Balancing Act: The Dual Roles of BAFF in Systemic Lupus Erythematosus

Abstract

In systemic lupus erythematosus (SLE) and other autoimmune diseases, B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play critical roles through three receptors, i.e., BAFF-Receptor (BAFF-R), transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI), and B-cell maturation antigen (BCMA), promoting the survival of self-reactive B cells and supporting their differentiation into antibody-producing cells. Several biologic therapies with anti-BAFF and anti-BAFF/APRIL agents induce profound suppression of immunoglobulin production and B-cell survival with variable safety profiles. While belimumab has demonstrated significant improvement of overall disease activity in clinical trials, some cases of de novo lupus nephritis have been reported suggesting a potential lack of protection in certain cases. The sustained reduction in B cell populations expressing regulatory markers, alongside a rapid decline in IL-10 levels following belimumab initiation, suggests that BAFF may have a previously underappreciated role in supporting the development or function of regulatory B cells (Bregs). Given the complex receptor interactions of BAFF and APRIL, as well as the heterogeneous phenotype of regulatory B cells and their different mechanisms for regulating the immune response, the involvement of BAFF in regulatory immune responses remains difficult to fully elucidate. This review explores the current evidence on the anti-BAFF/APRIL therapies and examines the unresolved question of whether BAFF exerts a context-dependent role in supporting regulatory B cell function.

Key Points

B-cell activating factor (BAFF) promotes the survival and maturation of autoreactive B cells that produce pathogenic autoantibodies, and elevated BAFF levels are closely associated with disease activity in systemic lupus erythematosus (SLE) and lupus nephritis (LN).

Anti-BAFF therapies such as belimumab have demonstrated efficacy and a favourable safety profile in clinical trials involving patients with SLE and LN when used in combination with standard background therapy.

Occurrence of de novo LN cases during belimumab therapy has been observed, suggesting that, in certain patients, BAFF inhibition may not provide sufficient protection. Given the established role of BAFF in B cell survival and emerging evidence linking BAFF signalling to IL-10 production in specific contexts, these observations raise the possibility that BAFF may also contribute to the homeostasis and function of regulatory B cells.

Introduction

B cells are central components of adaptive immunity, primarily due to their ability to differentiate into antibody-secreting plasma cells and to function as antigen-presenting cells [1]. B-cell development begins in the bone marrow and continues in secondary lymphoid organs. To ensure the generation of a functional and protective antibody repertoire, B cells undergo multiple developmental checkpoints to eliminate autoreactive B cells [2]. In the bone marrow, B cells under development undergo immunoglobulin gene rearrangements to express functional B cell receptors (BCRs) [3], which must signal appropriately (through tonic signalling) and demonstrate non-reactivity to self-antigens [4].

Although central tolerance eliminates most autoreactive clones, some self-reactive B cells evade deletion and migrate to the periphery [4]. Peripheral tolerance involves transitional B cells that require additional signals beyond the BCR for survival and maturation [1]. These co-stimulatory signals, provided through receptors such as Toll-like receptors (TLRs), CD40, and the B cell-activating factor (BAFF) receptor (BAFF-R), all play critical roles in determining the fate of transitional B cells, guiding their differentiation into either marginal zone (MZ) or follicular (FO) B cells [5]. The balance of these signals and intrinsic cellular regulatory mechanisms, prevent the development of autoreactive antibody-secreting cells (ASCs) in healthy subjects [6]. Several of these mechanisms such as BCR signalling regulators, self-reactive negative selection, or extrafollicular responses may be impaired or defective in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren’s disease (SjD), leading to untoward autoantibody production [7]. In this context, this review aims to examine the current evidence on anti-BAFF/a proliferation-inducing ligand (APRIL) therapies in SLE and to address the unresolved question of whether BAFF plays a context-dependent role in supporting regulatory B-cell function.

Approach to the Literature

A systematic literature search was conducted to identify studies evaluating biologic therapies in SLE and lupus nephritis (LN). Particular emphasis was placed on peer-reviewed literature published in high-impact journals indexed in the top quartiles (Q1/Q2) addressing anti-BAFF/APRIL biologic therapies, including agents targeting their receptors, with a focus on biological pathways and clinical trial outcomes, to provide a comprehensive synthesis of the most relevant therapeutic advances.

