Article

Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: Extension of a phase II, double-blind, placebo-controlled, dose-ranging study

January 2010
Arthritis & Rheumatology 62(1):201-10

DOI:10.1002/art.27189

Source
PubMed

Authors:

Arnd Jacobi

Hamburg University

Weiqing Huang

Northwell Health

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To understand the effects of long-term BLyS inhibition in human systemic lupus erythematosus (SLE). Seventeen patients with SLE who were enrolled in a clinical trial of belimumab, a BLyS-specific inhibitor, plus standard of care therapy were studied. Phenotypic analysis of lymphocytes was performed using flow cytometry. Circulating antibody-secreting cells were enumerated using enzyme-linked immunospot assay. Serum was analyzed by enzyme-linked immunosorbent assay using an antibody that recognizes products of the V(H)4-34 gene. Lymphocyte counts, Ig levels, and anti-double-stranded DNA antibody levels were available as part of the clinical trial analyses. Samples were collected on days 0, 84, 168, 365, and 532 and after day 730. The total number of B cells started to decrease from baseline between days 84 and 168. This was due to a decrease in naive and transitional B cells. CD27+IgD+ memory B cells and plasmablasts decreased only after 532 days, whereas CD27+IgD- memory B cells were not affected, and there were no changes in T cells. Serum IgM levels began to decline between days 84 and 168, but there were no changes in serum levels of IgG, IgG anti-DNA antibodies, or V(H)4-34 antibodies during the study. SLE patients had more IgM-, IgG-, and autoantibody-producing B cells than did normal controls on day 0. There was only a modest decrease in the frequency of total IgM-producing, but not IgG-producing, cells on days 365 and 532, consistent with the phenotypic and serologic data. Our data confirm the dependence of newly formed B cells on BLyS for survival in humans. In contrast, memory B cells and plasma cells are less susceptible to selective BLyS inhibition.

From systemic lupus erythematosus to lupus nephritis: The evolving road to targeted therapies

Article

Aug 2023
AUTOIMMUN REV

Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance against nuclear and cytoplasmic self-antigens, induction of immunity and tissue inflammation. Lupus nephritis (LN), the most important predictor of morbidity in SLE, develops in almost 30% of SLE patients at disease onset and in up to 50-60% within the first 10 years. Firstly, in this review, we put the pathogenic mechanisms of the disease into a conceptual frame, giving emphasis to the role of the innate immune system in this loss of self-tolerance and the induction of the adaptive immune response. In this aspect, many mechanisms have been described such as dysregulation and acceleration of cell-death pathways, an aberrant clearance and overload of immunogenic acid-nucleic-containing debris and IC, and the involvement of antigen-presenting cells and other innate immune cells in the induction of this adaptive immune response. This result in a clonal expansion of autoreactive lymphocytes with generation of effector T-cells, memory B-cells and plasma cells that produce autoantibodies that will cause kidney damage. Secondly, we review the immunological pathways of damage in the kidney parenchyma, initiated by autoantibody binding and immune complex deposition, and followed by complement-mediated microvascular injury, activation of kidney stromal cells and the recruitment of leukocytes. Finally, we summarize the rationale for the treatment of LN, from conventional to new targeted therapies, focusing on their systemic immunologic effects and the minimization of podocytary damage.

B Cell Kinetics upon Therapy Commencement for Active Extrarenal Systemic Lupus Erythematosus in Relation to Development of Renal Flares: Results from Three Phase III Clinical Trials of Belimumab

Article

Full-text available

Nov 2022
INT J MOL SCI

Renal flares constitute major determinants of poor prognosis in people living with systemic lupus erythematosus (SLE). The aim of the present study was to investigate changes in B cell subsets in relation to renal flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with SLE. Using data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) percentage changes in circulating CD19+ B cell subsets characterised through flow cytometry, anti-dsDNA antibodies, and complement levels with the occurrence of renal flares over one year. Patients who developed renal flares showed more prominent rapid decreases in CD19+CD20+CD138+ short-lived plasma cells (−50.4% vs. −16.7%; p = 0.019) and CD19+CD20-CD27bright plasmablasts (−50.0% vs. −29.9%; p = 0.020) compared to non-flaring patients, followed by a subsequent return. Less prominent rapid reductions in CD19+CD27-CD24brightCD38bright transitional B cells (−42.9% vs. −75.0%; p = 0.038) and CD19+CD20-CD138+ peripheral long-lived plasma cells (−11.3% vs. −29.2%; p = 0.019) were seen in belimumab-treated—but not placebo-treated—patients who developed renal flares compared to belimumab-treated patients who did not. Rapid and early changes in anti-dsDNA or complement levels showed no clear association with renal flares. In summary, a rapid drop followed by a subsequent return in circulating short-lived plasma cells and plasmablasts upon treatment for active extra-renal SLE portended renal flares, indicating a need for therapeutic adjustments in patients showing such B cell patterns. Rapid decreases in transitional B cells and peripheral long-lived plasma cells upon belimumab therapy commencement may signify a greater protection against renal flares. B cell kinetics may prove useful in early drug evaluation.

Early Changes in B and Plasma Cell Subsets and Traditional Serological Markers as Predictors of SRI-4 Response to Therapy in Systemic Lupus Erythematosus

Article

Full-text available

Apr 2022

Objective: With the premise of the hypothesis that early biological responses to therapy for active systemic lupus erythematosus (SLE) portend later clinical improvements, we studied changes in B cell subsets and traditional serological markers in relation to clinical response to standard therapy (ST) with or without the addition of belimumab. Patients and methods: We analyzed data from the BLISS-76, BLISS-SC, and BLISS Northeast Asia trials (N = 1712). Circulating CD19+ B cell subsets were determined by flow-cytometry. We studied associations of relative to baseline percentage changes in circulating B and plasma cell subsets, anti-dsDNA antibody levels and complement levels with SLE Responder Index (SRI)-4 response after 52 weeks of treatment. Changes occurring through week 8 were deemed "rapid," through week 24 "early," and thereafter "delayed". Results: In the analysis of the entire cohort, SRI-4 responders showed more prominent decreases from baseline through week 52 in CD19+CD20+CD27- naïve B cells (median change: -61.2% versus -50.0%; P = 0.004), CD19+CD20-CD27 bright plasmablasts (-44.9% versus -33.3%; P = 0.011), and CD19+CD20-CD138+ long-lived plasma cells (-48.2% versus -37.1%; P = 0.024), and a more prominent rapid (+92.0% versus +66.7%; P = 0.002) and early (+60.0% versus +49.5%; P = 0.033) expansion of CD19+CD20+CD27+ memory B cells than non-responders. More prominent rapid reductions in anti-dsDNA (-14.8% versus -8.7%; P = 0.043) and increases in C3 (+4.9% versus +2.1%; P = 0.014) and C4 levels (+11.5% versus +8.3%; P = 0.017) were documented in SRI-4 responders compared with non-responders among patients who received add-on belimumab, but not among patients who received non-biological ST alone. Conclusion: SRI-4 responders showed a more prominent rapid expansion of memory B cells and more prominent delayed reductions in naïve B cells, plasmablasts and long-lived plasma cells. Moreover, clinical response to belimumab was associated with preceding more prominent reductions of anti-dsDNA and increases in C3 and C4 levels. Monitoring biological changes may prove useful in SLE patient surveillance and early treatment evaluation.

Early B Cell and Plasma Cell Kinetics Upon Treatment Initiation Portend Flares in Systemic Lupus Erythematosus: A Post-Hoc Analysis of Three Phase III Clinical Trials of Belimumab

Article

Full-text available

Apr 2022

Objective To investigate changes in B cell subsets in relation to disease flares upon initiation of standard therapy (ST) plus belimumab or placebo in patients with systemic lupus erythematosus (SLE). Patients and Methods Using data from the BLISS-76, BLISS-SC and BLISS Northeast Asia trials, we investigated associations of relative to baseline rapid (through week 8) and early (through week 24) changes in peripheral B cell subsets, anti-dsDNA and complement levels with the occurrence of disease flares from week 24 through week 52 (Mann-Whitney U tests) or the entire study follow-up (Cox regression analysis), assessed using the SELENA-SLEDAI Flare Index. Results Patients on ST alone who flared displayed less prominent early decreases in CD19⁺CD20⁻CD138⁺ long-lived plasma cells (-16.1% versus -35.1%; P=0.012). In all arms combined, patients who developed severe flares showed less prominent early decreases in CD19⁺CD20⁻CD138⁺ long-lived plasma cells (-23.5% versus -39.4%; P=0.028) and CD19⁺CD27brightCD38bright SLE-associated plasma cells (-19.0% versus -27.8%; P=0.045). After adjustment for rapid changes, early increases in overall CD19⁺CD20⁺ B cells (HR: 1.81; 95% CI: 1.08–3.05; P=0.024) and early increases or no return after a rapid expansion in CD19⁺CD20⁺CD27⁺ memory B cells (HR: 1.58; 95% CI: 1.18–2.11; P=0.002) portended subsequent severe flares. Patients who developed flares of any severity showed no or less prominent rapid (0.0% versus -12.5%; P<0.001) or early (-1.9% versus -21.7%; P<0.001) decreases in anti-dsDNA levels, and patients who developed severe flares showed no or less prominent early decreases in anti-dsDNA levels (0.0% versus -13.3%; P=0.020). Changes in complement levels exhibited no ability to distinguish flaring from non-flaring patients. Conclusions Increase or lack of decrease in certain circulating B cell subsets or anti-dsDNA levels upon treatment initiation for active SLE heralded subsequent severe disease flares. A rapid expansion of memory B cells may signify sustained response to therapy when followed by a subsequent drop, while no return or delayed increases in memory B cells may portend flaring. Peripheral B cell and serological marker kinetics may help identify patients in whom therapeutic modifications could protect against flare development, and may hence prove a useful complement to traditional surveillance and early treatment evaluation in SLE.

BAFFR Activates PI3K/AKT Signaling in Human Naive But Not in Switched Memory B Cells Through Direct Interactions with B Cell Antigen Receptors

Article

Full-text available

Jan 2021

Binding of BAFF to BAFFR activates in mature B cells PI3K/AKT signaling regulating protein synthesis, metabolic fitness, and survival. In humans, naive and memory B cells express the same levels of BAFFR, but only memory B cells seem to survive without BAFF. Here, we show that BAFF activates PI3K/AKT only in naive B cells and changes the expression of genes regulating migration, proliferation, growth, and survival. BAFF-induced PI3K/AKT activation requires direct interactions between BAFFR and the B cell antigen receptor (BCR) components CD79A and CD79B and is enhanced by the AKT coactivator TCL1A. Compared to memory B cells, naive B cells express more surface BCRs, which interact better with BAFFR than IgG or IgA, thus allowing stronger responses to BAFF. As ablation of BAFFR in naive and memory B cells causes cell death independent of BAFF-induced signaling, BAFFR seems to act also as an intrinsic factor for B cell survival.

Anti-B-Cell-Activating Factor (BAFF) Therapy: A Novel Addition to Autoimmune Disease Management and Potential for Immunomodulatory Therapy in Warm Autoimmune Hemolytic Anemia

Article

Full-text available

Jul 2024

Although rituximab is not specifically approved for the treatment of warm autoimmune hemolytic anemia (WAIHA), the First International Consensus Group recommends considering its use as part of the initial therapy for patients with severe disease and as a second-line therapy for primary WAIHA. Some patients do not respond to rituximab, and relapses are common. These relapses are associated with elevated B-cell-activating factor (BAFF) levels and the presence of quiescent long-lived plasma cells (LLPCs) in the spleen. A new group of immunomodulatory drugs, B-cell-activating factor inhibitors (BAFF-i), demonstrated efficacy in multiple autoimmune diseases and have the potential to improve WAIHA treatment outcomes by targeting B-cells and LLPCs. This article reviews the role of BAFF in autoimmune disorders and the currently available literature on the use of BAFF-directed therapies in various immunologic disorders, including WAIHA. Collectively, the clinical data thus far shows robust potential for targeting BAFF in WAIHA therapy.

