at week 52 was a response on the modified SLE Responder Index 4 (SRI-4), with a response on this composite measure defined as a reduction of at least 4 points in the Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score (ranging from 0 to 105, with higher scores indicating greater disease activity), no new disease activity as measured on the British Isles Lupus Assessment Group index, and no worsening in the Physician’s Global Assessment score.ResultsOf 433 adults screened, 335 underwent randomization (167 to the telitacicept group and 168 to the placebo group). At week 52, significantly more participants receiving telitacicept had a response on the modified SRI-4 than those receiving placebo (67.1% vs. 32.7%; adjusted difference, 34.5 percentage points; 95% confidence interval [CI], 24.3 to 44.7; P<0.001). A reduction of at least 4 points from baseline in the SELENA-SLEDAI score had occurred in 70.1% of the telitacicept group and in 40.5% of the placebo group (difference, 29.6 percentage points; 95% CI, 13.1 to 46.1). Adverse events that were considered by the investigator to be related to the trial regimen were more common with telitacicept than with placebo (74.9% vs. 50.0%). Such events that occurred more frequently in the telitacicept group than in the placebo group included upper respiratory tract infection (31.7% vs. 19.0%), a reduced serum IgG level (15.6% vs. 1.2%), a reduced serum IgM level (15.0% vs. 0.6%), and injection-site reactions (12.6% vs. 0.6%).ConclusionsIn this 52-week trial involving participants with active SLE who were receiving background therapy, the incidence of a clinical response was higher with telitacicept than with placebo. However, the incidence of upper respiratory infections, reduced immunoglobulin levels, and injection-site reactions was also higher with telitacicept. (Funded by RemeGen; 18C010 ClinicalTrials.gov number, NCT04082416.)

AB0620 B lymphocyte stimulator(BLYS) levels are higher in younger caucasian patients with SLE

To examine the relationship between circulating B lymphocyte stimulator (BLyS) levels and humoral responses to influenza vaccination in systemic lupus erythematosus (SLE) patients, as well as the effect of vaccination on BLyS levels, and to investigate clinical and serologic features of SLE that are associated with elevated BLyS levels. Clinical history, disease activity measurements, and blood specimens were collected from 60 SLE patients at baseline and after influenza vaccination. Sera were tested for BLyS levels, lupus-associated autoantibodies, serum interferon-α (IFNα) activity, 25-hydroxyvitamin D (25[OH]D), and humoral responses to influenza vaccination. Thirty percent of the SLE patients had elevated BLyS levels, with African American patients having higher BLyS levels than white patients (P = 0.006). Baseline BLyS levels in patients were not correlated with humoral responses to influenza vaccination (P = 0.863), and BLyS levels increased postvaccination only in the subset of patients with BLyS levels in the lowest quartile (P = 0.0003). Elevated BLyS levels were associated with increased disease activity, as measured by the SLE Disease Activity Index, physician's global assessment, and Systemic Lupus Activity Measure in white patients (P = 0.035, P = 0.016, and P = 0.018, respectively), but not in African Americans. Elevated BLyS levels were also associated with anti-nuclear RNP (P = 0.0003) and decreased 25(OH)D (P = 0.018). Serum IFNα activity was a significant predictor of elevated BLyS in a multivariate analysis (P = 0.002). Our findings indicate that African American patients with SLE have higher BLyS levels regardless of disease activity. Humoral response to influenza vaccination is not correlated with baseline BLyS levels in SLE patients, and only those patients with low baseline BLyS levels demonstrate an increased BLyS response after vaccination.

This report evaluates the effects of blisibimod (A-623, AMG 623), a potent and selective inhibitor of B-cell activating factor (BAFF), on patient-reported fatigue and disease activity in the Phase 2b PEARL-SC clinical trial in patients with systemic lupus erythematosus (SLE). A total of 547 individuals who met the American College of Rheumatology (ACR) classification criteria for SLE, were positive for anti-double-stranded DNA or antinuclear antibodies, and had a Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥6 at baseline, were randomized to receive placebo or blisibimod for at least 24 weeks. Patient self-reported fatigue was evaluated using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and disease activity was evaluated using Physician's Global Assessment, SELENA-SLEDAI, and British Isles Lupus Assessment Group Score. Statistically significant improvements in FACIT-Fatigue score were observed among individuals randomized to blisibimod, especially in the 200 mg QW group where favorable effects on disease activity with blisibimod compared to placebo were observed as early as Week 8. The mean improvement from baseline of 6.9 points at Week 24, compared with 4.4 points with placebo, met the criteria for minimal clinically important improvement difference defined for patients with SLE. Despite concomitant improvements in FACIT-Fatigue, SLE Responder Index (SRI) and SLE biomarkers (reported previously), FACIT-Fatigue score correlated only weakly with disease activity. While poor correlation between fatigue and disease activity is not new, the observation that correlation remains poor despite concurrent population improvements in disease and fatigue brings a new facet to our understanding of SLE.