Systemic Lupus Erythematosus

Systemic lupus erythematosus is a chronic autoimmune disease characterised by widespread immune dysregulation, a diverse repertoire of autoantibodies, and systemic inflammation affecting virtually any organ system. Systemic lupus erythematosus arises from a complex interplay of genetic, epigenetic, hormonal, and environmental factors that collectively lead to a profound loss of immunological self-tolerance [8].

The innate immune system plays a pivotal role in initiating the disease through the accumulation of self-nucleic acids derived from aberrant apoptosis clearance or neutrophil extracellular traps (NETs). These nucleic acids activate TLR7, TLR8, and TLR9, especially in plasmacytoid dendritic cells (pDCs), triggering a chronic type I interferon (IFN-I) response [9]. This “interferon signature” amplifies the autoimmune cascade by promoting antigen presentation, B cell activation, and pro-inflammatory cytokine production [10].

T cells also contribute significantly to SLE pathogenesis, e.g., by follicular helper T cells (Tfh) providing aberrant help to B cells, through secretion of cytokines such as IL-17 and IL-21, failing to restrain immune activation due to deficiencies in regulatory T cells (Tregs) [11, 12]. B cell hyperactivity is a hallmark of SLE, with elevated levels of BAFF facilitating the survival of autoreactive B cells that escape central and peripheral tolerance checkpoints [13]. These aberrant B cells produce autoantibodies targeting, e.g., double-stranded (ds)DNA or the Smith (Sm) antigen, which form immune complexes (ICs) that may deposit in tissues such as the glomeruli of the kidneys [14]. Immune complexes can activate the complement system through the classical pathway and induce inflammation, which, eventually, may result in tissue damage [15].

BAFF-Axis

B cell-activating factor, also known as BLyS, TNFSF13B, or TALL-1, and a proliferation-inducing ligand (APRIL, TNFSF13), are related cytokines of the tumour necrosis factor (TNF) superfamily (Fig. 1) [16–18]. Both are initially synthesised as type II transmembrane proteins and undergo proteolytic cleavage at furin sites to release their soluble forms [18, 19]. B cell-activating factor and APRIL are mainly produced by myeloid cells, including macrophages, neutrophils, and dendritic cells, as well as by stromal cells, although activated B and T cells can also produce them [18, 20, 21]. Activated CD8⁺ T and natural killer (NK) cells can also produce BAFF, particularly upon IL-2 stimulation [22]. B cell-activating factor exists both in a membrane-bound form and as a soluble homotrimer, which can uniquely assemble into a highly active capsid-like 60-mer structure composed of 20 trimers through lateral “flap-flap” interactions [23–25]. In contrast, APRIL is primarily secreted in soluble form following intracellular processing in the Golgi apparatus [19].

Fig. 1.

B-cell activating factor (BAFF) and APRIL signalling. Schematic representation of the molecular interactions between BAFF and APRIL with their cognate receptors, highlighting downstream signalling pathways and associated biological outcomes. Multimeric 60-mer BAFF preferentially binds BAFF-R and TACI, whereas soluble BAFF interacts with all three receptors (BAFF-R, TACI and BCMA) and APRIL selectively signals through TACI and BCMA. Engagement of BAFF-R leads to recruitment of the TRAF 2 and 3, activating the non-canonical NF-κB2 pathway and promoting B-cell survival. In contrast, TACI signalling involves TRAF2 and TRAF6, triggering MyD88 and canonical NF-κB1 pathways that are critical for immunoglobulin class-switch recombination. BCMA signalling is mediated through a TRAF1-TRAF2-TRAF3 complex, resulting in activation of JNK and MAPK pathways, thereby supporting plasma cell function and antigen presentation. APRIL a proliferation-inducing ligand, BAFF B-cell activating factor, BAFF-R B-cell activating factor receptor, BCMA B-cell maturation antigen, CAML calcium-modulator and cyclophilin ligand, JNK c-Jun N-terminal kinase, MAPK mitogen-activated protein kinase, MyD88 myeloid differentiation primary response 88, NF-κB nuclear factor kappa-B, TACI transmembrane activator and CAML interactor, TNF tumour necrosis factor, TRAF TNF receptor-associated factor