Frequency and predictors for early-achieved lupus low disease activity state in systemic lupus erythematosus patients treated with telitacicept or belimumab: A real-life, single-center observational study

Article

Full-text available

Jun 2024

Objective To collect real-world data regarding the attainment of the early-achieved lupus low disease activity state (LLDAS) in systemic lupus erythematosus (SLE) patients receiving telitacicept or belimumab treatment, and identify factors predictive of target achievement. Methods Eighty-seven SLE patients who received telitacicept (N=42) or belimumab (N=45) were retrospectively reviewed in this observational study. Clinical and laboratory data, disease activity assessment, and glucocorticoid dosage were collected for analysis. Achieving LLDAS at least once within 24 weeks post-treatment was considered as early-achieved LLDAS. Multivariate regression was used to assess baseline predictive variables for early-achieved LLDAS. Subgroup analysis and interaction tests were also performed to examine the robustness of the results across different sets of baseline characteristics. Prognostic stratification for early-achieved LLDAS was established based on the identified risk factors. Results During the 24-week follow-up period, LLDAS was achieved by at least one time in 49.43% (43/87) of the patients, with sustained achievement through week 24 observed in 36 out of these 43 patients (83.27%). Multivariate analysis revealed that early achievement of LLDAS was particularly observed in patients with higher baseline lymphocyte counts [HR=1.79, 95% CI (1.19–2.67), P=0.005]and serum albumin levels [HR=1.06, 95% CI (1.003–1.12), P=0.039]. Conversely, hematological involvement [HR=0.48, 95% CI (0.24–0.93), P=0.031] predicted lower attainment of early-achieved LLDAS. The use of telitacicept was associated with a reduced risk of failing to attain early achievement of LLDAS [HR=2.55, 95% CI (1.36–4.79), P=0.004]. Subgroup analyses and interaction tests showed a stable relationship between the telitacicept use and LLDAS achievement. The results remained consistent across all subgroup analyses. Significant differences (P<0.001) were observed in the Kaplan-Meier estimates for LLDAS among risk groups based on the number of identified risk factors. Conclusion The achievement of LLDAS is attainable in the management of SLE patients undergoing treatment with telitacicept or belimumab in real-life clinical practice. Baseline lymphocyte counts, serum albumin levels, hematological involvement and the use of telitacicept serve as robust predictors for early-achieved LLDAS, helping to identify patients who are likely to benefit on the treatment.

Belimumab in the treatment of systemic lupus erythematosus: 20 years of basic research, 10 years of clinical practice

Article

Full-text available

Sep 2021

Currently, strong evidence has been obtained for the fundamental role of pathological activation of B cells in the pathogenesis of immunoinflammatory (autoimmune) rheumatic diseases (IMRD), and drugs that specifically modulate the function or cause depletion of various subpopulations of B cells and plasma cells are considered a promising direction. pharmacotherapy of these diseases. of particular interest is belimumab (BLM), a human monoclonal antibody (mAb) (IgG1λ) to BAFF (B cell-activating factor belonging to the TNF family), which is the first “targeted” biological drug specially developed for the treatment of systemic lupus erythematosus (SLE). The efficacy and safety of BLM in SLE in adults and children, including lupus nephritis, in combination therapy with rituximab, steroid-sparing effect, the ability to prevent irreversible damage to internal organs dictate the need for its wider application in clinical practice.

BAFFR controls GC-independent memory B cell response but is dispensable for germinal center function

Article

Full-text available

Oct 2020
J EXP MED

The TNF superfamily ligand BAFF maintains the survival of naive B cells by signaling through its surface receptor, BAFFR. Activated B cells maintain expression of BAFFR after they differentiate into germinal center (GC) or memory B cells (MBCs). However, the functions of BAFFR in these antigen-experienced B cell populations remain unclear. Here, we show that B cell–intrinsic BAFFR does not play a significant role in the survival or function of GC B cells or in the generation of the somatically mutated MBCs derived from them. Instead, BAFF/BAFFR signaling was required to generate the unmutated, GC-independent MBCs that differentiate directly from activated B cell blasts early in the response. Furthermore, amplification of BAFFR signaling in responding B cells did not affect GCs or the generation of GC-derived MBCs but greatly expanded the GC-independent MBC response. Although BAFF/BAFFR signaling specifically controlled the formation of the GC-independent MBC response, both types of MBCs required input from this pathway for optimal long-term survival.

Combination of anti-SSA/Ro60 and anti-dsDNA serotype is predictive of belimumab renal response in patients with lupus nephritis

Article

Full-text available

May 2024

Objectives To investigate the effectiveness of belimumab on active lupus nephritis (LN) and explore the predictors, including serological biomarkers, of renal response to belimumab in a real-world setting. Methods This multicentre, real-world observational study enrolled patients with active LN receiving intravenous belimumab as an add-on therapy with 24-hour urine protein≥1 g and estimated glomerular filtration rate≥30 mL/min/1.73 m ² at baseline. Complete renal response (CRR), partial renal response (PRR), no renal response (NRR) and primary efficacy renal response (PERR) were evaluated. Multivariable logistic regression was used to identify risk factors for NRR to belimumab at 6 months. Results Among the 122 patients enrolled, the proportions of patients achieving CRR, PRR, NRR and PERR were 35.9%, 17.1%, 47.0% and 44.4% at 6 months (n=117) and 55.6%, 19.4%, 26.4% and 58.3% at 12 months (n=72), respectively. Proteinuria, daily prednisone dosage and Systemic Lupus Erythematosus Disease Activity Index 2000 scores significantly decreased at 6 and 12 months (p<0.0001). NRR at 6 months (NRR6) was the strongest negative predictor of CRR at 12 months. Baseline anti-dsDNA positivity inversely predicted NRR6 (OR=0.32,95% CI=0.10 to 0.98, p=0.049), while anti-SSA/Ro60 positively predicted NRR6 (OR=3.16, 95% CI=1.14 to 8.74, p=0.027). The combination of anti-SSA/Ro60 and anti-dsDNA serotype quantitatively predicted belimumab renal response. Conclusion The effectiveness of belimumab was reproducible in Chinese patients with active LN. The simple yet interesting serotype predictive model needs further validation and its possible underlying mechanistic relevance deserves further exploration.

Effect of BAFF blockade on the B cell receptor repertoire and transcriptome in a mouse model of systemic lupus erythematosus

Article

Full-text available

Jan 2024

Introduction Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Anti-B-cell-activating factor (BAFF) therapy effectively depletes B cells and reduces SLE disease activity. This research aimed to evaluate the effect of BAFF blockade on B cell receptor (BCR) repertoire and gene expression. Methods Through next-generation sequencing, we analyzed gene expression and BCR repertoire in MRL/lpr mice that received long-term anti-BAFF therapy. Based on gene expression profiles, we predicted the relative proportion of immune cells using ImmuCellAI-mouse, validating our predictions via flow cytometry and FluoroSpot. Results The loss of BCR repertoire diversity and richness, along with increased clonality and differential frequency distribution of the immunoglobulin heavy chain variable (IGHV) segment gene usage, were observed in BAFF-blockade mice. Meanwhile, the distribution of complementarity-determining region 3 (CDR3) length and CDR3 amino acid usage remained unaffected. BAFF blockade resulted in extensive changes in gene expression, particularly that of genes related to B cells and immunoglobulins. Besides, the tumor necrosis factor (TNF)-α responses and interferon (IFN)-α/γ were downregulated, consistent with the decrease in IFN-γ and TNF-α serum levels following anti-BAFF therapy. In addition, BAFF blockade significantly reduced B cell subpopulations and plasmacytoid dendritic cells, and caused the depletion of antibody-secreting cells. Discussion Our comparative BCR repertoire and transcriptome analyses of MRL/lpr mice subjected to BAFF blockade provide innovative insights into the molecular pathophysiology of SLE.

Expression of S100A8 protein on B cells is associated with disease activity in patients with systemic lupus erythematosus

Article

Full-text available

May 2023
ARTHRITIS RES THER

Background Systemic lupus erythematosus (SLE) is an intractable disease characterized by autoantibody production and autoreactive B and T cell proliferation. Although several studies have revealed multiple genetic and environmental associations, the underlying mechanisms remain unknown. Methods We performed proteomics and transcriptomics using liquid chromatography-mass spectrometry and DNA microarray, using peripheral blood B cells from patients with SLE, and healthy controls (HC). We explored molecules associated with the pathophysiology of SLE by flow cytometry and B cell stimulation assay. Results We identified for the first time that expression of both S100A8 protein and mRNA were markedly upregulated in SLE B cells. The results obtained using flow cytometry showed that S100A8 was highly expressed on the surface of B cells of patients with active SLE (MFI; HC 102.5 ± 5.97, stable SLE 111.4 ± 12.87, active SLE 586.9 ± 142.9), and S100A8 on the cell surface was decreased after treatment (MFI; pre-treat 1094.5 ± 355.38, post-treat 492.25 ± 247.39); therefore, it is suggested that S100A8 may be a marker for disease activity. The mRNA expression of S100A8 was particularly upregulated in memory B cells of SLE (56.68 fold higher than HC), suggesting that S100A8 may be mainly secreted by memory B cells in the pathogenesis of SLE. Conclusions Our results imply that the S100A8 proteins secreted from memory B cells may stimulate granulocytes and monocytes through pattern recognition receptors, activate the innate immune system, and are involved in the pathogenesis of SLE.

Safety and Biological Activity of Rozibafusp alfa, a Bispecific Inhibitor of Inducible Costimulator Ligand and B Cell Activating Factor, in Patients With Rheumatoid Arthritis: Results of a Phase 1b, Randomized, Double‐Blind , Placebo‐Controlled , Multiple Ascending Dose Study

Article

Full-text available

Jul 2022

Objective: To assess the safety and biological activity of rozibafusp alfa, a first-in-class bispecific antibody-peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA). Methods: This phase 1b, double-blind, placebo-controlled, multiple ascending dose study included 34 patients (18-75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints-C-reactive protein [DAS28-CRP] >2.6, on stable methotrexate) randomized 3:1 to receive rozibafusp alfa (n = 26, in four ascending dose cohorts of 70, 140, 210, and 420 mg) or a placebo (n = 8) subcutaneously once every 2 weeks for 10 weeks (six total doses), with 24 weeks of follow-up. The primary end point was the incidence of treatment-emergent adverse events (TEAEs). Additional assessments included serum pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and RA disease activity measures (DAS28-CRP, Patient Global Assessment of Disease, and Physician Global Assessment of Disease). Results: TEAEs occurred in 96.2% and 87.5% of patients receiving rozibafusp alfa and the placebo, respectively; most were mild or moderate in severity. Two (7.7%) patients treated with rozibafusp alfa reported serious TEAEs; none were considered treatment related. Multiple doses of rozibafusp alfa showed nonlinear PK (mean t1/2 = 4.6-9.5 days) and dose-related, reversible PD (>90% ICOSL receptor occupancy in 210- and 420-mg cohorts; reduction in naïve B cells and increase in memory B cells in all cohorts). Five (20%) patients developed anti-rozibafusp alfa antibodies, with no apparent impact on safety. RA disease activity showed greater numerical improvement from baseline with rozibafusp alfa versus the placebo in the 210- and 420-mg cohorts. Conclusion: Multiple ascending doses of rozibafusp alfa were well tolerated, with PK and PD reflecting dual ICOSL and BAFF blockade. Findings support further clinical evaluation of rozibafusp alfa in autoimmune disease.

Expression of S100A8 protein on B cells is associated with disease activity in patients with systemic lupus erythematosus

Preprint

Full-text available

Jul 2022

Background Systemic lupus erythematosus (SLE) is an intractable disease characterized by autoantibody production and autoreactive B and T cell proliferation. Although several studies have revealed multiple genetic and environmental associations, the underlying mechanisms remain unknown. Methods We performed proteomics and transcriptomics using liquid chromatography-mass spectrometry and DNA microarray, using peripheral blood B cells from patients with SLE, and explored molecules associated with the pathophysiology of SLE. Results We identified for the first time that expression of both S100A8 protein and mRNA were markedly upregulated in SLE B cells. The results obtained using flow cytometry showed that S100A8 was highly expressed on the surface of B cells of patients with active SLE, and S100A8 on the cell surface was decreased after treatment; therefore, it is suggested that S100A8 may be a marker for disease activity. The mRNA expression of S100A8 was particularly upregulated in memory B cells, suggesting that S100A8 may be mainly secreted by memory B cells in the pathogenesis of SLE. Conclusions Our results imply that the S100A8 proteins secreted from memory B cells may stimulate granulocytes and monocytes through pattern recognition receptors, activate the innate immune system, and are involved in the pathogenesis of SLE.

New possibilities of pharmacotherapy for systemic lupus erythematosus: Prospects for the use of anifrolumab (monoclonal antibodies to type I interferon receptor)

Article

Full-text available

Oct 2021

Systemic lupus erythematosus (SLE) is a systemic autoimmune rheumatic disease of unknown etiology, characterized by overproduction of organ-specific autoantibodies to various components of the cell nucleus and the development of immune-inflammatory damage to internal organs. According to modern concepts, one of the key mechanisms of SLE immunopathogenesis is associated with dysregulation of type I interferon (IFN) synthesis The complex of data obtained in the process of fundamental and clinical research served as the basis for the development of a new approach to the pharmacotherapy of SLE, associated with the use of monoclonal antibodies (mAbs) that block the activity of IFN type I or its receptors. Among these drugs, anifrolumab (AFM) occupies a special place, which is a human IgG1 mAbs that bind to cellular receptors for IFN-α. The article discusses the materials of the main studies concerning the efficacy and safety of AFM in SLE, and the prospects for the use of this drug in the treatment of this disease.