There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE). To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE. Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002. 16 university-affiliated rheumatology clinics or practices in 11 U.S. states. 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE. 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group. The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite. Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis. Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis. Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo.

Anti-double-stranded DNA (dsDNA) antibody has been reported to have a close relationship with systemic lupus erythematosus (SLE) flares and participates in the pathogenesis of lupus nephritis (LN) as well as causing damage to other organs. However, whether early use of mycophenolate mofetil (MMF) could prevent SLE flares is not clear. To assess the efficacy and safety of MMF plus prednisone and hydroxychloroquine sulfate compared with prednisone and hydroxychloroquine sulfate alone in patients with SLE. This investigator-initiated, multicenter, observer-blinded randomized clinical trial enrolled 130 participants aged 18 to 65 years and was conducted in 3 hospitals across China. Treatment-naive patients with newly diagnosed SLE, a high titer of anti-dsDNA antibody, and no major organ involvement were included. The study was started September 1, 2018, and the follow-up was completed September 30, 2021. Data were analyzed from December 1, 2021, to March 31, 2022. Patients were randomized 1:1 to receive oral prednisone (0.5 mg/kg/d) and hydroxychloroquine sulfate (5 mg/kg/d) (control group) or prednisone (0.5 mg/kg/d) and hydroxychloroquine sulfate (5 mg/kg/d) plus MMF (500 mg twice daily) (MMF group) for 96 weeks. The primary outcome was the proportion of patients presenting with flares according to the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare Index. The secondary outcomes included the proportion with lupus low disease activity state at week 96, 36-Item Short Form Health Survey scores before and after treatment, proportion of adverse events (AEs), and changes in SLEDAI-2000 scores and prednisone doses. Among 130 randomized patients (mean [SD] age, 34.5 [12.5] years; 112 [86.2%] women), 119 (91.5%) completed the follow-up. The risk of severe flare was significantly lower in the MMF group (7 of 65 [10.8%]) vs the control group (18 of 65 [27.7%]) (relative risk [RR], 0.39 [95% CI, 0.17-0.87]; P = .01). Additionally, 1 of 65 patients in the MMF group (1.5%) and 9 of 65 in the control group (13.8%) manifested LN (RR, 0.11 [95% CI, 0.01-0.85]; P = .008). Most common serious study drug-related AEs were infections (20 of 65 [30.8%] in the control group and 22 of 65 [33.8%] in the MMF group). The findings of this randomized clinical trial suggest that MMF may reduce the rate of severe flare and lower the incidence of LN in patients with new-onset SLE and a high titer of anti-dsDNA antibody without major organ involvement. Chinese Clinical Trial Registry: ChiCTR1800017540.

To determine the association of plasma B lymphocyte stimulator (BLyS) levels, immunosuppressive therapy, and other clinical parameters with disease activity in systemic lupus erythematosus (SLE). Two hundred forty-five SLE patients were evaluated prospectively over a 2-year period at 4 centers. Assessments were performed every 3-6 months. Univariate analysis was used to determine the association among the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, serum anti-double-stranded DNA (anti-dsDNA), and plasma BLyS levels. A multivariate repeated-measures model incorporating immunosuppressive therapy was utilized. Ninety-two percent of the patients were female. Sixty-seven percent were white, 31% African American, and 2% Asian (all of these groups may include Hispanic). Mean values at baseline were as follows: age 41.5 years, disease duration 8.1 years, SELENA-SLEDAI 3.3 (median 2, range 0-18), BLyS 5.57 ng/ml, IgG 1,439 mg/dl, C3 104.4 mg/dl, and C4 21.3 mg/dl; among those positive for anti-dsDNA, the median titer was 1:40 (range 1:10-1:1,280). Univariate analysis showed that plasma BLyS levels were associated with anti-dsDNA titers (P = 0.0465) and SELENA-SLEDAI scores (P = 0.0002). In multivariate analyses, a greater increase in the SELENA-SLEDAI score from the previous visit was associated with higher BLyS levels at the previous visit (P = 0.0042) and with a greater increase in the BLyS level from the previous visit (P = 0.0007). The findings of association between a greater increase in the BLyS level from the previous visit and a greater increase in the SELENA-SLEDAI score at the subsequent visit, and between an elevated BLyS level at the previous visit and a greater SELENA-SLEDAI score at the subsequent visit, demonstrate a relationship between circulating BLyS levels and SLE disease activity. These results lend support to the notion that BLyS is a candidate for therapeutic targeting in SLE.