B cell-activating factor is a central cytokine in B cell survival, activation, and homeostasis, particularly at the transitional T1–T2 checkpoint. Excess BAFF contributes to the survival of autoreactive B cells that would otherwise be eliminated [26]. Elevated levels of soluble BAFF (sBAFF) and soluble APRIL (sAPRIL) are frequently observed in the serum of patients with SLE compared with healthy individuals [27, 28]. Although studies have reported mixed findings regarding the correlation between sBAFF and overall or organ-specific SLE disease activity [29], elevated baseline levels of sBAFF (≥ 2 ng/mL) have been predictive of increased flare risk during standard therapy [30, 31].

Genetically, a variant in the TNFSF13B gene known as BAFF-var results in a shorter mRNA transcript that escapes microRNA-mediated regulation, leading to increased production of sBAFF. Carriers of this variant exhibit a higher incidence of lupus nephritis (LN) and elevated markers of renal activity compared with non-carriers [32–35].

B cell-activating factor and APRIL signal through three receptors expressed on B lineage cells: BAFF-R (TNFRSF13C), which specifically binds BAFF; transmembrane activator and CAML interactor (TACI) (TNFRSF13B), which binds both BAFF and APRIL and is preferentially activated by oligomeric forms [36]; and BCMA (TNFRSF17), which also binds both ligands, although it has a higher affinity for APRIL [37]. Notably, APRIL can also bind heparan sulfate proteoglycans (HSPG) [38]. During B cell differentiation, BCMA expression increases while BAFF-R expression is lost, especially in CD27^hi plasma cells [39].

These three receptors mediate distinct biological functions: BAFF-R signalling is essential for the survival and maturation of immature B cells; TACI is crucial for T cell-independent antibody responses, B cell regulation, and class-switch recombination; and BCMA promotes the survival of long-lived plasma cell in the periphery and in tissues, including the bone marrow, through its interaction with APRIL [40]. However, recent evidence suggests that BCMA may also play a regulatory role by acting as a decoy receptor that neutralises APRIL [41]. Intracellularly, BAFF binding to BAFF-R strongly activates the non-canonical nuclear factor kappa B subunit 2 (NF-κB2) pathway and weakly activates the classical NF-κB1 pathway, while also engaging phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling to support protein synthesis and metabolic fitness [42]. Moreover, BAFF enhances B cell chemotaxis in response to CCL21, CXCL12, and CXCL13 through PI3K/AKT and p38MAPK pathways [43].

While BAFF is primarily a B cell survival factor, it also affects T cells by co-stimulating their proliferation, particularly when anti-CD3 stimulation is suboptimal. B-cell activating factor receptor expression is induced in activated T cells [44]. B-cell activating factor overexpression enhances Th1 inflammatory responses and suppresses Th2 responses in mice [45].

BAFF as a Regulatory Player

Although most IL-10–producing B cell populations have been categorised as Bregs, their origin remains heterogeneous [46], and various surface markers have been proposed to define them. In mice, markers such as CD1d^hiCD5⁺CD21^hiCD24^hi and CD138^hi are commonly used [47–50], while in humans, CD27⁺CD38^hiCD24^hi and CD24^hiCD27⁺ along with molecules such as PD-L1, FasL, TGF-β, granzyme B, IDO, and IL-35 [51–55], are associated with Breg phenotypes. While BAFF is well known for supporting short-lived plasma cell differentiation and autoantibody production in autoimmunity, evidence from BAFF-transgenic (BAFF-Tg) mice suggests that BAFF may also support regulatory functions in B cells. In these mice, increased CD4⁺FoxP3⁺ Tregs capable of suppressing effector T cell responses were observed in a B cell-dependent manner [56, 57]. Low concentrations of BAFF (~20 ng/mL) induce a CD1d^hiCD5⁺ B cell population in cultured splenic mice cells that produce IL-10 [47] and IL-35 [58] with regulatory capacity in autoimmune mice models. Similarly, APRIL-transgenic mice exhibit anti-inflammatory responses, promoting IL-10-producing CD19⁺CD21^hiCD23^hi B cells in an antigen-induced arthritis model [59], whereas in human naïve B cells, APRIL induces an IgA⁺IL-10⁺ population that expresses PD-L1 and FasL [60]. The APRIL-induced IL-10⁺ B cells show an increased TACI expression in healthy subjects and RA patients with decreasing IL-10⁺ B cells after STAT3 inhibition in vitro [61]. Human B cells stimulated with high concentrations of BAFF or APRIL (~ 125 ng/mL) in the presence of TLR agonists such as R848 or CpG can produce IL-10, undergo IgA class-switch recombination, and secrete IL-6 [62].