Peripheral blood lymphocytes and monocytes heterogeneity in SLE patients treated by Belimumab

Preprint

Full-text available

Jun 2021

Objective: To estimate the effect of Belimumab on the heterogeneity of peripheral blood lymphocytes and monocytes subsets in systemic lupus erythematosus (SLE). Methods: There were three groups of populations, namely health controls (HC, n = 92), SLE patients treated (n = 26) and un-treated with BAFF (n = 155) in the present study. Cell subsets of CD3⁺T cells, CD3⁺CD4⁺T cells, CD3⁺CD8⁺T cells, CD19⁺B cells, CD16⁺CD56⁺NK cells, CD14⁺HLA-DR⁺monocytes, CD14⁺CD206⁺monocytes and CD14⁺CD163⁺monocytes were estimated by flow cytometry. Results: Compared with HC group, SLE patients had a higher level of CD3⁺T cells and CD3⁺CD8⁺T cells, but a lower level of CD3⁺CD4⁺T cells, CD16⁺CD56⁺NK cells, CD14⁺CD206⁺monocytes, and CD14⁺CD163⁺monocytes. Besides, the ratio of CD3⁺CD4⁺/CD3⁺CD8⁺T cells was much lower in SLE patients. Belimumab could effectively decrease CD19⁺B cells but increase CD3⁺T cell and CD3⁺CD8⁺T cells in the peripheral blood of SLE patients. Moreover, SLE patients had decreased CD14⁺CD206⁺ monocytes and CD14⁺CD163⁺ monocytes in peripheral blood, while Belimumab therapy did not affect the heterogeneity of monocytes in SLE. Conclusions: Our results revealed the heterogeneity of lymphocytes and monocytes in SLE patients. The clinical efficacy of Belimumab in SLE treatment is remarkable due to its significant effect on down-regulating B cell but up-regulating CD3⁺T cell and CD3⁺CD8⁺T cells in SLE.

Sequential therapy with rituximab and belimumab in patients with systemic lupus erythematosus

Article

Full-text available

Nov 2020

Objective : to determine the efficiency of sequential (combined) therapy with rituximab (RTM) and belimumab (BLM) in patients with active systemic lupus erythematosus (SLE). Patients and method s. Twelve patients with true SLE having moderate-to-high activity were followed up. Six of them were noted to have skin and articular manifestations and 6 had kidney damage, vasculitis. The patients took RTM at 500–2000-mg doses, with 6-methylprednisolone as premedication, whereupon they were prescribed BLM according to the standard regimen of 10 mg/kg once monthly. The follow-up period was 1 year. At baseline and every three months after RTM administration, the efficiency and tolerability of therapy were evaluated, the concentrations of autoantibodies and complement components was estimated, and the dose of oral glucocorticoids (GCs) was recorded. Results and discussion . During combined therapy with the biological agents (BAs), there was a considerable clinical and laboratory improvement: reductions in disease activity (median (Me) SLEDAI-2K scores were 12 [9.5; 17] at baseline and 2 [2; 6] at Visit 4), the Me concentrations of anti-double-stranded DNA (anti-ds-DNA) antibodies, 101 [39; 250] and 28 [6; 112] U/ml, respectively; those of complement component 3 (C3), 0.44 [0.39; 0.59] and 0.83 [0.81; 0.87] g/L, respectively; and those of complement C4, 0.06 [0.031; 0.1] and 0.16 [0.15; 0.18] g/l, respectively). Most patients received the medium and low doses of oral GCs as initiating therapy. During the year, the dose of GCs was reduced by more than a quarter and they could be completely discontinued. evaluated, the concentrations of autoantibodies and complement components was estimated, and the dose of oral glucocorticoids (GCs) was recorded. Results and discussion. During combined therapy with the biological agents (BAs), there was a considerable clinical and laboratory improvement: reductions in disease activity (median (Me) SLEDAI-2K scores were 12 [9.5; 17] at baseline and 2 [2; 6] at Visit 4), the Me concentrations of anti-double-stranded DNA (anti-ds-DNA) antibodies, 101 [39; 250] and 28 [6; 112] U/ml, respectively; those of complement component 3 (C3), 0.44 [0.39; 0.59] and 0.83 [0.81; 0.87] g/L, respectively; and those of complement C4, 0.06 [0.031; 0.1] and 0.16 [0.15; 0.18] g/l, respectively). Most patients received the medium and low doses of oral GCs as initiating therapy. During the year, the dose of GCs was reduced by more than a quarter and they could be completely discontinued. Conclusion. Combined biological therapy with RTM and BLM is a promising treatment for active SLE. The use of this regimen promotes a rapid and effective reduction in disease activity, normalization of laboratory markers of SLE (anti-ds-DNA antibody and complement C3 and C4 levels), and decreases in the dose of oral GCs and, as a consequence, in the risk of irreversible organ damages.. Combined biological therapy with RTM and BLM is a promising treatment for active SLE. The use of this regimen promotes a rapid and effective reduction in disease activity, normalization of laboratory markers of SLE (anti-ds-DNA antibody and complement C3 and C4 levels), and decreases in the dose of oral GCs and, as a consequence, in the risk of irreversible organ damages.

Analysis of Trans-Ancestral SLE Risk Loci Identifies Unique Biologic Networks and Drug Targets in African and European Ancestries

Article

Nov 2020

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of African ancestry (AA) experience the disease more severely and with an increased co-morbidity burden compared to European ancestry (EA) populations. We hypothesize that the disparities in disease prevalence, activity, and response to standard medications between AA and EA populations is partially conferred by genomic influences on biological pathways. To address this, we applied a comprehensive approach to identify all genes predicted from SNP-associated risk loci detected with the Immunochip. By combining genes predicted via eQTL analysis, as well as those predicted from base-pair changes in intergenic enhancer sites, coding-region variants, and SNP-gene proximity, we were able to identify 1,731 potential ancestry-specific and trans-ancestry genetic drivers of SLE. Gene associations were linked to upstream and downstream regulators using connectivity mapping, and predicted biological pathways were mined for candidate drug targets. Examination of trans-ancestral pathways reflect the well-defined role for interferons in SLE and revealed pathways associated with tissue repair and remodeling. EA-dominant genetic drivers were more often associated with innate immune and myeloid cell function pathways, whereas AA-dominant pathways mirror clinical findings in AA subjects, suggesting disease progression is driven by aberrant B cell activity accompanied by ER stress and metabolic dysfunction. Finally, potential ancestry-specific and non-specific drug candidates were identified. The integration of all SLE SNP-predicted genes into functional pathways revealed critical molecular pathways representative of each population, underscoring the influence of ancestry on disease mechanism and also providing key insight for therapeutic selection.

The BAFFling persistence of memory B cells

Article

Full-text available

Feb 2021

Although BAFF/BLyS and its receptor, BAFFR, play critical roles in naive B cell survival, the pathways involved in the persistence of memory B cells are largely unknown. In this issue of JEM, two groups, Müller-Winkler et al. (https://doi.org/10.1084/jem.20191393) and Lau et al. (https://doi.org/10.1084/jem.20191167), take complementary approaches to identify an essential role for BAFFR in the survival of memory B cells.

Critical requirement for BCR, BAFF, and BAFFR in memory B cell survival

Article

Full-text available

Oct 2020
J EXP MED

Memory B cells (MBCs) are long-lived cells that form a critical part of immunological memory, providing rapid antibody responses to recurring infections. However, very little is known about signals controlling MBC survival. Previous work has shown that antigen is not required for MBC survival, but a requirement for the B cell antigen receptor (BCR) has not been tested. Other studies have shown that, unlike naive B cells, MBCs do not express BAFFR and their survival is independent of BAFF, the ligand for BAFFR. Here, using inducible genetic ablation, we show that survival of MBCs is critically dependent on the BCR and on signaling through the associated CD79A protein. Unexpectedly, we found that MBCs express BAFFR and that their survival requires BAFF and BAFFR; hence, loss of BAFF or BAFFR impairs recall responses. Finally, we show that MBC survival requires IKK2, a kinase that transduces BAFFR signals. Thus, MBC survival is critically dependent on signaling from BCR and BAFFR.

Early decrease of T-bet+ B cells during subcutaneous belimumab predicts response to therapy in systemic lupus erythematosus patients

Article

Dec 2024
IMMUNOL LETT

The essential roles of memory B cells in the pathogenesis of systemic lupus erythematosus

Article

Nov 2024

The emerging role of BLyS/APRIL in autoimmune diseases: Biological characteristics, functions, and therapeutic potential

Article

Nov 2024
J AUTOIMMUN

Systemic lupus erythematosus: pathogenesis and targeted therapy

Article

Full-text available

Oct 2024

Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by dysregulated immune responses and autoantibody production, which affects multiple organs and varies in clinical presentation and disease severity. The development of SLE is intricate, encompassing dysregulation within the immune system, a collapse of immunological tolerance, genetic susceptibilities to the disease, and a variety of environmental factors that can act as triggers. This review provides a comprehensive discussion of the pathogenesis and treatment strategies of SLE and focuses on the progress and status of traditional and emerging treatment strategies for SLE. Traditional treatment strategies for SLE have mainly employed non-specific approaches, including cytotoxic and immunosuppressive drugs, antimalarials, glucocorticoids, and NSAIDs. These strategies are effective in mitigating the effects of the disease, but they are not a complete cure and are often accompanied by adverse reactions. Emerging targeted therapeutic drugs, on the other hand, aim to control and treat SLE by targeting B and T cells, inhibiting their activation and function, as well as the abnormal activation of the immune system. A deeper understanding of the pathogenesis of SLE and the exploration of new targeted treatment strategies are essential to advance the treatment of this complex autoimmune disease.

Efficacy, safety, and optimal intervention of belimumab for proliferative lupus nephritis patients in real-world settings: LOOPS registry

Article

Sep 2024

Objectives This study investigated the efficacy, safety, and predictive factors of belimumab (BEL) in induction therapy for patients with proliferative lupus nephritis (LN) in real-world settings. Methods Patients with biopsy-proven ISN/RPS class III or IV LN, with or without coexisting class V LN, who underwent standard of care (SoC), glucocorticoid (GC), and either mycophenolate mofetil or cyclophosphamide treatments were included. Participants were treated with SoC (SoC group, n = 32) or BEL and SoC (BEL+SoC group, n = 30). The primary end point was complete renal response (CRR) at 52 weeks. Results Baseline patient characteristics were not significantly different between the two groups. The 52-week retention rate of BEL was 90.0%. The BEL+SoC group showed significantly higher CRR and primary efficacy renal response achievement at 52 weeks and significantly lower GC dosage, adverse events, and Systemic Lupus International Collaborating Clinics damage index scores. Multivariate analysis of CRR achievement at 52 weeks revealed that the lack of estimated glomerular filtration rate (eGFR) improvement at 4 weeks was associated with CRR failure in the SoC group. A shorter duration (cut-off of 42 days) between the start of induction therapy and addition of BEL was also related to the CRR in the BEL+SoC group. Conclusion BEL, in addition to SoC, controls disease activity, reduces GC use, and suppresses organ damage in case of proliferative LN. Earlier BEL induction within 6 weeks may help achieve CRR in treatment-resistant cases without eGFR improvement at 4 weeks after induction therapy.

Interferon signature in the development of SLE: molecular mechanisms, approaches to diagnosis and treatment

Article

Jun 2024

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation of connective tissue and damage to various organs, including joints, skin, kidneys and heart. The disease has a significant gender predisposition and is more common in women. The pathogenesis of SLE is based on a violation of immunological tolerance, accompanied by activation of B lymphocytes and the production of autoantibodies. Recent advances in basic research have significantly deepened the understanding of the immunopathogenetic mechanisms of SLE, which justifies the use of new pharmacotherapeutic approaches. These approaches involve the use of biological drugs aimed at blocking the activity of type I interferon (IFN) or its receptors. The article discusses the molecular mechanisms of activation of the interferon response in SLE, modern methods for diagnosing the interferon signature, and new approaches to treatment aimed at blocking the interferon pathway. The possible role of the interferon signature in the stratification of SLE patients is also discussed. Such stratification will make it possible to more effective select treatment regimens taking into account the individual characteristics of the immune response of each patient. This may increase the effectiveness of treatment, reduce the likelihood of side effects and improve the prognosis for patients with SLE.

