A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis.

BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.

A 6-month open-label extension study of the safety and efficacy of subcutaneous belimumab in patients with systemic lupus erythematosus.

Objective To evaluate the safety, tolerability and efficacy of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE) beyond 1 year. Methods This was a 24-week, open-label extension following a 52-week, double-blind, placebo-controlled trial of belimumab SC. Patients who completed the double-blind phase were eligible to enter the open-label phase. All patients received weekly belimumab 200 mg SC plus standard SLE therapy. Outcome measures included safety and efficacy (SLE Response Index (SRI) and SLE Flare Index (SFI) rates), and changes in biomarker and B cell levels. Results Of 677 patients who completed the 52-week, double-blind phase, 662 entered the open-label phase; 206 had previously received placebo and 456 had previously received belimumab. Despite differences in total belimumab exposure (24 weeks in the placebo-to-belimumab group versus 76 weeks in the belimumab group), the proportions of patients experiencing more than one adverse event (AE) or a serious AE in the open-label phase were similar between groups (placebo-to-belimumab: 51.5 and 6.8%; belimumab: 48.2 and 5.5%, respectively). Most AEs were mild/moderate in severity. Efficacy was maintained through the extension phase. An SRI response was achieved by 16.1% of patients in the placebo-to-belimumab group and 76.3% patients in the belimumab group. Furthermore, 1.0% of patients in the placebo-to-belimumab group and 2.6% of patients in the belimumab group experienced a severe SFI flare. Conclusion Belimumab SC was well tolerated and efficacy was maintained during the extension phase of this study. The safety profile of belimumab SC is consistent with that of previous experience with belimumab. Trial registration ClinicalTrials.gov identifier: NCT01484496.

HIV Nef promotes expression of B-lymphocyte stimulator by blood dendritic cells during HIV infection in humans.

Dendritic cells (DCs) modulate B-cell survival and differentiation, mainly through production of growth factors such as B lymphocyte stimulator (BLyS; also known as "B-cell factor belonging to the tumor necrosis factor family" [BAFF]). We have recently shown that, in human immunodeficiency virus (HIV)-infected individuals with rapid and those with classic disease progression, B-cell dysregulations were associated with increased BLyS expression in plasma and by blood myeloid DCs (mDCs), in contrast to aviremic HIV-infected individuals with slow disease progression (also known as "elite controllers"). In previous work with transgenic mice expressing HIV genes, B-cell dysregulations were concomitant with altered mDCs and dependent on HIV negative factor (Nef). We now report that HIV Nef is detected early after infection and despite successful therapy in plasma and BLyS-overexpressing blood mDCs of HIV-infected rapid and classic progressors, whereas it is low to undetectable in aviremic slow progressors. In vitro, HIV Nef drives monocyte-derived DCs toward BLyS overexpression through a process involving STAT1. Importantly, this is counteracted in the presence of all-trans retinoic acid. Nef thus contributes to high BLyS proinflammatory profiles in HIV-infected individuals.

Activation of LXR attenuates collagen-induced arthritis via suppressing BLyS production.

B-lymphocyte stimulator (BLyS) plays a critical role in the pathogenesis and progression of rheumatoid arthritis (RA). Liver X receptor (LXR), a nuclear receptor, has an important anti-inflammatory effect. However, it is unclear whether the BLyS expression is regulated by LXR. In this study, we found that treatment with LXR agonist in collagen-induced arthritis (CIA) mice significantly attenuated arthritis progression, and markedly decreased BLyS production in serum and splenocytes as well as the production of serum IFNγ and TGFß. Activation of LXR in B lymphocytes dramatically suppressed the basal and IFNγ/TGFß-induced BLyS expression. Moreover, LXR agonist prominently suppressed the binding of NF-κB to BLyS promoter region, and decreased the promoter's transcriptional activity. Additionally, activation of LXR obviously repressed IFNγ-induced STAT1 activation and TGFß-induced SMAD3 activation. These results indicated that downregulation of BLyS may be a novel mechanism by which LXR ameliorates RA, and LXR/BLyS pathway may serve as a novel target for the treatment of RA.

Blockade of BLyS inhibits B-cell responses and antibody production for the prevention of chronic transplant rejection.