Different cytokine combinations with TLR agonists can induce strong IL-10 production as well as production of other pro-inflammatory cytokines such as TNF or IL-6, without a unique set of activation markers [63]. Depending on the duration of stimulation, the proportion in the production of IL-10 and pro-inflammatory cytokines can vary [64].

The CD24⁺CD38⁺ transitional B cells appear to consistently produce IL-10 with minimal TNF, suggesting a more stable regulatory phenotype [64]. Engagement of CD40 is critical for Breg induction and function. Co-culture experiments with T cells and pDCs have shown that CD19⁺CD24⁺CD38^hi B cells exhibit the strongest regulatory capacity in a contact-dependent manner [53, 65, 66].

While CD19⁺CD24⁺CD38⁺ B cells from healthy donors can regulate efficiently T cell activation, B cells from patients with SLE are refractory [65]. This defect has been linked to impaired STAT3 signalling [53, 67]. Even though SLE patients show similar CD19⁺CD24⁺CD38⁺ B cells frequencies, these cells display a decreased capacity to produce IL-10 (Fig. 2) [53, 65, 66, 68, 69]. Although BAFF and APRIL can support IL-10 production under certain conditions, it remains unclear whether BAFF or APRIL directly induce or merely support Breg development in humans.

Fig. 2.

Dysfunction of regulatory B cells (Bregs) in SLE. Breg activation is initiated through direct interaction with T cells via the CD40L-CD40 and CD28-CD80 costimulatory axes. Under physiological conditions, these signals efficiently trigger intracellular pathways leading to robust phosphorylation of STAT3, which drives high-level secretion of IL-10. In contrast, in SLE, STAT3 phosphorylation is markedly impaired, resulting in reduced IL-10 production and a loss of Breg suppressive capacity. Bregs regulatory B cells, CD40L cluster of differentiation 40 ligand, IL-10 interleukin 10, SLE systemic lupus erythematosus, STAT3 Signal Transducer and Activator of Transcription 3

Despite its well-established anti-inflammatory role, IL-10 also promotes plasma cell differentiation and drives isotype switching, contributing to autoantibody production, especially in extrafollicular contexts [70]. For instance, specific subsets of IL-10–producing CD4⁺ helper T cells such as CXCR5^-CXCR3⁺PD-1^hi T cells and CCR6⁺IL-7R⁺ T cells are expanded in SLE, providing B cell help via IL-10 and contributing to autoantibody production [71, 72].

Human CD19^hiCD11c⁺ B cells generated through in vitro stimulation were found to express IL-10 although with lower levels than transitional CD24⁺CD38⁺ B cells [64]. Also, it has been reported that IgA2⁺ plasmablasts and CD11c⁺T-bet⁺ B cells from SLE patients express elevated levels of BAFF-R and can produce higher levels of IL-10 compared to IgA1⁺ plasmablast and CD11c^-T-bet^- B cells after CpG stimulation [73].

This suggests that BAFF may promote IL-10 production in specific cellular contexts and B-cell subpopulations. Although direct evidence regarding BAFF or APRIL effect on regulatory Bregs is currently lacking, relevant insights can be inferred from clinical trials and mechanistic studies involving anti-BAFF and anti-APRIL therapies.

