Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials

Manzi, Susan; Sánchez‐Guerrero, Jorge; Merrill, Joan T.; Furie, Richard; Gladman, Dafna D.; Navarra, Sandra V.; Ginzler, Ellen M.; D’Cruz, David; Doria, Andrea; Cooper, Simon; Zhong, Z. John; Hough, Douglas R.; Freimuth, William W.; Petri, Michelle

doi:10.1136/annrheumdis-2011-200831

Cited by 359 publications

(238 citation statements)

References 17 publications

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“…Patients with severe LN were excluded from the BLISS-56 and BLISS-76 trials, but data from those patients with moderate nephritis raise hope that belimumab could also be efficient in severe LN. 94 Such a trial is currently underway. Other B cell-directed strategies include atacicept (TACI-Ig), LY2127399 (anti-BAFF), and anti-BR3 (anti-BAFF-R).…”

Section: Novel Moieties That Target Specific Leukocyte Subsetsmentioning

confidence: 99%

The Pathogenesis of Lupus Nephritis

Lech¹,

Anders

2013

Journal of the American Society of Nephrology

395

295

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Lupus nephritis is an immune complex GN that develops as a frequent complication of SLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms. The extrarenal etiology of systemic lupus is based on multiple combinations of genetic variants that compromise those mechanisms normally assuring immune tolerance to nuclear autoantigens. This loss of tolerance becomes clinically detectable by the presence of antinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neutrophils activate innate and adaptive immunity via viral nucleic acid-specific Toll-like receptors. Therefore, many clinical manifestations of systemic lupus resemble those of viral infection. In lupus, endogenous nuclear particles trigger IFN-a signaling just like viral particles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasma cells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology of lupus nephritis involves antibody binding to multiple intrarenal autoantigens rather than the deposition of circulating immune complexes. Tertiary lymphoid tissue formation and local antibody production add to intrarenal complement activation as renal immunopathology progresses. Here we provide an update on the pathogenic mechanisms that lead to lupus nephritis and provide the rationale for the latest and novel treatment strategies.

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Section: Novel Moieties That Target Specific Leukocyte Subsetsmentioning

confidence: 99%

The Pathogenesis of Lupus Nephritis

Lech¹,

Anders

2013

Journal of the American Society of Nephrology

395

295

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“…BAFF-transgenic mouse studies demonstrated that overexpression of BAFF results in development of SLE-like autoimmune pathology including increased autoantibody production (46)(47)(48). Belimumab (Benlysta), a specific inhibitor of BAFF, shows significant efficacy in evidence-based clinical trials for SLE, further supporting the role of BAFF in SLE pathology (49)(50)(51)(52)(53)(54).…”

mentioning

confidence: 98%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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“…Nevertheless, improvement in disease activity was judged relevant by all physicians involved, even though clinical manifestations were not dissected in detail. Interestingly, by improving control of disease activity belimumab was shown to reduce work disability, being thus cost-effective both in terms of employment and in decreasing health resource utilization and emergency room visits [11,12], and to ameliorate fatigue as well, which is among the major complaints of SLE patients [6,9,10,13,14].…”

Section: Observations On Belimumab Use In Clinical Practicementioning

confidence: 99%