Sustained depression of B cell counts in lupus nephritis after treatment with rituximab and/or belimumab is associated with fewer disease flares

Article

Jun 2024
LUPUS

Objective To study the risk of lupus nephritis flare (LNF) or severe lupus flare (SLF) as a function of B cell count kinetics in lupus nephritis (LN) patients after they achieve at least a partial renal response (PRR) with induction treatment that includes rituximab (RTX) and/or belimumab (BLM). Methods We performed a retrospective analysis of a cohort of 19 patients with severe LN that received a B cell agent (BCA), RTX and/or BLM, as part of an initial treatment regimen for an LN flare and had subsequent CD19+ B cell measurements in peripheral blood. We then characterized the follow-up periods, after B cell depressions occurred and PRR were achieved, by the corresponding trajectories of B cell counts (BCC). Time periods with sustained low BCC were type 1 (T1) episodes, while those with repletion of BCC>100 cells/μL were called type 2 (T2) episodes. Time periods with rapid BCC repletion, defined as >50 cells/μL in ≤6 months, were called T2b episodes. Corresponding C3, C4, and anti-dsDNA levels were recorded for each episode. The time from PRR until an event, either a LNF or SLF, or to censoring, either at the end of the study period or the end of available patient follow-up, was assessed for each episode type. Kaplan-Meier survival analysis was used to compare time to flare between T1 and T2 episodes. Results There were 26 episodes of B cell depression. Seventeen (65%) were T1 and 9 (35%) were T2. Compared to T1 episodes, T2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio (HR) = 9.0, 95% CI for HR = 2.2-36.7); this risk was even larger for T2b vs T1 episodes. Median BCC was 14 cells/μL in T1 and 160 cells/μL in T2 episodes. Both C3 and C4 levels significantly increased over the duration of the episode in T1 episodes only. Conclusion Sustained low BCC was associated with prolonged serologic and clinical response, whereas repletion, and particularly rapid repletion, of B cells after treatment with BCA was associated with subsequent disease flare.

The Role of the BAFF and Lymphotoxin Pathways in B Cell Biology

Chapter

Jan 2015

Lymphocytes and Infection in Autoimmune Diseases

Chapter

Jan 2024

Long-term results of therapy with sequential use of rituximab and belimumab in patients with systemic lupus erythematosus

Article

Oct 2023

Objective: To evaluate the efficacy of combination therapy with rituximab (RTM) and belimumab (BLM) in patients with systemic lupus erythematosus (SLE) during long-term follow-up. Material and methods. Twelve patients with definite high- and moderate activity SLE were included in the study. Nine of them had skin and joint manifestations, and the others had renal, peripheral nervous system involvement, and vasculitis. Patients received RTM at a dose of 500–2000 mg with premedication with 6-methylprednisolone and then BLM according to the standard regimen of 10 mg/kg once a month. Patients were divided into two groups according to the timing of assessment of long-term outcomes. In the 1 st group, data were evaluated after 7–9 years (n = 4), and in the 2 nd group – after 2–4 years (n = 8) after the prescription of biologic disease-modifying antirheumatic drugs (bDMARDs). Efficacy and tolerability of therapy, SLE activity, and dose of oral glucocorticoids (GC) were evaluated. Results and discussion. Against the background of combination therapy, clinical and immunological response was achieved in 11 of 12 patients after one year (median SLEDAI-2K at baseline – 10 [9.5; 14.5] points, 6 and 12 months after administratrion of BLM – 4 [2; 6] points). When bDMARDs were prescribed in the first two years of the disease, patients responded better to therapy and showed more significant positive dynamics in clinical and laboratory parameters. Subsequently, BLM therapy was limited to an average of 2 years, during which a stable remission was achieved. Prescribing bDMARDs allowed GC to be used as initial therapy in an exacerbation of SLE in medium and low doses (subsequently further reduced). Clinical remission was achieved and maintained in 7 patients, exacerbation at different time points after discontinuation of bDMARDs occurred in 3 patients, efficacy waned in one patient, and no result was achieved with combination therapy in another patient. Conclusion. The most pronounced positive result can be expected when a bDMARDs are prescribed as early as possible after diagnosis of SLE (in the first 2 years of the disease). It is advisable to administer BLM infusions as recommended once a month without long breaks between injections for at least 2 years and to continue until a durable effect is achieved. The use of low-dose GC and its discontinuation is an achievable goal, but careful monitoring of patients is needed to detect early symptoms of exacerbation.

The role of B-cell ferroptosis in the pathogenesis of systemic lupus erythematosus

Article

Sep 2023
CLIN IMMUNOL

Translational implications of newly characterized pathogenic pathways in systemic lupus erythematosus

Article

Aug 2023
BEST PRACT RES CL RH

Improved characterization of relevant pathogenic pathways in systemic lupus erythematosus (SLE) has been further delineated over the last decades. This led to the development of targeted treatments including belimumab and anifrolumab, which recently became available in clinics. Therapeutic targets in SLE encompass interferon (IFN) signaling, B-T costimulation including immune checkpoints, and increasing modalities of B lineage targeting, such as chimeric antigen receptor (CAR) T cells directed against CD19 or sequential anti-B cell targeting. Patient profiling based on characterization of underlying molecular abnormalities, often performed through comprehensive omics analyses, has recently been shown to better predict patients' treatment responses and also holds promise to unravel key molecular mechanisms driving SLE. SLE carries two key signatures, namely the IFN and B lineage/plasma cell signatures. Recent advances in SLE treatments clearly indicate that targeting innate and adaptive immunity is successful in such a complex autoimmune disease. Although those signatures may interact at the molecular level and provide the basis for the first selective treatments in SLE, it remains to be clarified whether these distinct treatments show different treatment responses among certain patient subsets. In fact, notwithstanding the remarkable amount of novel clues for innovative SLE treatment, harmonization of big data within tailored treatment strategies will be instrumental to better understand and treat this challenging autoimmune disorder. This review will provide an overview of recent improvements in SLE pathogenesis, related insights by analyses of big data and machine learning as well as technical improvements in conducting clinical trials with the ultimate goal that translational research results in improved patient outcomes.

Belimumab treatment of adult idiopathic inflammatory myopathy

Article

Jun 2023
Rheumatology

Objective To evaluate belimumab addition to standard of care (SoC) in patents with refractory Idiopathic Inflammatory Myopathy (IIM). Methods We conducted a 40-week multicentre randomized, double-blind, placebo-controlled trial with 1:1 IV belimumab 10 mg/kg or placebo randomization and a 24-week open-label extension. Clinical responses were measured by the Definition of Improvement (DOI) and Total Improvement Score (TIS). Flow cytometry analyses were performed on available samples before randomization, at 24 and 60–64wk. Descriptive statistics, t test, Fisher’s exact test and ANOVA tests were used. Results 17 patients were randomized, 15 received ≥ 5 doses of belimumab or placebo and were included in the intention -to-treat analysis. More belimumab patients vs placebo attained TIS ≥ 40 (55.5% vs 33.3%; p=NS) and achieved DOI (33.3% vs 16.7%; p = NS) at Wk40 and Wk64; mean TIS was similar among groups. Two patients achieved major responses (TIS= 72.5) after Wk40 in the belimumab arm, none in the placebo arm. No improvement in placebo arm after switching to the open label phase was observed. There was no steroid-sparing effect. No new safety signals were detected. Although total B-cells were not reduced, belimumab induced naïve B-cells depletion while enhancing memory B cells number and frequency. Conclusion The study did not meet the primary end point and no statistically significant differences were observed in clinical responses between arms. More patients achieved sustained TIS ≥ 40 and reached DOI. Most patients who received belimumab longer than 40 weeks had clinical improvement. Phenotypic changes in B cell populations were not associated with clinical responses. Clinical trial registration number Clinicaltrials.gov, https://clinicaltrials.gov/, NCT02347891

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Properties of Rozibafusp Alfa, a Bispecific Inhibitor of BAFF and ICOSL : Analyses of Phase I Clinical Trials

Article

May 2023
CLIN PHARMACOL THER

Rozibafusp alfa (AMG 570) is a first-in-class bispecific IgG2-peptide fusion designed to inhibit inducible T-cell costimulator ligand (ICOSL) and B-cell activating factor (BAFF). The pharmacokinetics (PK) and pharmacodynamics (PD) of rozibafusp alfa were investigated in two randomized, placebo-controlled clinical studies: a phase 1a single ascending-dose study (7-700 mg subcutaneously [SC]) in healthy subjects and a phase 1b multiple ascending-dose study (70-420 mg subcutaneously every 2 weeks [Q2W]) in patients with rheumatoid arthritis. Rozibafusp alfa exhibited nonlinear PK and dose-related and reversible dual-target engagement. Maximal reduction of naïve B cells from baseline (>40%), reflective of BAFF inhibition, was achieved with rozibafusp alfa exposure (AUCinf and AUCtau ) above 51 and 57 days•μg/mL for the single-dose (≥70 mg) and multiple-dose studies (≥70 mg Q2W), respectively. ICOSL receptor occupancy (RO) on circulating B cells, a surrogate PD endpoint for ICOSL inhibition, was directly related to drug concentration. PK/PD analysis showed >90% RO at rozibafusp alfa ≥22.2 μg/mL (≥420-mg single dose or ≥210 mg Q2W multiple dose), with saturation occurring at higher drug concentrations. These results informed the design and dose selection of a phase 2b study assessing the safety and efficacy of rozibafusp alfa in patients with active systemic lupus erythematosus.

Combination strategies for lupus nephritis: facts and controversies

Article

Mar 2023

cc Mok

Introduction There is an unmet need to improve the efficacy of therapeutic regimens in lupus nephritis (LN). Cocktail immunosuppressive therapy for a synergistic effect of individual drugs may enhance the efficacy and enable dosage reduction. However, the potential increase in the risk of serious and opportunistic infections is a concern. Moreover, the timing of combination therapy, adoption of a step-up or step-down approach, and the choice of drugs is still controversial, partly related to the cost-effectiveness issue. Areas covered Evidence of combination of conventional, newer immunosuppressive and biologic/targeted agents in LN. Expert opinion Early combination of conventional regimens with anti-B cell activation factor (anti-BAFF) or the calcineurin inhibitors (CNIs) enhances the therapeutic effect without increasing serious adverse events in LN. However, combining anti-CD20 and anti-BAFF biologics appears to be less promising from results of clinical trials. Initial combination strategy may be more cost-effective for patients at risk of treatment failure and renal function deterioration. With the availability of more options, the treat-to-target approach in LN is increasingly feasible and further studies are needed to compare the step-up and step-down approach in the treatment of LN.

The rapid inhibition of B-cell activation markers by belimumab was associated with disease control in systemic lupus erythematosus patients

Article

Full-text available

Feb 2023

Objective: To examine the kinetics of B cell subsets and activation markers in the early stage of belimumab treatment and their correction with treatment response. Methods: We enrolled 27 systemic lupus erythematosus (SLE) patients receiving 6 months belimumab treatment. Flow cytometry was used to test their B cell subsets and activation markers (including CD40, CD80, CD95, CD21low, CD22, p-SYK and p-AKT). Results: During belimumab treatment, SLEDAI-2K declined, the proportions of CD19⁺ B cells and naïve B cells decreased, whereas the switched memory B cells and non-switched B cells increased. The larger variations of the B cell subsets and the activation markers were in the first 1 month than the other later time frames. The ratio of p-SYK/p-AKT on non-switched B cell at 1 month was associated with the SLEDAI-2K decline rate in the 6 months of belimumab treatment. Conclusion: B cell hyperactivity was rapidly inhibited in the early stage of belimumab treatment, and the ratio of p-SYK/p-AKT may predict SLEDAI-2K decline. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT04893161?term=NCT04893161&draw=2&rank=1; identifier: NCT04893161.

B cells in systemic lupus erythematosus: Targets of new therapies and surveillance tools

Article

Full-text available

Aug 2022

B cell hyperactivity is a hallmark of the complex autoimmune disease systemic lupus erythematosus (SLE), which has justified drug development focusing on B cell altering agents during the last decades, as well as the off-label use of B cell targeting biologics. About a decade ago, the anti-B cell activating factor (BAFF) belimumab was the first biological agent to be licensed for the treatment of adult patients with active yet non-renal and non-neuropsychiatric SLE, to later be expanded to include treatment of pediatric SLE and, recently, lupus nephritis. B cell depletion is recommended as an off-label option in refractory cases, with the anti-CD20 rituximab having been the most used B cell depleting agent to date while agents with a slightly different binding specificity to CD20 such as obinutuzumab have also shown promise, forming a part of the current pipeline. In addition, terminally differentiated B cells have also been the targets of experimental therapies, with the proteasome inhibitor bortezomib being one example. Apart from being promising drug targets, B and plasma cells have also shown promise in the surveillance of patients with SLE, especially for monitoring B cell depleting or B cell altering therapies. Inadequate B cell depletion may signify poor expected clinical response to rituximab, for example, while prominent reductions in certain B cell subsets may signify a protection against flare development in patients treated with belimumab. Toward an era with a richer therapeutic armamentarium in SLE, including to a large extent B cell altering treatments, the challenge that emerges is to determine diagnostic means for evidence-based therapeutic decision-making, that uses clinical information, serological markers, and gene expression patterns to guide individualized precision strategies.