Anti-BAFF-Axis Therapies

The key role of BAFF and APRIL in SLE has driven the development of targeted biologic therapies (Fig. 3), marking a shift from non-specific immunosuppression toward selective immune modulation. B-cell activating factor-axis inhibitors (Table 1) aim to achieve deeper immunomodulation by targeting both mature B cells and plasma cells, thereby reducing long-term organ damage. B-cell activating factor inhibition predominantly affects peripheral B lymphocytes at early stages of maturation, leading to a marked reduction in naïve and transitional B cell populations, which critically depend on BAFF/BAFF-R signalling for survival and homeostasis [74–76]. This selective depletion also enhances the negative selection of autoreactive B cells [77, 78]. However, its effects on memory B cells and long-lived bone marrow plasma cells are considerably more limited and delayed, as these populations can maintain BAFF-independent survival through APRIL-mediated signalling [79]. Dual neutralisation of BAFF and APRIL eliminates survival signalling mediated through BCMA and TACI, thereby extending therapeutic activity beyond the peripheral B cell compartment. As a result, this strategy not only reduces circulating peripheral B lymphocytes but also induces profound suppression of plasmablasts and mature plasma cells, including both short- and long-lived subsets, which constitute the principal immunoglobulin-producing effector populations [80]. Consequently, combined blockade leads to a substantial and coordinated reduction in total serum immunoglobulin (IgG, IgM, and IgA) and autoantibody levels [81].

Fig. 3.

BAFF-axis-targeted therapies. Belimumab selectively neutralises sBAFF, whereas ianalumab directly blocks BAFF-R on B cells. Tabalumab and blisibimod exert dual activity by inhibiting both sBAFF and mBAFF. In contrast, the fusion proteins telitacicept, atacicept, and povetacicept simultaneously neutralise sBAFF and sAPRIL. The lower panel illustrates the proposed immunomodulatory effect of belimumab treatment associated with a reduction in IL-10 production by Bregs, which may compromise their suppressive capacity within an inflammatory microenvironment. BAFF B-cell activating factor, BAFF-R B-cell activating factor receptor, Bregs regulatory B cells, IL-10 Interleukin 10, mBAFF membrane-bound BAFF, sAPRIL soluble a proliferation-inducing ligand, sBAFF soluble B-cell activating factor

Table 1.

Overview of anti-BAFF/APRIL therapeutic agents: B-cell effects, immunoglobulin changes, and clinical outcomes

Agent	Target(s)	Structure	Effects on B-cell populations	Immunoglobulin changes	Key clinical outcomes	References
Belimumab	Soluble BAFF	Fully human IgG1λ mAb	Total B cells $\downarrow$ Naïve B cells (CD20+CD27-) $\downarrow$ Transitional B cells (CD24hiCD38hi) $\downarrow$ Bregs subsets in cSLE $\downarrow$ Memory B cells (CD20+CD27+) *	IgG $\downarrow$ IgA $\downarrow$ IgM $\downarrow \downarrow$ Anti-dsDNA titers $\downarrow$	Achievement of SRI-4 at 52 weeks. Superiority over placebo was demonstrated in multiple Phase III trials. Approved for SLE and LN	[74, 76, 77, 90, 97, 126]
Tabalumab	Soluble and membrane BAFF	Human IgG4 mAb	Naïve B cells $\downarrow \downarrow$ Transient initial increase in total CD20+ B-cell counts followed by a progressive reduction below baseline levels	IgG $\downarrow$ IgA $\downarrow$ IgM $\downarrow$ Anti-dsDNA titers $\downarrow$ C3 and C4 $\uparrow$	ILLUMINATE-1 did not reach the primary SRI-5 endpoint for any dose in the primary analysis ILLUMINATE-2 met the primary endpoint (SRI-5) at Week 52	[100, 101, 127]
Blisibimod	Soluble and membrane BAFF	BAFF-binding "peptibody" (Fc fusion)	Total B cells $\downarrow$ Naïve B cells $\downarrow \downarrow$ Memory B cells *	IgG $\downarrow$ IgA $\downarrow$ IgM $\downarrow$ C3 and C4 $\uparrow$	Although secondary benefits were clear, the primary SRI-6 endpoint was not met in the Phase III CHABLIS-SC1 trial	[102, 103]
Atacicept	BAFF, APRIL, and heterotrimers	Soluble recombinant fusion protein	Total CD19+ B cells $\downarrow$ Memory B cells *	IgG $\downarrow \downarrow$ IgA $\downarrow \downarrow$ IgM $\downarrow$ Anti-dsDNA titers $\downarrow$ C3 and C4 $\uparrow$	In SLE trials (ADDRESS II), atacicept showed positive trends in SRI-4/6 responses and increased attainment of LLDAS. Discontinued in LN due to hypogammaglobulinaemia	[81, 105, 107, 128]
Telitacicept	Soluble BAFF and APRIL	Recombinant TACI-Fc fusion protein	Total B cells $\downarrow$ Naïve B cells $\downarrow$ Transitional B cells $\downarrow$ Short-lived plasma cells $\downarrow$ Bregs $\uparrow$	IgG $\downarrow$ IgA $\downarrow$ IgM $\downarrow \downarrow$	Consistently high SRI-4 response rates in Phase III trials. Approved for SLE in China (2021)	[80, 112, 129, 130]
Povetacicept	BAFF and APRIL	Engineered TACI variant (vTD-Fc)	Plasmablasts $\downarrow \downarrow$ Plasma cells $\downarrow \downarrow$	IgG $\downarrow$ IgA $\downarrow$ IgM $\downarrow$ IgE $\downarrow$ Anti-dsDNA titers $\downarrow$ (In SLE mouse models)	Under evaluation in patients with active proliferative lupus nephritis in the open-label, multiple dose trial RUBY-3	[114, 116]
Ianalumab	BAFF receptor (BAFF-R)	Fully human, afucosylated IgG1 mAb	Total B cells $\downarrow \downarrow$	IgG $\downarrow \downarrow$ IgA $\downarrow$ IgM $\downarrow$ C3 and C4 $\uparrow$ Anti-dsDNA, anti-C1q, and ENAs (U1-RNP and Smith) titers $\downarrow$	Superiority in response (SRI-4 and SRI-6). Profound reduction in the incidence of moderate to severe flares	[118]