BACKGROUND: Chronic rejection, closely related to the activation of B cells and donor-specific antibody (DSA) production, has unsatisfactory therapeutic outcomes. B lymphocyte stimulator (BLyS) is a major regulatory factor that controls the activation and differentiation of B cells. However, it remains unclear whether BLyS blockade can regulate B and plasma cells in the transplantation setting and affect chronic rejection. Here, we investigated the efficacy of the BLyS inhibitors belimumab and telitacicept in controlling B-cell response and preventing chronic rejection. METHODS: The effects of belimumab and telitacicept on B-cell activation, differentiation, and antibody production in vitro were determined. A chronic rejection model in mouse was established by allogeneic cardiac transplantation with CTLA4-Ig treatment. Allograft survival, histology, DSA levels, and B-cell responses were analyzed to evaluate the chronic rejection-preventive effects of belimumab and telitacicept. RESULTS: In vitro experiments confirmed that belimumab and telitacicept inhibited B-cell activation and differentiation and reduced antibody production. In vivo experiments indicated that they significantly prolonged allograft survival, attenuated chronic rejection through significant suppression of myocardial ischemic necrosis and interstitial fibrosis, and reduced DSA-IgG levels, C4d deposition, and inflammatory cell infiltration. Furthermore, the frequencies of B cells, plasma cells, and IgG-producing cells in the recipients' spleen, lymph nodes, bone marrow, and blood were decreased after BLyS inhibitors treatment. CONCLUSIONS: This study demonstrated that belimumab and telitacicept inhibit B-cell responses and antibody production and alleviate chronic transplant rejection. Therefore, BLyS inhibitors are expected to be used for the prevention of chronic rejection in clinical practice.

B cell pathway dual inhibition for systemic lupus erythematosus: a prospective single-arm cohort study of telitacicept.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with B-cell hyperactivity. Telitacicept is a transmembrane activator, calcium modulator, and cyclophilin ligand interactor-Fc fusion protein, which can neutralize both B-cell lymphocyte stimulator and a proliferation-inducing ligand. Patients with active SLE who received telitacicept were prospectively followed at month 1, 3, 6, 9, and 12 after telitacicept initiation. Thirty-seven participants were involved and followed for 6.00 [3.00, 6.00] months. SRI-4 rate at month 6 was 44.7%. The median dosage of prednisone was decreased by 43.8% (from 10 to 5.62 mg/d) at month 6. The anti-dsDNA level was significantly decreased, while complement levels were significantly increased at month 6 from baseline. Continuously significant reductions in serum immunoglobin (Ig)G IgA, and IgM levels were also observed. Patients experienced significant decreases in the numbers of total and naive B cells, whereas memory B cells and T cell populations did not change. The number of NK cells was significantly increased during the follow-up. At month 6, 58.3% (14 out of 24) patients experienced improved fatigue accessed by FACIT-Fatigue score exceeding the minimum clinically important difference of 4. Most adverse events were mild, but one each case of severe hypogammaglobulinemia, psychosis with suicidal behavior, and B-cell lymphoma were occurred. In our first prospective real-world study, telitacicept treatment led to a significant clinical and laboratory improvement of disease activity, as well as fatigue amelioration in patients with SLE. Safety profile was favorable overall, but more studies are greatly needed.

Reprint of: B cell elimination in systemic lupus erythematosus. Clin. Immunol. 146(2) 90-103.

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution, potentially life-threatening with considerable morbidity. The elimination of pathogenic B cells has emerged as a rational therapeutic option. Many open label studies have reported encouraging results in which clinical and serological remission have invariably been described, often enabling the reduction of steroid and immunosuppressive treatment. However, the results from randomized controlled studies have been disappointing and several questions remain to be answered. In this review we will focus on results of B cell direct depletion in the treatment of patients with systemic lupus erythematosus.

Elevated B lymphocyte stimulator levels are associated with increased damage in an Irish systemic lupus erythematosus cohort.