ObjectivesA regulatory T cell (Treg) insufficiency due to shortage of interleukin-2 (IL-2) is central to the pathophysiology of systemic lupus erythematosus (SLE). We performed a multicentre, double-blinded, randomised, placebo-controlled phase...

The British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) and the Systemic Lupus Erythematosus Responder Index 4 (SRI4) responses are the most common primary endpoints in SLE clinical trials. We examined the concordance and the reasons for discordance in BICLA/SRI4 responses in participants with SLE receiving placebo and standard of care (SOC) in two randomised controlled trials. This post-hoc analysis included data from the placebo arm (participants treated with SOC) of the EXPLORER (n=87; NCT00137969) and ATHOS (n=80; NCT02908100) trials. Disease activity was measured using BILAG and SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index) in the EXPLORER trial and BILAG-2004 and SLEDAI-2000K in the ATHOS trial. For this analysis, participants were classified as responders or non-responders based on BICLA and SRI4 and the presence of intercurrent events. Concordance and discordance frequencies between BICLA and SRI4 were determined. In EXPLORER, the BICLA response rates were lower than the SRI4 response rates (29.9% vs 41.4% at week 52, respectively), whereas in ATHOS the BICLA and SRI4 response rates were similar (41.2% vs 43.8% at week 48, respectively). The overall BICLA/SRI4 concordance (Cohen's κ score) was moderate (0.46 in EXPLORER and 0.54 in ATHOS at weeks 52 and 48, respectively). At weeks 52 and 48, BICLA+/SRI4- and BICLA-/SRI4+ discordance, respectively, was 6.9% and 18.4% in EXPLORER and 10.0% and 12.5% in ATHOS. In an analysis of ATHOS subgroups based on the presence or absence of rash at baseline, BICLA response was higher at week 48 in participants with arthritis only than in those with arthritis and mucocutaneous comanifestations (63.2% vs 33.9%, respectively). BICLA-/SRI4+ and BICLA+/SRI4- discordance was lower in participants with low compared with normal complement at baseline. BICLA and SRI4 may be discordant in SLE trials. Arthritis and rash were the primary drivers of the discordance, and serology influenced BICLA and SRI4 response, suggesting the need for evaluation of multiple efficacy endpoints rather than a single measure.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with well-recognized female predominance; however, disease expression and severity may differ by gender. Data on gender-based differences in SLE from Bangladesh remain limited. This study aimed to compare sociodemographic characteristics, clinical manifestations, immunological profiles and disease activity indicators between male and female patients with SLE. This cross-sectional study was conducted at the Lupus Clinic, Department of Rheumatology, Bangladesh Medical University (BMU), Dhaka, Bangladesh, from December 2019 to January 2021. A total of 140 patients who fulfilled the classification criteria for SLE were enrolled, including 130 females and 10 males. Demographic data, clinical features, immunological and serological parameters, Safety of Estrogens in Systemic Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI) were analyzed and compared by gender. The female-to-male ratio was approximately 13:1. Male patients presented at younger ages (p=0.002) and had earlier disease onset than females (p=0.011). Lupus nephritis was significantly more frequent among male patients (p=0.037). Anti-dsDNA levels were higher in male patients, though not statistically significant; complement (C3) levels were significantly lower in male patients (p=0.014). Male patients had significantly higher disease activity (SELENA-SLEDAI) scores than females (p=0.044), whereas cumulative organ damage was comparable. Despite lower prevalence, male SLE patients exhibited more severe disease manifestations and higher activity. These findings underscore the importance of heightened clinical vigilance and gender-sensitive management strategies in SLE.

IntroductionSLE is a chronic inflammatory systemic autoimmune disease with relapsing–remitting pattern. B-lymphocyte stimulator was involved in the pathogenesis of SLE. The humanised monoclonal antibody belimumab with 10 mg/kg was effective...

Low-dose belimumab reduced risk of flares in patients with systemic lupus erythematosus: a multicentre, randomised, double-blind, placebo-controlled trial.