Anti-dsDNA anti-double-stranded DNA, APRIL a proliferation-inducing ligand, BAFF B-cell activating factor, BAFF-R BAFF receptor, BCMA B cell maturation antigen, Bregs regulatory B cells, C3/C4 complement component 3/4, cSLE childhood-onset systemic lupus erythematosus, Fc fragment crystallisable region, IgA, IgE, IgG, IgM immunoglobulin A, E, G and M, LLDAS Lupus Low Disease Activity State, LN lupus nephritis, mAb monoclonal antibody, SLE systemic lupus erythematosus, SRI SLE responder Index, TACI transmembrane activator and CAML interactor, vTD-Fc variant TACI domain-Fc fusion

^* Initial transient increase before returning to baseline levels

Belimumab

Belimumab was first approved by regulatory authorities in 2011 as the first new treatment for SLE in more than 50 years. Belimumab is a fully human IgG1λ monoclonal antibody that neutralises soluble BAFF [74, 82]. Its mechanism extends beyond simple receptor blockade, as it also interferes with BAFF oligomerisation by preventing the formation of the highly active 60-meric form through the generation of less active BAFF–belimumab complexes, although it does not fully neutralise this multimeric form [83]. Naïve and transitional B cells, which express high levels of BAFF-R, decrease rapidly and persistently during belimumab treatment, thereby regulating key developmental checkpoints and promoting the removal of autoreactive clones [75]. At the molecular level, belimumab treatment leads to the upregulation of the transcription factor NR4A1 in naïve B cells, a critical regulator of peripheral tolerance that limits the survival of self-reactive B cells under conditions of restricted BAFF availability and suppresses their differentiation into age- or autoimmunity-associated B cells (ABCs), a subset of B cells implicated in autoimmunity [77, 78].