OBJECTIVE: The overall aim of this study is to identify clinical and serological features that are associated with B lymphocyte stimulator (BLyS) elevation in a homogeneous Caucasian SLE population and thereby identify patients who are most likely to benefit from BLyS blockade. METHODS: Patients with SLE (as per ACR criteria) were recruited. Clinical history, disease activity measures and laboratory measures of disease were recorded. BLyS levels were determined by ELISA. RESULTS: BLyS elevation was defined as being higher than the 95th percentile of BLyS levels measured in controls. Patients were divided into two groups: those with elevated BLyS levels (group 1, n = 23) and those with normal BLyS levels (group 2, n = 22). Elevated BLyS levels were significantly associated with patients of younger age and shorter disease duration. In keeping with previous reports, patients with elevated BLyS levels had more active disease (SLEDAI 5.1 vs 0.86, P < 0.001); however, our analysis also demonstrates that BLyS elevation was significantly associated with increased organ damage at 5-year follow-up [Systemic Lupus International Collaborating Clinics/ACR Damage Index (SLICC/ACR DI) 0.53 vs 0.13, P = 0.012]. Furthermore, the presence of Sm autoantibody significantly predicted elevated BLyS levels in a Caucasian population. BLyS levels were significantly higher in those with musculoskeletal involvement, malar rash, renal disease and evidence of immunological activity. CONCLUSION: BLyS blockade may be most beneficial if introduced early in the course of disease in young Caucasian patients presenting with renal, musculoskeletal and skin disease in an effort to reduce long-term damage.

A Systemic Lupus Erythematosus Patient with Cutaneous Mycobacterium haemophilum Infection under Belimumab Treatment: A Case Report.

A 38-year-old female with systemic lupus erythematosus (SLE) initiated belimumab treatment. One month later, she presented with a reddish painful swelling on her right lower leg. She was treated with ceftriaxone and vancomycin. However, novel erythematous papules and indurated nodules appeared on both her lower legs. Skin biopsy revealed microabscess formation with mixed cell granuloma surrounded by inflammatory cell infiltration within the dermis with subcutaneous fat tissue. A large number of acid-fast bacilli were observed with Ziehl-Neelsen staining. DNA sequencing of both the hsp65 and the 16S rRNA sequences showed a 100% match with the corresponding region of Mycobacterium haemophilum. Mycobacterial culture revealed satellite growth enhancement on Middlebrook 7H11 agar plates around a paper strip containing hemin. She was treated with levofloxacin, rifabutin, and ethambutol. Within 13 months, her cutaneous lesions improved markedly without any side effects. The B cell-targeted biologic belimumab, a fully humanized IgG1γ monoclonal antibody that inactivates B lymphocyte stimulator, has been considered to be beneficial for active SLE. However, this therapy could increase the risk for the development of biologic therapy-associated mycobacterial infections, both tuberculosis and nontuberculous mycobacteria infections.

Belimumab Decreases Autophagy and Citrullination in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus.

Belimumab (BLM) is a B lymphocyte stimulator (BLyS) inhibitor approved for the treatment of systemic lupus erythematosus (SLE). Autophagy is a cell survival mechanism involved in the pathogenesis of SLE. Citrullination is a post-translational modification catalyzed by peptidylarginine deiminase (PAD) enzymes. Autophagy and citrullination may generate neoepitopes, evoking an autoimmune response. No previous studies have investigated the connection of these processes, and how BLM could affect them, in SLE. Ex vivo autophagy and protein citrullination were analyzed by western blot in lysates from 26 SLE patients' PBMCs at baseline and after 2, 4, and 12 weeks of BLM administration, and from 16 healthy donors' PBMCs. Autophagic PBMCs were identified by the immunofluorescent detection of the autophagy-associated proteins LC3B (LC3 puncta) and LAMP-1. Autophagosome accumulation was evaluated in CD14- (PBLs) and CD14+ (monocytes) SLE cells. The presence of the BLyS receptors BAFF-R, BCMA, and TACI on SLE CD4+, CD8+ T cells and monocytes, as well as serum IL-18 levels, was also assessed. Following BLM administration, we observed a decrease in autophagy and citrullination, with a lowering of LC3-II, citrullinated vimentin, and PAD4 expression levels in PBMCs from SLE patients. LC3-II levels showed a correlation with the SLE Disease Activity Index 2000 (SLEDAI-2K) after 12 weeks of therapy. The LC3B/LAMP-1 analysis confirmed the reduction in autophagy. A lesser autophagosome accumulation occurred in PBLs and monocytes which, in turn, seemed to be the main cellular populations contributing to autophagy. A reduction in patients' serum IL-18 concentrations occurred. CD4+ and CD8+ cells weakly expressed BAFF receptors; monocytes expressed only BAFF-R. BLM could impact on autophagy and citrullination, offering an opportunity for a deeper understanding of these mechanisms in SLE, and a possible tool for the clinical management of SLE.

SARS-Cov2 acute and post-active infection in the context of autoimmune and chronic inflammatory diseases.