Editorial: Insights in Rheumatology: 2021

Article

Full-text available

Jul 2022

BAFFR activates PI3K/AKT signaling in human naive but not in switched memory B cells through direct interactions with B cell antigen receptors

Article

Jun 2022

Reductions in circulating B cell subsets and immunoglobulin G levels with long-term belimumab treatment in patients with SLE

Article

Full-text available

Feb 2022

Objective To examine the long-term changes in circulating B cell subsets and IgG levels at 5+ years of continuous belimumab treatment and their correlations with efficacy and safety measures. Methods This was a post hoc analysis of a continuation study (BEL112233; NCT00724867 ) of eligible US patients who completed the 76-week BLISS-76 Study (BEL110751; NCT00410384 ), with up to eight calendar-years of follow-up and median (IQR) belimumab exposure of 310 (209, 364) weeks. From week 76, patients initially randomised to intravenous belimumab 1 mg/kg or 10 mg/kg every 4 weeks in BLISS-76 continued to receive the same dose in the continuation study, while those initially randomised to placebo received belimumab 10 mg/kg intravenous every 4 weeks during continuation. All patients continued to receive standard SLE therapy. Biomarker data were collected, and the effects on baseline and early changes (weeks 0–24 after starting belimumab) from baseline in biomarkers on SLE Responder Index (SRI-4) and infection rate were evaluated. Results Of the 819 patients from BLISS-76, 268 self-selecting patients entered BEL112233. Compared with baseline, B cell subset counts decreased by 40%–99% after 312 weeks (6 years), and serum IgG levels decreased by 28% after 284 weeks. Higher baseline naïve B cell counts were associated with greater SRI-4 response rates (p<0.05), whereas higher baseline SLE subset plasma and short-lived plasma B cell counts were associated with lower SRI-4 response rates (p<0.05). Elevated baseline IgG levels were associated with increased infection rates over the treatment period (p<0.05), and early greater decreases in IgG levels were associated with higher SRI-4 response rates (p<0.05). Conclusions Belimumab treatment up to 312 weeks (6 years) resulted in substantial decreases in several circulating B cell subsets and IgG levels. Higher baseline naïve B cell counts and IgG levels were associated with improved SRI-4 response and increased infection rates, respectively.

Belimumab in Lupus Nephritis: A Systematic Review and Meta-Analysis

Article

Full-text available

Dec 2021

Belimumab is a recombinant human IgG-1λ monoclonal antibody. It inhibits the B-cell activating factor (BAFF) and is approved for patients with systemic lupus erythematosus (SLE) older than five years with positive autoantibody. We aimed to evaluate the role of belimumab in the maintenance phase of treatment for lupus nephritis (LN). PubMed, PubMed Central (PMC), Cochrane Library, and Embase were searched using appropriate keywords. The screening of title and abstract was done in Covidence, followed by data extraction of the relevant studies based on inclusion criteria. Review manager (RevMan 5.4) was used for data analysis with random or fixed effects model based on heterogeneities. Two randomized controlled trials were included in the quantitative analysis. There were 1.71 times higher odds of complete renal response in the belimumab group than in the control group (odds ratio (OR), 1.71; 95% confidence interval (CI), 1.12-2.60; I-square (I2) = 0%). Similarly, there was 34% lower odds for having no response among the belimumab group (OR, 0.66; 95% CI, 0.45-0.96; I2 = 0%). No significant differences between the two groups were observed for the occurrence of treatment-related adverse events (TRAEs) (OR, 1.07; 95% CI, 0.74-1.56; I2 = 0%), treatment-related serious adverse events (OR, 0.54; 95% CI, 0.15-1.96; I2 = 68%), and treatment-related infections (OR, 0.65; 95% CI, 0.27-1.55; I2 = 21%).Therefore, belimumab and standard treatment were instrumental for beneficial renal response in patients with lupus nephritis and were not associated with increased odds of adverse effect compared with the standard treatment alone.

Durable renal response and safety with add-on belimumab in patients with lupus nephritis in real-life setting (BeRLiSS-LN). Results from a large, nationwide, multicentric cohort

Article

Sep 2021
J AUTOIMMUN

Background: Belimumab was recently approved for treatment of lupus glomerulonephritis (LN). Aim: To evaluate renal response and its predictors in LN patients receiving belimumab in real-life. Patients and methods: We considered all patients fulfilling the SLEDAI-2K renal items and/or having estimated glomerular filtration rate (eGFR)≤60 ml/min/1.73 m2, with positive anti-dsDNA and/or low C3/C4 enrolled in the multicentre Italian lupus cohort BeRLiSS (BElimumab in Real LIfe Setting Study), treated with monthly IV Belimumab 10 mg/kg over standard treatment. Primary efficacy renal response (PERR), defined as proteinuria ≤0.7 g/24 h, eGFR≥60 ml/min/1.73 m2 without rescue therapy, was considered as primary outcome. Complete renal response (CRR; proteinuria <0.5 g/24 h, eGFR≥90 ml/min/1.73 m2) was considered as secondary outcome. Prevalence and predictors of PERR were evaluated at 6, 12, 24 months by multivariate logistic regression. Results: Among the 466 SLE patients of BeRLiSS, 91 fulfilled the inclusion criteria, 79 females, median age 41.0 (33.0-47.0) years, median follow-up 22.0 (12.0-36.0) months. Sixty-four (70.3%) achieved PERR, of whom 38.4% reached CRR. Among patients achieving PERR at 6 months, 86.7% maintained response throughout the follow-up. At multivariable analysis, hypertension (OR [95%CI]: 0.28 [0.09-0.89], p = 0.032), high baseline serum creatinine (0.97 [0.95-0.99], p = 0.01) and high baseline proteinuria (0.37, [0.19-0.74], p = 0.005) negatively predicted PERR. Positive predictors of PERR at 12 and 24 months were baseline anti-Sm positivity (OR [95%CI]: 6.2 [1.21-31.7], p = 0.029; 19.8 [2.01-186.7], p = 0.009, respectively) and having achieved PERR at 6 months (14.4 [3.28-63.6]; 11.7 [2.7-48.7], p = 0.001 for both). Conclusions: Add-on therapy with belimumab led to durable renal response in patients with LN in a real-life setting.

BLyS neutralization results in selective anti-HLA alloantibody depletion without successful desensitization

Article

Sep 2021
TRANSPL IMMUNOL

Pre-existing anti-HLA allo-antibodies (allo-Abs) are a major barrier to successful kidney transplantation, resulting in an elevated risk for antibody-mediated rejection (AMR) and eventual graft loss. The cytokine B lymphocyte stimulator (BLyS) promotes B cell maturation and plasma cell survival; consequently, anti-BLyS therapy represents a potential therapeutic opportunity in diminishing pre-existing allo-Abs. Here we report that in our 1-year pilot trial, BLyS neutralization failed to reduce total anti-HLA allo-Ab levels in highly sensitized candidates awaiting kidney transplant in a clinically meaningful way. Additionally, we performed a post hoc analysis using sera from trial candidates which revealed selective depletion of anti-HLA class I and class II Abs in response to belimumab treatment, restricted to certain allele specificities and IgG subclasses. Altogether, we observed that BLyS blockade only results in selective depletion of anti-HLA Abs recognizing a few discrete HLA allele specificities.

Belimumab for the treatment of children with frequently relapsing nephrotic syndrome: the BELNEPH study

Article

Aug 2021

Background Effectiveness of rituximab in pediatric idiopathic nephrotic syndrome suggests that B cells play a pathogenic role. We tested safety and efficacy of the B-cell-modulating agent belimumab in frequently relapsing nephrotic syndrome (FRNS).Methods An open-label, prospective, single-arm pilot study (EUDRACT 2017-003839-11) was designed to treat 10 children with FRNS with i.v. belimumab for 12 months. Prednisone was tapered/stopped. Safety, number of relapses, cumulative prednisone dose and B-cell subset "levels" are referred to both B cell subset and immunoglobulin.ResultsFive patients were enrolled, and four reached the primary 6-month endpoint. Of these, two completed the 12-month endpoint. Three patients experienced ≥2 relapses while on belimumab, requiring additional immunosuppression. Compared to the 6 months before belimumab treatment, the mean number of relapses (1.4 vs. 2, p=0.21) and the mean cumulative prednisone dose (1.86 vs. 2.62 g/m2, p=0.17) were not significantly reduced during the 6 months on belimumab. This study was terminated by the steering committee after the interim evaluation because belimumab failed to show clear benefits to counterbalance the inconvenience of monthly i.v. infusion. During follow-up, total and mature-naïve B cells decreased, while no change in memory B-cells was observed. Serum immunoglobulins remained stable. No infusion reaction was observed.Conclusions Short-term treatment with belimumab in pediatric FRNS was well tolerated. The number of patients was too small to draw conclusions on efficacy. Nonetheless, we did not observe clear improvements. The burden of monthly in-hospital i.v. infusions outweighed potential benefits. Persistence of circulating memory B cells supports their pathogenic role in the disease.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information.

BAFF signaling in health and disease

Article

Aug 2021

BAFF is a critical cytokine supporting the survival of mature naïve B cells, acting through the BAFFR receptor. Recent studies show that BAFF and BAFFR are also required for the survival of memory B cells, autoimmune B cells as well as malignant chronic lymphocytic leukaemia (CLL) cells. BAFFR cooperates with other receptors, notably the B cell antigen receptor (BCR), a process which is critical for the expansion of autoimmune and CLL cells. This crosstalk may be mediated by TRAF3 which interacts with BAFFR and with CD79A, a signalling subunit of the BCR and the downstream SYK kinase, inhibiting its activity. BAFF binding to BAFFR leads to degradation of TRAF3 which may relieve inhibition of SYK activity transducing signals to pathways required for B cell survival. BAFFR activates both canonical and non-canonical NF-κB signalling and both pathways play important roles in the survival of B cells and CLL cells.

BAFF receptor polymorphisms and deficiency in humans

Article

Aug 2021
CURR OPIN IMMUNOL

The BAFF-receptor (BAFFR) is a member of the TNF-receptor family. It is expressed only by B cells and binds BAFF as single ligand, which activates key signaling pathways regulating essential cellular functions, including survival, protein synthesis, and metabolic fitness. In humans, BAFFR deficiency interrupts B cell development at the transition from immature to mature B cells and causes B lymphopenia, hypogammaglobulinemia, and impaired humoral immune responses. Polymorphisms in TNFRSF13C gene affecting BAFFR oligomerization and signaling have been described in patients with immunodeficiency, autoimmunity and B cell lymphomas. Despite a uniform expression pattern of BAFFR in peripheral mature B cells, depletion of BAFF with neutralizing antibodies in patients with systemic lupus erythematosus does not affect the survival of switched memory B cells. These findings imply a distinct dependency of mature B cell subsets on BAFF/BAFFR interaction and highlight the contribution of BAFFR-derived signals in peripheral B cell development and homeostasis.

Successful Treatment with Belimumab in a Patient with Refractory Systemic Lupus Erythematosus after Initiation of Hemodialysis: Considering the Synergistic Effect of Belimumab and Immunological Burn-Out Phenomenon in End-Stage Renal Disease Patients on Hemodialysis

Article

Apr 2021
BLOOD PURIFICAT

Background: In patients with systemic lupus erythematosus (SLE), disease activity can persist even after initiating dialysis. However, guidelines for the treatment of patients with SLE after dialysis is initiated have not yet been established. Case presentation: We describe the case of a 54-year-old Japanese woman who was diagnosed with SLE at age 12, progressed to end-stage renal disease (ESRD), and initiated hemodialysis for lupus nephritis. However, SLE activity persisted after hemodialysis. Cyclophosphamide and mycophenolate mofetil were administered in addition to prednisolone and immunoadsorption, but this treatment strategy was limited by side effects. The patient was subsequently treated with belimumab, and the activity of SLE decreased rapidly. Conclusions: ESRD patients with SLE show no significant decrease in transitional B cells and have elevated levels of B-cell activating factor (BAFF). Both transitional B cells and BAFF are important therapeutic targets for belimumab, indicating that patients with ESRD may benefit from belimumab therapy. However, the effects of belimumab may be potentiated in patients with uremia, who may be more susceptible to adverse events such as infections. Patients with SLE who receive belimumab after initiation of hemodialysis therefore require careful follow-up. Here, we report the first case of belimumab administration in a patient with SLE after initiation of hemodialysis.

