Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE

Dooley, MA; Houssiau, Frédéric; Aranow, Cynthia; D’Cruz, D; Askanase, Anca; Roth, D.; Zhong, Z. John; Cooper, Simon; Freimuth, Ww; Ginzler, EM

doi:10.1177/0961203312465781

Cited by 253 publications

(177 citation statements)

References 21 publications

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“…Increased BAFF levels have been suggested to play a role in both SLE and pSS (8,9). Indeed, because of the increased BAFF levels in serum of SLE and pSS patients, biologics have been developed to block BAFF (10,11). BAFF blockade using a human anti-BAFF mAb (belimumab) is the first U.S. Food and Drug Administration-approved treatment of SLE using a biologic (12); in addition, promising phase II clinical trials are completed for belimumab in pSS (11).…”

mentioning

confidence: 99%

The Expression of BAFF Is Controlled by IRF Transcription Factors

Sjöstrand

Johansson

Aqrawi

et al. 2016

The Journal of Immunology

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Patients with systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) are typically characterized by the presence of autoantibodies and an IFN-signature. The strength of the IFN-signature positively correlates with disease severity, suggesting that type I IFNs are active players in these diseases. BAFF is a cytokine critical for development and proper selection of B cells, and the targeting of BAFF has emerged as a successful treatment strategy of SLE. Previous reports have suggested that BAFF expression is directly induced by type I IFNs, but the precise mechanism for this remains unknown. In this article, we demonstrate that BAFF is a bona fide ISG and that IFN regulatory factors (IRFs) control the expression of BAFF. We identify IRF1 and IRF2 as positive regulators of BAFF transcription and IRF4 and IRF8 as potent repressors; in addition, we have mapped the precise binding site for these factors in the BAFF promoter. IFN-β injections induced BAFF expression mainly in neutrophils and monocytes, and BAFF expression in neutrophils from pSS patients strongly correlated with the strength of the IFN-signature. In summary, we show that BAFF expression is directly induced by type I IFNs via IRF1 and IRF2, whereas IRF4 and IRF8 are negative regulators of BAFF expression. These data suggest that type I IFN blockade in SLE and pSS patients will lead to downregulation of BAFF and a consequential reduction of autoreactive B cell clones and autoantibodies.

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mentioning

confidence: 99%

The Expression of BAFF Is Controlled by IRF Transcription Factors

Sjöstrand

Johansson

Aqrawi

et al. 2016

The Journal of Immunology

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“…Patients more likely to respond receiving standard of care therapy were those with highly serologically active disease (low C/anti-dsDNA+) at baseline. The relative rate of any improvement with belimumab 10 mg/kg versus placebo was 12.8% (OR 1.69) in the low complement/anti-dsDNA+ subgroup compared to 7% (OR 1.33) in the overall population [32]. These data, albeit interesting, need to be interpreted with caution.…”

Section: Renal Diseasementioning

confidence: 82%

Developing novel drugs for systemic lupus erythematosus. Lessons learned from the belimumab trials

Pamfil

Fanouriakis

Boumpas

2012

RHC

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Systemic lupus erythematosus is the prototypic autoimmune disease with a broad range of clinical manifestations and a complex pathogenesis. B-cells hold a central role in its pathogenesis, not only as autoantibody producing cells, but also by producing other inflammatory mediators and by presenting autoantigens to autoreactive T cells. BlyS, a soluble ligand of the TNF cytokine family, is a key factor affecting B-cell homeostasis and survival and its blockade ameliorated the disease in animal models and preclinical studies of SLE. Following an unsuccessful phase II trial of belimumab, a monoclonal antibody targeting BlyS, two large phase III studies in patients with mild-to-moderate disease, BLISS-52 and BLISS-76, met their primary endpoints showing better efficacy of the drug over standard of care alone. To this end, development of a novel more sensitive responder index and improvements in study designs were crucial. As a result, belimumab became the first drug to get approval for the treatment of SLE after more than 50 years. In this paper we discuss the rationale, development, indications, lessons learned, pitfalls and challenges for this novel therapy and point-out to additional issues that need to be addressed in the future.http://dx.doi.org/10.7175/rhc.v3i3.206

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“…Combined results show Belimumab is effective in treating musculoskeletal and mucocutaneous manifestations and slows down the worsening of the BILAG haematological and renal domains than placebo [186]. Post Hoc analysis suggests that patients with renal involvement especially those with serological activity or receiving MMF at baseline might also benefit from Belimumab [187]. In addition, Belimumab treatment helps to normalize complement levels and reduce anti-dsDNA antibodies and decrease certain B cells populations [188].…”

Section: Belimumabmentioning

confidence: 96%

B cells biology in systemic lupus erythematosus—from bench to bedside

Zhang

2015

Sci. China Life Sci.

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Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease that can involve multi-organs. B cells play a central role in the immunopathogenesis via antibody-dependent and antibody-independent ways. Excessive autoantibodies production, hyperresponsiveness and prolonged survival of autoreactive B cells are characteristics of SLE. In this article, mechanisms of self-tolerance loss of B cells and promising B cell-targeting therapies in lupus are reviewed and discussed. Systemic lupus erythematosus (SLE), the paradigm of autoimmune disease with the underlying mechanisms involving multiple immunological abnormalities, is a severely debilitating disease with multi-organ involvement and diverse autoantibodies spectrum [1]. Among the multiple elements in the pathogenesis, B cells play a central role in SLE through antibody dependent and independent manners [2]. Presence of pathogenic autoantibodies is not only the hallmark of SLE and the clue for diagnosis, but also associated with characteristic pathological injury and specific clinical manifestations [3][4][5]. In addition, the pathogenic role of B cells is also attributed to its antibody independent functions, including but not limited to antigen presentation, T cell crosstalk, dendritic cells (DCs) recruitment, pro-inflammatory cytokine secretion. Why and how auto-reactive B cells in lupus lose self-tolerance, escape from central and peripheral checkpoints, become over-activated and spontaneously produce autoantibodies, are always the focus of clinical and basic research. Therefore, it is important to summarize our current knowledge about the underlying mechanisms of self-tolerance breakdown and pathogenic functioning pathways of B cells in SLE. So we review here about B cell biology in SLE, including its differentiation and selection, functioning and signaling, surviving and apoptosis, and the resulting potential therapeutic targets both in mice and human lupus.

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Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE

Cited by 253 publications

References 21 publications

The Expression of BAFF Is Controlled by IRF Transcription Factors

The Expression of BAFF Is Controlled by IRF Transcription Factors

Developing novel drugs for systemic lupus erythematosus. Lessons learned from the belimumab trials

B cells biology in systemic lupus erythematosus—from bench to bedside

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