The clinical and immunological spectrum of acute and post-active COVID-19 syndrome overlaps with criteria used to characterize autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Indeed, following SARS-Cov2 infection, the innate immune response is altered with an initial delayed production of interferon type I (IFN-I), while the NF-kappa B and inflammasome pathways are activated. In lung and digestive tissues, an alternative and extrafollicular immune response against SARS-Cov2 takes place with, consequently, an altered humoral and memory T cell response leading to breakdown of tolerance with the emergence of autoantibodies. However, the risk of developing severe COVID-19 among SLE and RA patients did not exceed the general population except in those having pre-existing neutralizing autoantibodies against IFN-I. Treatment discontinuation rather than COVID-19 infection or vaccination increases the risk of developing flares. Last but not least, a limited number of case reports of individuals having developed SLE or RA following COVID-19 infection/vaccination have been reported. Altogether, the SARS-Cov2 pandemic represents an unique opportunity to investigate the dangerous interplay between the immune response against infectious agents and autoimmunity, and to better understand the triggering role of infection as a risk factor in autoimmune and chronic inflammatory disease development.

The role of baseline BLyS levels and type 1 interferon-inducible gene signature status in determining belimumab response in systemic lupus erythematosus: a post hoc meta-analysis.

BACKGROUND: Elevated B lymphocyte stimulator (BLyS) levels in patients with systemic lupus erythematosus (SLE) correlate positively with disease activity; BLyS expression is directly linked to interferon (IFN) pathway activation. This post hoc meta-analysis of BLISS-52 and BLISS-76 explored the relationship between baseline BLyS mRNA/protein levels and/or type 1 IFN-inducible gene signature (IFN-1) and responses to the BLyS-targeting monoclonal antibody belimumab in SLE. METHODS: In BLISS-52 and BLISS-76, patients with autoantibody-positive SLE and a SELENA-SLEDAI score ≥ 6 and receiving stable standard SLE therapy were randomised to intravenous belimumab 10 mg/kg or placebo, plus standard of care (SoC), for 52 or 76 weeks. For this post hoc meta-analysis, patients with an appropriate mRNA sample were stratified by BLyS mRNA expression (tertiles: high/medium/low; revised quantiles: high/low), IFN-1 mRNA expression (high/low) and BLyS protein level (high/low). Co-primary endpoints were correlation between baseline BLyS and IFN-1 mRNA levels and SLE Responder Index (SRI)4 response at week 52 within BLyS/IFN-1 subgroups. Secondary endpoints included time to first severe SELENA-SLEDAI Flare Index (SFI) flare. RESULTS: Of 554 patients included in this analysis, 281 had received belimumab and 273 had received placebo. Baseline BLyS and IFN-1 mRNA levels were highly correlated (Spearman's rank correlation coefficient 0.7799; 95% confidence interval [CI] 0.7451, 0.8106; p < 0.0001). The proportion of SRI4 responders was higher with belimumab versus placebo in all subgroups, but the difference reached statistical significance in the medium BLyS mRNA tertile (odds ratio [OR] 2.17; 95% CI 1.16, 4.04; p = 0.0153), high BLyS mRNA quantile (OR 1.58; 95% CI 1.02, 2.44; p = 0.0402), high IFN-1 mRNA (OR 1.58; 95% CI: 1.08, 2.31; p = 0.0186) and high BLyS protein (OR 3.57; 95% CI 1.63, 7.83; p = 0.0015) subgroups only. The risk of severe SFI flare was significantly lower with belimumab than placebo in the high BLyS mRNA quantile (hazard ratio [HR] 0.59; 95% CI 0.36, 0.97; p = 0.0371) and high BLyS protein (HR 0.39; 95% CI 0.19, 0.79; p = 0.0090) subgroups. CONCLUSIONS: This post hoc meta-analysis demonstrated a tendency towards improved response to add-on intravenous belimumab 10 mg/kg versus SoC alone in patients with high baseline BLyS protein and IFN-1 mRNA levels and medium/high BLyS mRNA levels.

Curcumin attenuates lupus nephritis in MRL/lpr mice by suppressing macrophage-secreted B cell activating factor (BAFF).