Belimumab for systemic lupus erythematosus

Article

Feb 2021

Background: Belimumab, the first biologic approved for the treatment of systemic lupus erythematosus (SLE), has been shown to reduce autoantibody levels in people with SLE and help control disease activity. Objectives: To assess the benefits and harms of belimumab (alone or in combination) in systematic lupus erythematosus. Search methods: An Information Specialist carried out the searches of CENTRAL, MEDLINE, Embase, CINAHL, Web of Science, the World Health Organization (WHO) International Clinical Trials Registry Platform, and clinicaltrials.gov from inception to 25 September 2019. There were no language or date restrictions. Selection criteria: We included randomized controlled trials (RCTs) or controlled clinical trials (CCTs) of belimumab (alone or in combination) compared to placebo/control treatment (immunosuppressive drugs, such as azathioprine, cyclosporine, mycophenolate mofetil or another biologic), in adults with SLE. Data collection and analysis: We used standard methodologic procedures expected by Cochrane. Main results: Six RCTs (2917 participants) qualified for quantitative analyses. All included studies were multicenter, international or US-based. The age range of the included participants was 22 to 80 years; most were women; and study duration ranged from 84 days to 76 weeks. The risk of bias was generally low except for attrition bias, which was high in 67% of studies. Compared to placebo, more participants on belimumab 10 mg/kg (Food and Drug Administration (FDA)-approved dose) showed at least a 4-point improvement (reduction) in Safety of Estrogen in Lupus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, a validated SLE disease activity index: (risk ratio (RR) 1.33, 95% confidence interval (CI) 1.22 to 1.45; 829/1589 in belimumab group and 424/1077 in placebo; I2= 0%; 4 RCTs; high-certainty evidence). Change in health-related quality of life (HRQOL), assessed by Short Form-36 Physical Component Summary score improvement (range 0 to 100), showed there was probably little or no difference between groups (mean difference 1.6 points, 95% CI 0.30 to 2.90; 401 in belimumab group and 400 in placebo; I2= 0%; 2 RCTs; moderate-certainty evidence). The belimumab 10 mg/kg group showed greater improvement in glucocorticoid dose, with a higher proportion of participants reducing their dose by at least 50% compared to placebo (RR 1.59, 95% CI 1.17 to 2.15; 81/269 in belimumab group and 52/268 in placebo; I2= 0%; 2 RCTs; high-certainty evidence). The proportion of participants experiencing harm may not differ meaningfully between the belimumab 10 mg/kg and placebo groups: one or more serious adverse event (RR 0.87, 95% CI: 0.68 to 1.11; 238/1700 in belimumab group and 199/1190 in placebo; I2= 48%; 5 RCTs; low-certainty evidence; ); one or more serious infection (RR 1.01, 95% CI: 0.66 to 1.54; 44/1230 in belimumab group and 40/955 in placebo; I2= 0%; 4 RCTs; moderate-certainty evidence); and withdrawals due to adverse events (RR 0.82, 95% CI: 0.63 to 1.07; 113/1700 in belimumab group and 94/1190 in placebo; I2= 0%; 5 RCTs; moderate-certainty evidence). Mortality was rare, and may not differ between belimumab 10 mg/kg and placebo (Peto odds ratio 1.15, 95% CI 0.41 to 3.25; 9/1714 in belimumab group and 6/1203 in placebo; I2= 4%; 6 RCTs; low-certainty evidence). Authors' conclusions: The six studies that provided evidence for benefits and harms of belimumab were well-designed, high-quality RCTs. At the FDA-approved dose of 10 mg/kg, based on moderate to high-certainty data, belimumab was probably associated with a clinically meaningful efficacy benefit compared to placebo in participants with SLE at 52 weeks. Evidence related to harms is inconclusive and mostly of moderate to low-certainty evidence. More data are needed for the longer-term efficacy of belimumab.

Belimumab: a step forward in the treatment of systemic lupus erythematosus

Article

Feb 2021

Introduction : Systemic Lupus Erythematosus (SLE) is a chronic B cell-mediated autoimmunedisease which can potentially involve several organs and systems. The development of SLE is associated with a complexity of genetic, hormonal and environmental factors leading to immune deregulation and production of autoantibodies. Therefore, novel therapies have focused on B cells as key effectors of SLE pathogenesis. Belimumab is a fully humanized monoclonal antibody thatantagonizes B-lymphocyte stimulator (BLyS); it is the first and the only biological drug approved for SLE in over 50 years. Areas Covered: In this review we discuss the pharmacological properties of belimumab, new recommendations for its use in clinical practice and its evidence of efficacy and safety based on clinical trial and real-life data. Expert Opinion: Efficacy and safety of belimumab in clinical practice has been well established. To date, it is known that early introduction of belimumab in SLE can maximize the efficacy of the drug. A number of questions are still open, such as the timing of belimumab discontinuation and its possible association with other biological drugs, which need to be assessed in future studies.

B Cells and Generation of Antibodies

Chapter

Jan 2019

The humoral immune response protects an organism from environmental pathogens by producing antibodies (immunoglobulins) that mediate the destruction or inactivation of microbial organisms and their toxins. It also produces antibodies to self to assist in the removal of cellular debris in a noninflammatory fashion. To perform these functions, the immune system generates antibodies to a diverse and changing array of antigens, yet it must do so without generating pathogenic antibodies to self. The production of high-affinity antibodies that bind to self-determinants is a prominent feature of systemic lupus erythematosus (SLE).¹ Some autoantibodies in SLE are considered markers for disease (e.g., antinuclear antibody) because they have no established pathogenicity, whereas others also play a role in disease pathogenesis and tissue damage.²⁻⁶ There have been extensive investigations of autoantibodies in SLE, which address a number of specific questions: 1.What is the genetic contribution to pathogenic antibody generation? 2.Do B cells producing autoantibodies arise from an antigen-triggered and antigen-selected response? If so, are these triggering and selecting antigens self or foreign? 3.Are particular B-cell lineages or differentiation pathways responsible for autoantibody production? 4.What defects in immune regulation permit the sustained production of pathogenic autoantibodies? 5.What are the characteristics of pathogenic autoantibodies, and how do they mediate pathology? This chapter discusses autoantibody structure, assembly, and regulation as well as the B-cell subsets that produce antibodies. Based on new advances in the knowledge of autoantibody structure and regulation, novel potential therapeutic strategies are also briefly addressed.

BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact

Article

Full-text available

Oct 2008
P NATL ACAD SCI USA

We have used an inhibiting antibody to determine whether preimmune versus antigen-experienced B cells differ in their requisites for BLyS, a cytokine that controls differentiation and survival. Whereas in vivo BLyS inhibition profoundly reduced naïve B cell numbers and primary immune responses, it had a markedly smaller effect on memory B cells and long-lived plasma cells, as well as secondary immune responses. There was heterogeneity within the memory pools, because IgM-bearing memory cells were sensitive to BLyS depletion whereas IgG-bearing memory cells were not, although both were more resistant than naïve cells. There was also heterogeneity within B1 pools, as splenic but not peritoneal B1 cells were diminished by anti-BLyS treatment, yet the number of natural antibody-secreting cells remained constant. Together, these findings show that memory B cells and natural antibody-secreting cells are BLyS-independent and suggest that these pools can be separately manipulated.

Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice

Article

Full-text available

Mar 2000
P NATL ACAD SCI USA

TALL-1/Blys/BAFF is a member of the tumor necrosis factor (TNF) ligand superfamily that is functionally involved in B cell proliferation. Here, we describe B cell hyperplasia and autoimmune lupus-like changes in transgenic mice expressing TALL-1 under the control of a β-actin promoter. The TALL-1 transgenic mice showed severe enlargement of spleen, lymph nodes, and Peyer's patches because of an increased number of B220+ cells. The transgenic mice also had hypergammaglobulinemia contributed by elevations of serum IgM, IgG, IgA, and IgE. In addition, a phenotype similar to autoimmune lupus-like disease was also seen in TALL-1 transgenic mice, characterized by the presence of autoantibodies to nuclear antigens and immune complex deposits in the kidney. Prolonged survival and hyperactivity of transgenic B cells may contribute to the autoimmune lupus-like phenotype in these animals. Our studies further confirm TALL-1 as a stimulator of B cells that affect Ig production. Thus, TALL-1 may be a primary mediator in B cell-associated autoimmune diseases.

Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus

Article

Full-text available

Aug 2009
NAT IMMUNOL

Studies have suggested involvement of interleukin 17 (IL-17) in autoimmune diseases, although its effect on B cell biology has not been clearly established. Here we demonstrate that IL-17 alone or in combination with B cell-activating factor controlled the survival and proliferation of human B cells and their differentiation into immunoglobulin-secreting cells. This effect was mediated mainly through the nuclear factor-kappaB-regulated transcription factor Twist-1. In support of the relevance of our observations and the potential involvement of IL-17 in B cell biology, we found that the serum of patients with systemic lupus erythematosus had higher concentrations of IL-17 than did the serum of healthy people and that IL-17 abundance correlated with the disease severity of systemic lupus erythematosus.

Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice

Article

Full-text available

Apr 2000

TALL-1/Blys/BAFF is a member of the tumor necrosis factor (TNF) ligand superfamily that is functionally involved in B cell proliferation. Here, we describe B cell hyperplasia and autoimmune lupus-like changes in transgenic mice expressing TALL-1 under the control of a beta-actin promoter. The TALL-1 transgenic mice showed severe enlargement of spleen, lymph nodes, and Peyer's patches because of an increased number of B220+ cells. The transgenic mice also had hypergammaglobulinemia contributed by elevations of serum IgM, IgG, IgA, and IgE. In addition, a phenotype similar to autoimmune lupus-like disease was also seen in TALL-1 transgenic mice, characterized by the presence of autoantibodies to nuclear antigens and immune complex deposits in the kidney. Prolonged survival and hyperactivity of transgenic B cells may contribute to the autoimmune lupus-like phenotype in these animals. Our studies further confirm TALL-1 as a stimulator of B cells that affect Ig production. Thus, TALL-1 may be a primary mediator in B cell-associated autoimmune diseases.

Disturbed Peripheral B Lymphocyte Homeostasis in Systemic Lupus Erythematosus

Article

Full-text available

Dec 2000

In patients with active systemic lupus erythematosus (SLE), a marked B lymphocytopenia was identified that affected CD19(+)/CD27(-) naive B cells more than CD19(+)/CD27(+) memory B cells, leading to a relative predominance of CD27-expressing peripheral B cells. CD27(high)/CD38(+)/CD19(dim)/surface Ig(low)/CD20(-)/CD138(+) plasma cells were found at high frequencies in active but not inactive SLE patients. Upon immunosuppressive therapy, CD27(high) plasma cells and naive CD27(-) B cells were markedly decreased in the peripheral blood. Mutational analysis of V gene rearrangements of individual B cells confirmed that CD27(+) B cells coexpressing IgD were memory B cells preferentially using V(H)3 family members with multiple somatic mutations. CD27(high) plasma cells showed a similar degree of somatic hypermutation, but preferentially employed V(H)4 family members. These results indicate that there are profound abnormalities in the various B cell compartments in SLE that respond differently to immunosuppressive therapy.

Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance

Article

Full-text available

Nov 2001

The study of human B cell tolerance has been hampered by difficulties in identifying a sizable population of autoreactive B lymphocytes whose fate could be readily determined. Hypothesizing that B cells expressing intrinsically autoreactive antibodies encoded by the VH4-34 heavy chain gene (VH4-34 cells) represent such a population, we tracked VH4-34 cells in healthy individuals. Here, we show that naive VH4-34 cells are positively selected and mostly restricted to the follicular mantle zone. Subsequently, these cells are largely excluded from the germinal centers and underrepresented in the memory compartment. In healthy donors but not in patients with systemic lupus erythematosus (SLE), these cells are prevented from differentiating into antibody-producing plasma cells. This blockade can be overcome ex vivo using cultures of naive and memory VH4-34 cells in the presence of CD70, IL-2, and IL-10. VH4-34 cells may therefore represent an experimentally useful surrogate for autoantibody transgenes and should prove valuable in studying human B cell tolerance in a physiological, polyclonal environment. Our initial results suggest that both positive and negative selection processes participate in the maintenance of tolerance in autoreactive human B cells at multiple checkpoints throughout B cell differentiation and that at least some censoring mechanisms are faulty in SLE.

Splenic T Zone Development Is B Cell Dependent

Article

Full-text available

Jan 2002

The factors regulating growth and patterning of the spleen are poorly defined. We demonstrate here that spleens from B cell-deficient mice have 10-fold reduced expression of the T zone chemokine, CCL21, a threefold reduction in T cell and dendritic cell (DC) numbers, and reduced expression of the T zone stromal marker, gp38. Using cell transfer and receptor blocking approaches, we provide evidence that B cells play a critical role in the early postnatal development of the splenic T zone. This process involves B cell expression of lymphotoxin (LT)alpha1beta2, a cytokine that is required for expression of CCL21 and gp38. Introduction of a B cell specific LTalpha transgene on to the LTalpha-deficient background restored splenic CCL21 and gp38 expression, DC numbers, and T zone size. This work also demonstrates that the role of B cells in T zone development is distinct from the effect of B cells on splenic T cell numbers, which does not require LTalpha1beta2. Therefore, B cells influence spleen T zone development by providing: (a) signals that promote T cell accumulation, and: (b) signals, including LTalpha1beta2, that promote stromal cell development and DC accumulation. Defects in these parameters may contribute to the immune defects associated with B cell deficiency in mice and humans.