This study aimed to investigate the therapeutic effects and mechanism of action of curcumin against a MRL/lpr lupus model. Eight-week-old female MRL/lpr mice were used to establish the lupus nephritis model. Histologic and immunohistochemical analysis was conducted for lupus nephritis. Anti-dsDNA IgG and BAFF level were detected by ELISA. Cells directly isolated from the spleen were used to detect macrophage subsets and activation status by FACS. Curcumin reduced the total IgG and anti-dsDNA IgG levels in blood and reduced the activation of B cells in MRL/lpr mice. Moreover, curcumin prevented activation of macrophages in MRL/lpr mice. Levels of BAFF in serum, spleens and kidneys were also reduced in curcumin-treated MRL/lpr mice. In vitro experiments showed that curcumin reduced the activation of macrophage and leaded to the decrease of BAFF from them upon toll like receptor (TLR) 4 stimulation. Curcumin attenuates lupus nephritis in MRL/lpr mice by inhibiting macrophages activation and their secreting BAFF, which may be a potential therapeutic candidate for the treatment of SLE.

Exploring the Possible Prognostic Role of B-Lymphocyte Stimulator (BLyS) in a Large Series of Patients with Neuroendocrine Tumors.

BACKGROUND AND OBJECTIVE: BLyS (B-Lymphocyte stimulator) is over-expressed in several tumoral settings, with direct or indirect effects on neoplastic proliferation and possibly representing a therapeutic target. In this study, we explored the role of BLyS in a large population of patients with neuroendocrine tumors (NETs). METHODS: The study analyzed the stored sera of 124 consecutive unselected patients with NETs: 36 lung carcinoids (24 typical, 12 atypical), 47 gastroenteric tract and 41 pancreatic (30 non-functioning and 11 functioning: 9 insulinomas, 2 glucagonomas). In 23 cases, BLyS was repeatedly assessed during the follow-up and the disease was monitored (progression, stabilization or remission) according to the RECIST criteria. Patients were compared to 92 age and sex-matched blood donors (BDs). Serum levels of BLyS and Chromogranin A (CgA) were analyzed by ELISA. RESULTS: NET patients showed significantly higher BLyS levels than BDs (1274±809 pg/ml vs. 587±173 pg/ml; p<0.0001). BLyS correlated weakly with CgA (r=0.19 and p=0.035) but did not correlate with Ki67, grading, metastasis, histological type and site. In patients with sustained remission after surgery, BLyS and CgA both showed a gradual reduction over time. Patients with progressing disease showed higher BLyS levels compared to stable patients (1524±694 pg/ml vs. 1168± 373 pg/ml; p= 0.033). BLyS serum levels remained stable in remission and therapy-controlled patients, while increased in the follow-up of progressing cases. CONCLUSION: Higher BLyS levels identify patients with a more severe disease, characterized by progression despite treatments, possibly representing a factor implicated in the proliferation of the neoplastic cells or in sustaining the neoplastic environment.

Belimumab in the management of systemic lupus erythematosus - an update.

INTRODUCTION: Belimumab is a fully humanised mAb against B lymphocyte stimulator (B-LyS). It is the first biological drug licensed and approved by the US FDA and the European Medicines Agency (EMA) for use in combination with standard immunosuppressants in autoantibody-positive systemic lupus erythematosus (SLE). Areas covered: This manuscript evalues the recent data concerning belimumab's safety and clinical effectiveness and its current place in the treatment of SLE. This includes an overview of the recent data coming from the post-hoc analyses of the BLISS trials, real-life experience with belimumab and the accumulating data on its safety. Attention is also paid to the progress made in the identification of predictors of response to belimumab, recent phase I/II/III studies with subcutaneous belimumab, and experience with B cell modulation coming from recent trials with other B cell modulating drugs. Expert opinion: Belimumab currently has its established role in the treatment of patients with SLE with serologic activity and clinical activity namely in mucocutaneous and musculoskeletal domains despite standard of care treatment. Better identification of patients who can benefit from treatment with belimumab is warranted. Data from ongoing studies in lupus nephritis and other data from observational studies are eagerly awaited.