Normal Induction but Attenuated Progression of Germinal Center Responses in BAFF and BAFF-R Signaling-Deficient Mice

Article

Full-text available

Nov 2003

The factors regulating germinal center (GC) B cell fate are poorly understood. Recent studies have defined a crucial role for the B cell-activating factor belonging to TNF family (BAFF; also called BLyS) in promoting primary B cell survival and development. A role for this cytokine in antigen-driven B cell responses has been suggested but current data in this regard are limited. A BAFF receptor expressed by B cells (BAFF-R/BR3) is defective in A/WySnJ mice which exhibit a phenotype similar to BAFF-deficient (BAFF-/-) animals. Here, we show that although GC responses can be efficiently induced in both A/WySnJ and BAFF-/- mice, these responses are not sustained. In BAFF-/- mice, this response is rapidly attenuated and accompanied by perturbed follicular dendritic cell development and immune complex trapping. In contrast, analysis of the A/WySnJ GC response revealed a B cell autonomous proliferative defect associated with reduced or undetectable Ki67 nuclear proliferation antigen expression by GC B cells at all stages of the response. These data demonstrate a multifaceted role for the BAFF pathway in regulating GC progression.

Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions

Article

Full-text available

Dec 2003

To determine the role of CD154-CD40 interactions in the B cell overactivity exhibited by patients with active systemic lupus erythematosus (SLE), CD19+ peripheral B cells were examined before and after treatment with humanized anti-CD154 mAb (BG9588, 5c8). Before treatment, SLE patients manifested activated B cells that expressed CD154, CD69, CD38, CD5, and CD27. Cells expressing CD38, CD5, or CD27 disappeared from the periphery during treatment with anti-CD154 mAb, and cells expressing CD69 and CD154 disappeared from the periphery during the post-treatment period. Before treatment, active-SLE patients had circulating CD38 (bright) Ig-secreting cells that were not found in normal individuals. Disappearance of this plasma cell subset during treatment was associated with decreases in anti-double-stranded DNA (anti-dsDNA) Ab levels, proteinuria, and SLE disease activity index. Consistent with this finding, peripheral B cells cultured in vitro spontaneously proliferated and secreted Ig in a manner that was inhibited by anti-CD154 mAb. Finally, the CD38(+/++)IgD(+), CD38(+++), and CD38(+)IgD(-) B cell subsets present in the peripheral blood also disappeared following treatment with humanized anti-CD154. Together, these results indicate that patients with active lupus nephritis exhibit abnormalities in the peripheral B cell compartment that are consistent with intensive germinal center activity, are driven via CD154-CD40 interactions, and may reflect or contribute to the propensity of these patients to produce autoantibodies.

BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells

Article

Full-text available

Feb 2004

Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this alpha-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor-immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA-/- mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.

Mechanism of Action of Transmembrane Activator and Calcium Modulator Ligand Interactor-Ig in Murine Systemic Lupus Erythematosus

Article

Full-text available

Oct 2004

B cell-activating factor belonging to the TNF family (BAFF) blockade prevents the onset of disease in systemic lupus erythematosus (SLE)-prone NZB/NZW F(1) mice. To determine the mechanism of this effect, we administered a short course of TACI-Ig with and without six doses of CTLA4-Ig to 18- to 20-wk-old NZB/NZW F(1) mice and evaluated the effect on B and T cell subsets and on anti-dsDNA Ab-producing B cells. Even a brief exposure to TACI-Ig had a beneficial effect on murine SLE; CTLA4-Ig potentiated this effect. The combination of TACI-Ig and CTLA4-Ig resulted in a temporary decrease in serum IgG levels. However, after cessation of treatment, high titers of IgG anti-dsDNA Abs appeared in the serum and IgG Abs deposited in the kidneys. Despite the appearance of pathogenic autoantibodies, the onset of proteinuria was markedly delayed; this was associated with prolonged depletion of B cells past the T1 stage, a decrease in the size of the spleen and lymph nodes, and a decrease in the absolute number of activated and memory CD4(+) T cells. TACI-Ig treatment normalized serum levels of IgM that are markedly elevated in NZB/W F(1) mice; this appeared to be due to a prolonged effect on the ability of the splenic microenvironment to support short-lived IgM plasma cells. Finally, a short course of combination TACI-Ig and CTLA4-Ig prolonged life and even reversed proteinuria in aged NZB/W F(1) mice, suggesting that BAFF blockade may be an effective therapeutic strategy for active SLE.

BLyS and APRIL in rheumatoid arthritis

Article

Full-text available

Dec 2005

The cytokines B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) enhance autoimmune disease by sustaining B cell activation. In RA, B cells contribute to the formation of 3 functionally distinct types of lymphoid microarchitectures in the inflamed synovium: ectopic GCs; T cell-B cell aggregates lacking GC reactions; and unorganized, diffuse infiltrates. We examined 72 tissues representing the 3 types of synovitis for BLyS and APRIL production and for expression of APRIL/BLyS receptors. Biologic effects of BLyS and APRIL were explored by treating human synovium-SCID mouse chimeras with the APRIL and BLyS decoy receptor transmembrane activator and CAML interactor:Fc (TACI:Fc). GC+ synovitis had the highest levels of APRIL, produced exclusively by CD83+ DCs. BLyS was present in similar levels in all tissue types and derived exclusively from CD68+ macrophages. In GC+ synovitis, treatment with TACI:Fc resulted in GC destruction and marked inhibition of IFN-gamma and Ig transcription. In contrast, inhibition of APRIL and BLyS in aggregate and diffuse synovitis left Ig levels unaffected and enhanced IFN-gamma production. These differential immunomodulatory effects correlated with the presence of TACI+ T cells in aggregate and diffuse synovitis and their absence in GC+ synovitis. We propose that BLyS and APRIL regulate B cell as well as T cell function and have pro- and antiinflammatory activities in RA.

Article

Full-text available

Apr 2006

B cells have multiple roles in immune activation and inflammation separate from their capacity to produce antibodies. B cell depletion is currently under intense investigation as a therapeutic strategy for autoimmune diseases. The TNF family members B cell-activating factor of the TNF family (BAFF) and its homolog A proliferation-inducing ligand (APRIL) are B cell survival and differentiation factors and are therefore rational therapeutic targets. We compared the effects of BAFF receptor-Ig, which blocks only BAFF, with those of transmembrane activator and calcium modulator ligand interactor-Ig, which blocks both BAFF and APRIL, in a murine SLE model. Both reagents prolonged the life of NZB/W F1 mice when given either before or after disease onset. Many immunologic effects of the 2 reagents were similar, including B cell and B cell subset depletion and prevention of the progressive T cell activation and dendritic cell accumulation that occurs with age in NZB/W mice without substantial effects on the emergence of the IgG anti-double-stranded DNA response. Furthermore, both reagents inhibited the T cell-independent marginal zone B cell response to particulate antigen delivered i.v., but not the B1 B cell response to the same antigen delivered i.p. In contrast, blockade of both BAFF and APRIL, but not blockade of BAFF alone, reduced the serum levels of IgM antibodies, decreased the frequency of plasma cells in the spleen, and inhibited the IgM response to a T cell-dependent antigen. The differences between selective and nonselective BAFF blockade are relevant to the choice of a BAFF blocking agent for the treatment of autoimmune and malignant diseases.

Chronic Administration of Belimumab, a BLyS Antagonist, Decreases Tissue and Peripheral Blood B-Lymphocyte Populations in Cynomolgus Monkeys: Pharmacokinetic, Pharmacodynamic, and Toxicologic Effects

Article

Full-text available

Jul 2006

The tolerability, pharmacodynamic effects, and pharmacokinetics of belimumab (LymphoStat-B) were evaluated in cynomolgus monkeys. Belimumab is a fully human IgG1lambda antibody directed against B-lymphocyte stimulator (BLyS) protein. BLyS is a TNF family member that supports B-lymphocyte maturation and survival and has been implicated in the pathogenesis of autoimmune diseases and B-lymphocyte malignancies. Belimumab was developed to antagonize BLyS activity in autoimmune diseases and B-lymphocyte malignancies, where undesirable effects of B-lymphocyte activity may cause or contribute to disease. Pharmacodynamic effects of belimumab were monitored by immunophenotyping of peripheral blood. Pathology end points, including tissue immunophenotyping, are described after 13 and 26 weeks of treatment and after a 34-week treatment-free (recovery) period. Belimumab was safe and well tolerated in repeat-dose toxicology studies at 5-50 mg/kg for up to 26 weeks. Monkeys exposed to belimumab had significant decreases in peripheral blood B lymphocytes by 13 weeks of exposure, continuing into the recovery period, despite total lymphocyte counts similar to the controls. There were concomitant decreases in spleen and lymph node B-lymphocyte representation after 13 or 26 weeks of treatment with belimumab. Microscopically, monkeys treated with belimumab for 13 or 26 weeks had decreases in the number and size of lymphoid follicles in the white pulp of the spleen. All findings were generally reversible within a 34-week recovery period. These data confirm the specific pharmacologic activity of belimumab in reducing B lymphocytes in the cynomolgus monkey. The favorable safety profile and lack of treatment-related infections also support continued clinical development of belimumab.

Paucity of Clinical Disease despite Serological Autoimmunity and Kidney Pathology in Lupus-Prone New Zealand Mixed 2328 Mice Deficient in BAFF

Article

Full-text available

Sep 2006

Constitutive overexpression of B cell-activating factor belonging to the TNF family (BAFF) promotes development of systemic lupus erythematosus (SLE), and treatment of SLE mice with BAFF antagonists ameliorates disease. To determine whether SLE can develop de novo in BAFF-deficient hosts, BAFF-deficient New Zealand Mixed (NZM) 2328 (NZM.Baff(-/-)) mice were generated. In NZM.Baff(-/-) mice, spleen B cells (including CD5(+) B1a and CD5(-) B1b B cells), germinal centers, Ig-secreting cells, and T cells were reduced in comparison to NZM.Baff(+/+) mice. Serum total Ig and autoantibody levels were reduced at 4-6 mo but approached wild-type levels with increasing age, indicating that autoreactive B cells can survive and secrete autoantibodies despite the complete absence of BAFF. At least some of these autoantibodies are nephrophilic in that glomerular deposition of total IgG and IgG1 (but not of IgG2a, IgG2b, or C3) was substantial in NZM.Baff(-/-) mice by 12-13 mo of age. Despite proliferative glomerulonephritis, highlighted by widespread glomerular hyaline thrombi, being common among NZM.Baff(-/-) mice by 6-7 mo of age, severe proteinuria and mortality were greatly attenuated. These results demonstrate that the lifelong absence of BAFF does not protect NZM 2328 mice from serological autoimmunity and renal pathology. Nevertheless, the character of the renal pathology is altered, and the mice are largely spared from clinically overt disease (severe proteinuria and premature death). These observations may have profound ramifications for the use of BAFF antagonists in human SLE and related diseases.

A New Population of Cells Lacking Expression of CD27 Represents a Notable Component of the B Cell Memory Compartment in Systemic Lupus Erythematosus

Article

Full-text available

Jun 2007

Human memory B cells comprise isotype-switched and nonswitched cells with both subsets displaying somatic hypermutation. In addition to somatic hypermutation, CD27 expression has also been considered a universal memory B cell marker. We describe a new population of memory B cells containing isotype-switched (IgG and IgA) and IgM-only cells and lacking expression of CD27 and IgD. These cells are present in peripheral blood and tonsils of healthy subjects and display a degree of hypermutation comparable to CD27+ nonswitched memory cells. As conventional memory cells, they proliferate in response to CpG DNA and fail to extrude rhodamine. In contrast to other recently described CD27-negative (CD27neg) memory B cells, they lack expression of FcRH4 and recirculate in the peripheral blood. Although CD27neg memory cells are relatively scarce in healthy subjects, they are substantially increased in systemic lupus erythematosus (SLE) patients in whom they frequently represent a large fraction of all memory B cells. Yet, their frequency is normal in patients with rheumatoid arthritis or chronic hepatitis C. In SLE, an increased frequency of CD27neg memory cells is significantly associated with higher disease activity index, a history of nephritis, and disease-specific autoantibodies (anti-dsDNA, anti-Smith (Sm), anti-ribonucleoprotein (RNP), and 9G4). These findings enhance our understanding of the B cell diversification pathways and provide mechanistic insight into the immunopathogenesis of SLE.

TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity

Article

Full-text available

Jun 2007

We formulate a two-phase paradigm of autoimmunity associated with systemic lupus erythematosus, the archetypal autoimmune disease. The initial Toll-like receptor (TLR)-independent phase is mediated by dendritic cell uptake of apoptotic cell debris and associated nucleic acids, whereas the subsequent TLR-dependent phase serves an amplification function and is mediated by uptake of TLR ligands derived from self-antigens (principally nucleic acids) complexed with autoantibodies. Both phases depend on elaboration of type I interferons (IFNs), and therapeutic interruption of induction or activity of these cytokines in predisposed individuals might have a substantial mitigating effect in lupus and other autoimmune diseases.

TLR Stimulation Modifies BLyS Receptor Expression in Follicular and Marginal Zone B Cells

Article

Full-text available

Jul 2007

Through their differential interactions with B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), the three BLyS family receptors play central roles in B cell survival and differentiation. Recent evidence indicates BLyS receptor levels shift following BCR ligation, suggesting that activation cues can alter overall BLyS receptor profiles and thus ligand sensitivity. In this study, we show that TLR stimuli also alter BLyS receptor expression, but in contrast to BCR ligation, TLR9 and TLR4 signals, preferentially increase transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI) expression. Although both of these TLRs act through MyD88-dependent mechanisms to increase TACI expression, they differ in terms of their downstream mediators and the B cell subset affected. Surprisingly, only TLR4 relies on c-Rel and p50 to augment TACI expression, whereas TLR9 does not. Furthermore, although all follicular and marginal zone B cells up-regulate TACI in response to TLR9 stimulation, only marginal zone B cells and a subset of follicular B cells respond to TLR4. Finally, we find that both BLyS and APRIL enhance viability among quiescent and BCR-stimulated B cells. However, although BLyS enhances viability among TLR stimulated B cells, APRIL does not, suggesting that TACI but not BLyS receptor 3 may share survival promoting pathways with TLRs.

BAFF and MyD88 signals promote a lupuslike disease independent of T cells

Article

Full-text available

Jul 2007
J EXP MED

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies. However, the underlying cause of disease appears to relate to defects in T cell tolerance or T cell help to B cells. Transgenic (Tg) mice overexpressing the cytokine B cell-activating factor of the tumor necrosis factor family (BAFF) develop an autoimmune disorder similar to SLE and show impaired B cell tolerance and altered T cell differentiation. We generated BAFF Tg mice that were completely deficient in T cells, and, surprisingly, these mice developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did, however, require B cell-intrinsic signals through the Toll-like receptor (TLR)-associated signaling adaptor MyD88, which controlled the production of proinflammatory autoantibody isotypes. TLR7/9 activation strongly up-regulated expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which is a receptor for BAFF involved in B cell responses to T cell-independent antigens. Moreover, BAFF enhanced TLR7/9 expression on B cells and TLR-mediated production of autoantibodies. Therefore, autoimmunity in BAFF Tg mice results from altered B cell tolerance, but requires TLR signaling and is independent of T cell help. It is possible that SLE patients with elevated levels of BAFF show a similar basis for disease.

Activated Renal Macrophages Are Markers of Disease Onset and Disease Remission in Lupus Nephritis

Article

Full-text available

Mar 2008

Costimulatory blockade with CTLA4Ig and anti-CD40L along with a single dose of cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F(1) mice. To understand the mechanisms for remission and for impending relapse, we examined the expression profiles of 61 inflammatory molecules in the perfused kidneys of treated mice and untreated mice at different stages of disease. Further studies using flow cytometry and immunohistochemistry allowed us to determine the cellular origins of several key markers. We show that only a limited set of inflammatory mediators is expressed in the kidney following glomerular immune complex deposition but before the onset of proteinuria. Formation of a lymphoid aggregate in the renal pelvis precedes the invasion of the kidney by inflammatory cells. Regulatory molecules are expressed early in the disease process and during remission but do not prevent the inevitable progression of active inflammation. Onset of proliferative glomerulonephritis and proteinuria is associated with activation of the renal endothelium, expression of chemokines that mediate glomerular cell infiltration, and infiltration by activated dendritic cells and macrophages that migrate to different topographical areas of the kidney but express a similar profile of inflammatory cytokines. Increasing interstitial infiltration by macrophages and progressive tubular damage, manifested by production of lipocalin-2, occur later in the disease process. Studies of treated mice identify a type II (M2b)-activated macrophage as a marker of remission induction and impending relapse and suggest that therapy for systemic lupus erythematosus nephritis should include strategies that prevent both activation of monocytes and their migration to the kidney.

Cutting edge: The dependence of plasma cells and independence of memory B cells on BAFF and APRIL

Article

Full-text available

Apr 2008

Memory B (B(MEM)) cells and long-lived bone marrow plasma cells (BM-PCs) persist within local environmental survival niches that afford cellular longevity. However, the factors supporting B(MEM) cell survival within the secondary lymphoid organs and allowing BM-PC persistence in the bone marrow remain poorly characterized. We report herein that long-lived B(MEM) cell survival and function are completely independent of BAFF (B cell-activating factor of the TNF family) or APRIL (a proliferation-inducing ligand). Thus, B(MEM) cells represent the only mature B2 lineage subset whose survival is independent of these ligands. We have previously shown that the TNFR family member receptor BCMA (B cell maturation Ag) is a critical survival receptor for BM-PC survival in vivo. We identify in this study the ligands critical for BM-PC survival and show that either BAFF or APRIL supports the survival of BM-PCs in vivo. These data define the BAFF/APRIL-dependent and -independent components of long-lived humoral immunity.

Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus

Article

Jan 1997
ARTHRIT RHEUM-ARTHR

M.C. Hochberg

Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis (Journal of Immunology (2008) 180 (1938-1947))

Article

Mar 2008

Splenic T Zone Development Is B Cell Dependent

Article

Dec 2001

Vu N. Ngo

The factors regulating growth and patterning of the spleen are poorly defined. We demonstrate here that spleens from B cell–deficient mice have 10-fold reduced expression of the T zone chemokine, CCL21, a threefold reduction in T cell and dendritic cell (DC) numbers, and reduced expression of the T zone stromal marker, gp38. Using cell transfer and receptor blocking approaches, we provide evidence that B cells play a critical role in the early postnatal development of the splenic T zone. This process involves B cell expression of lymphotoxin (LT)α1β2, a cytokine that is required for expression of CCL21 and gp38. Introduction of a B cell specific LTα transgene on to the LTα-deficient background restored splenic CCL21 and gp38 expression, DC numbers, and T zone size. This work also demonstrates that the role of B cells in T zone development is distinct from the effect of B cells on splenic T cell numbers, which does not require LTα1β2. Therefore, B cells influence spleen T zone development by providing: (a) signals that promote T cell accumulation, and: (b) signals, including LTα1β2, that promote stromal cell development and DC accumulation. Defects in these parameters may contribute to the immune defects associated with B cell deficiency in mice and humans.

Derivation of the SLEDAI. A disease activity index for lupus patients

Article

Jun 1992
ARTHRIT RHEUM-ARTHR

Objective. To standardize outcome measures in systemic lupus erythematosus (SLE). Three indices were identified which could adequately describe outcome (disease activity, damage from disease, and health status); we describe here the development of the Disease Activity Index. Methods. Twenty-four variables were identified as important factors in a disease activity index. These were used to generate 574 patient profiles, which were rated on a disease activity scale of 0–10 by 14 rheumatologists. A second rating of 10 of the profiles yielded scores that were not significantly different from the first, indicating that experienced clinicians can reliably make global estimates of disease activity. Multiple regression models were used to estimate the relative importance of the 24 clinical variables in the physicians' global rating of disease activity. These were estimated on a ‘training set’ of 75% of physicians' ratings, and then validated on a ‘testing set,’ consisting of the remaining 25% of physicians' ratings. Results. The explanatory power of the models in the training set was high (R2 = 0.93). The models' regression coefficients for the organ systems were simplified for easier use in clinical practice. This generated a ‘weighted’ index of 9 organ systems for disease activity in SLE, the SLEDAI, as follows: 8 for central nervous system and vascular, 4 for renal and musculoskeletal, 2 for serosal, dermal, immunologic, and 1 for constitutional and hematologic. The maximum theoretical score is 105, but in practice, few patients have scores greater than 45. The SLEDAI predicted well the physicians' ratings in the testing set (Pearson's correlation coefficients = 0.64–0.79). Conclusion. The SLEDAI is a validated model of experienced clinicians' global assessments of disease activity in lupus. It represents the consensus of a group of experts in the field of lupus research.

Update of the American College of Rheumatology Revised Criteria for Classification of Systemic Lupus Erythematosus

Article

Sep 1997
ARTHRIT RHEUM-ARTHR

Marc C Hochberg

A Phase II, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Belimumab in Patients With Active Systemic Lupus Erythematosus

Article

Sep 2009

To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE). Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score >/=4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52-week study. Coprimary end points were the percent change in the SELENA-SLEDAI score at week 24 and the time to first SLE flare. Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA-SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24-52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer >/=1:80 and/or anti-double-stranded DNA [anti-dsDNA] >/=30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA-SLEDAI score (-28.8% versus -14.2%; P = 0.0435), physician's global assessment (-32.7% versus -10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63-71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti-dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups. Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

Human B cell memory

Article

Jul 2009

Following an immune response two types of differentiated B cells persist in the memory pool: plasma cells, which confer immediate protection by the secretion of specific antibodies; and memory B cells, which confer rapid and enhanced response to secondary challenge. We will review recent advances in understanding the heterogeneity, dynamics, and persistence of human memory B cells and plasma cells as well as new methods to isolate human monoclonal antibodies. These findings offer new insights into the human B cell response, which are relevant for vaccination and therapeutic intervention.

Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis

Article

Oct 2008
P NATL ACAD SCI USA

Rheumatoid arthritis (RA) is a chronic disease characterized by synovial inflammation and joint damage. Although both T cells and B cells mediate the disease pathogenesis, proinflammatory cytokines are critically involved. The TNF superfamily member B cell-activating factor (BAFF) plays an important role in humoral immunity and in autoimmune diseases, including RA. Here, we show that intra-articular injection of lentivirus expressing shRNA for BAFF gene silencing provides long-term suppression of arthritic development in a collagen-induced arthritis model. Local BAFF gene targeting inhibited proinflammatory cytokine expression, suppressed generation of plasma cells and Th17 cells, and markedly ameliorated joint pathology. Lentivirus targets dendritic cells in the joint tissue and BAFF gene silencing inhibits dendritic cell maturation and their function in driving Th17-cell differentiation in vitro. Moreover, we revealed a previously unrecognized role for BAFF in promoting the expansion of Th17 cells and demonstrated IL-17 as a crucial effector cytokine for BAFF-mediated proinflammatory effects during collagen-induced arthritis development. Taken together, these findings identify BAFF as a valuable gene-silencing target potentially for the effective treatment of RA.

Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE

Article

Jul 1992

To standardize outcome measures in systemic lupus erythematosus (SLE). Three indices were identified which could adequately describe outcome (disease activity, damage from disease, and health status); we describe here the development of the Disease Activity Index. Twenty-four variables were identified as important factors in a disease activity index. These were used to generate 574 patient profiles, which were rated on a disease activity scale of 0-10 by 14 rheumatologists. A second rating of 10 of the profiles yielded scores that were not significantly different from the first, indicating that experienced clinicians can reliably make global estimates of disease activity. Multiple regression models were used to estimate the relative importance of the 24 clinical variables in the physicians' global rating of disease activity. These were estimated on a "training set" of 75% of physicians' ratings, and then validated on a "testing set," consisting of the remaining 25% of physicians' ratings. The explanatory power of the models in the training set was high (R2 = 0.93). The models' regression coefficients for the organ systems were simplified for easier use in clinical practice. This generated a "weighted" index of 9 organ systems for disease activity in SLE, the SLEDAI, as follows: 8 for central nervous system and vascular, 4 for renal and musculoskeletal, 2 for serosal, dermal, immunologic, and 1 for constitutional and hematologic. The maximum theoretical score is 105, but in practice, few patients have scores greater than 45. The SLEDAI predicted well the physicians' ratings in the testing set (Pearson's correlation coefficients = 0.64-0.79). The SLEDAI is a validated model of experienced clinicians' global assessments of disease activity in lupus. It represents the consensus of a group of experts in the field of lupus research.

Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus

Article

Oct 1997

Marc C Hochberg

TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease

Article

May 2000

B cells are important in the development of autoimmune disorders by mechanisms involving dysregulated polyclonal B-cell activation, production of pathogenic antibodies, and co-stimulation of autoreactive T cells. zTNF4 (BLyS, BAFF, TALL-1, THANK) is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo. Here we identify two receptors for zTNF4 and demonstrate a relationship between zTNF4 and autoimmune disease. Transgenic animals overexpressing zTNF4 in lymphoid cells develop symptoms characteristic of systemic lupus erythaematosus (SLE) and expand a rare population of splenic B-Ia lymphocytes. In addition, circulating zTNF4 is more abundant in NZBWF1 and MRL-lpr/lpr mice during the onset and progression of SLE. We have identified two TNF receptor family members, TACI and BCMA, that bind zTNF4. Treatment of NZBWF1 mice with soluble TACI-Ig fusion protein inhibits the development of proteinuria and prolongs survival of the animals. These findings demonstrate the involvement of zTNF4 and its receptors in the development of SLE and identify TACI-Ig as a promising treatment of autoimmune disease in humans.

Effect of long-term belimumab treatment on B cells in systemic lupus erythematosus: Extension of a phase II, double-blind, placebo-controlled, dose-ranging study

Abstract

No full-text available