Glucocorticoid-induced leucine zipper expression is associated with response to treatment and immunoregulation in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disorder in which cytokine balance is disturbed. Glucocorticoids (GCs) are shown to balance immune response by transcriptional regulation of glucocorticoid receptor target genes such as Glucocorticoid-induced leucine zipper (GILZ) which has been introduced as an endogenous anti-inflammatory mediator. In the present study, we assessed the expression of GILZ in association with interferon-γ (IFN-γ), interleukine-10 (IL-10), and B lymphocyte stimulator (BLyS) plasma levels in SLE patients. A total of 40 female patients (18 under treatment and 22 newly diagnosed) were recruited in this study. Real-time RT PCR was conducted to quantify the mRNA expression of GILZ. The plasma levels of IFN-γ, IL-10, and BLyS were evaluated using ELISA method. GILZ was overexpressed among under treatment SLE patients. The mRNA expression of GILZ was significantly correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. IFN-γ and BLyS were downregulated in response to therapies with negative correlations to GILZ. Moreover, IL-10 was upregulated among treated patients. The levels of IFN-γ and BLyS were correlated with the severity of disease, while IL-10 was negatively correlated with SLEDAI score. GILZ could be introduced as one of the acting molecules in mediating the regulatory effects of GCs on producing pro- and anti-inflammatory cytokines in SLE.

Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children.

Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in less than 10-20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function. In this study, a total of 38 vertically transmitted HIV-1 infected antiretroviral therapy (ART) naïve children and 25 seronegative controls were recruited. Based on the CD4 counts and years post-infection, infected children were categorized as long-term non-progressors (LTNPs) (n = 20) and progressors (n = 18). Eight of these progressors were followed up at 6-12 months post-ART. Percentages (%) of DCs, B cell subsets, and expression of BLyS on DCs were analyzed by flow-cytometry. Plasma levels of B cell growth factors were measured by ELISA and viral neutralization activity was determined using TZM-bl assay. Lower (%) of myeloid DCs (mDCs), plasmacytoid DCs, and high expression of BLyS on mDCs were observed in HIV-1 infected progressors than seronegative controls. Progressors showed lower % of naive B cells, resting memory B cells and higher % of mature activated, tissue-like memory B cells as compared to seronegative controls. Higher plasma levels of IL-4, IL-6, IL-10, and IgA were observed in progressors vs. seronegative controls. Plasma levels of IgG were high in progressors and in LTNPs than seronegative controls, suggesting persistence of hypergammaglobulinemia at all stages of disease. High plasma levels of BLyS in progressors positively correlated with poor viral neutralizing activity. Interestingly on follow up, treatment naïve progressors, post-ART showed increase in resting memory B cells along with reduction in plasma BLyS levels that correlated with improvement in viral neutralization. This is the first study to demonstrate that reduction in plasma BLyS levels correlates with restoration of B cell function, in terms of viral neutralization in HIV-1-infected children.

Belimumab in Systemic Lupus Erythematosus.

Belimumab is the only approved biological agent for the treatment of systemic lupus erythematosus (SLE). It is a fully humanized IgG1γ monoclonal antibody directed against soluble B lymphocyte stimulator (BLyS). It is indicated as an add-on therapy for the treatment of adult patients with active, autoantibody-positive SLE, who are receiving standard therapy. Belimumab is generally well-tolerated, common adverse effects include infections, infusion reactions, hypersensitivity, headache, nausea, and fatigue. Psychiatric events including suicidal tendency, progressive multifocal leukoencephalopathy and malignancies too have been reported. Apart from SLE, the drug is also being tried for other autoimmune disorders.

Efficacy, pharmacokinetic and pharmacodynamic profile of belimumab for systemic lupus erythematosus.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a severe autoimmune disease and a sizeable proportion of patients remain refractory to currently available immunosuppressive agents. The burden of uncontrolled disease is significant as disease flare and persistent inflammation lead to long-term damage accrual and increased morbidity. Belimumab , a humanized monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), is the first drug to be approved by the US FDA for the treatment of SLE in 50 years. AREAS COVERED: In this review, we provide an overview of novel therapeutic agents under development for the treatment of SLE, a description of the pharmacodynamic and pharmacokinetic properties of belimumab, evidence of efficacy of belimumab as demonstrated in clinical trials, safety and tolerability data and a summary of ongoing clinical trials of belimumab in SLE. This information was amassed following a comprehensive MEDLINE and Cochrane library search. Ongoing clinical trial information was obtained from ClinicalTrials.gov. EXPERT OPINION: Two, large Phase III trials have demonstrated the clinical efficacy of belimumab in musculoskeletal, mucocutaneous, haematologic and constitutional features of SLE. Patients with severe disease manifestations such as lupus nephritis and CNS disease were excluded from these trials and hence the role of belimumab in the overall management of SLE has yet to be established. Studies in lupus nephritis are ongoing.