Clinically, belimumab reduces circulating autoantibodies, normalises complement (C) protein levels (C3 and C4), and significantly lowers anti-dsDNA levels [76]. The greatest clinical benefit is observed in patients with serologically active disease prior to belimumab treatment commencement [84]. Protection against renal flares appears enhanced when belimumab is combined with antimalarial agents (AMA) [85]. In addition, reduced organ damage progression compared with standard therapy alone has been reported [86]. Real-world data suggest a plateau in pharmacodynamic response, raising the possibility that lower doses of belimumab may offer comparable efficacy [87]. In conformity with this notion, low-dose belimumab (intravenous [IV] 120 mg) showed reduced risk of flares in SLE patients in a recent randomised clinical trial in China [88], whereas low-dose belimumab (IV 1-mg/kg and subcutaneous [SC] 200-mg weekly) yielded lower hazard of de novo flares in SLE [89]. More recently, belimumab was also approved for active LN [90]. However, some studies have raised the possibility of insufficient prevention of de novo LN in some cases. Real-world data have reported biopsy-proven cases of de novo LN in belimumab-treated patients at higher rates than in those receiving conventional therapies [91]. By contrast, concomitant antimalarial therapy was reported to exert a protective effect against the development of LN in patients receiving belimumab [89]. Overall, it is plausible that baseline serological activity, concomitant medications (including antimalarials), and non-renal SLE disease activity influenced the risk of development of de novo LN in patients treated with belimumab in different directions. Nevertheless, both patients without prior kidney involvement and those with a history of nephritis were reported to develop biopsy-proven lupus nephritis during belimumab therapy [91–95]. Moreover, add-on belimumab has been associated with marked reductions in serum IL-10 levels in SLE patients [96], as well as a pronounced decline in IL-10–producing Breg subsets (CD27⁺CD24⁺, CD38⁺CD24⁺, CD38⁺CD19⁺) compared with standard therapy alone in childhood SLE [97]. Conversely, increased frequencies of regulatory B cells have been observed in patients treated with anti-BAFF therapy (BAFF-R:Fc) [98] or combined anti-BAFF/APRIL therapy (telitacicept) [80]. These findings suggest that BAFF/APRIL signalling may influence regulatory B cell populations. Whether the occurrence of LN can be directly attributed to belimumab remains uncertain.

Tabalumab

Tabalumab is a fully human IgG4 monoclonal antibody that selectively neutralises BAFF without inducing profound depletion of BAFF-expressing cells. Tabalumab can bind and neutralise both the soluble trimeric ligand and the membrane-bound form of BAFF, thereby preventing receptor engagement [99]. The clinical efficacy of tabalumab in SLE was evaluated in two Phase III randomised trials, ILLUMINATE-1 and ILLUMINATE-2, which enrolled patients with active moderate-to-severe disease and followed them for 52 weeks. Both trials used the SLE Responder Index-5 (SRI-5) as the primary endpoint, defined as a ≥  5-point reduction in SELENA-SLEDAI without worsening in BILAG scores. ILLUMINATE-1 failed to meet its primary endpoint for either of two tabalumab dosing regimens: SC 120 mg every 2 weeks or every 4 weeks [100].

In contrast, ILLUMINATE-2 met its primary endpoint for the dose of 120 mg every 2 weeks, demonstrating significantly higher SRI-5 response rates compared with placebo, whereas the dose of 120 mg every 4 weeks narrowly missed statistical significance [101]. Patients with serologically active disease (anti-dsDNA positivity and low complement levels) showed greater benefit. Pharmacodynamic analyses across both studies confirmed significant declines in serum IgG, IgM, and IgA, reductions in anti-dsDNA antibodies, and increases in complement C3 and C4 levels. Also, the trials documented reductions in peripheral B cells with tabalumab, following an initial transient rise with increased BAFF concentrations at Week 52, suggesting a BAFF-anti-BAFF Ig complex accumulation [100, 101].

Blisibimod

Blisibimod (AMG 623/A-623) is a potent and selective BAFF antagonist with a unique tetravalent “peptibody” structure fused to the human IgG1 Fc region that confers high affinity for both soluble and membrane-bound BAFF [102]. Blisibimod has been shown to induce marked reductions in total B cells (CD19⁺CD20⁺) and naïve B cells (CD19⁺IgD⁺CD27^-), and a transient increase in memory B cells (CD19⁺CD27⁺), along with decreases in serum anti-dsDNA antibodies and immunoglobulins (IgG and IgM) and increases in complement C3 and C4 levels [103].

The Phase III CHABLIS-SC1 trial enrolled 442 patients with clinically active SLE (SELENA-SLEDAI ≥ 10), positive ANA and/or anti-dsDNA antibody levels, and ongoing glucocorticoid therapy. Patients received SC blisibimod 200 mg once weekly. The study did not meet its primary endpoint (SRI-6 at Week 52), potentially due to the unexpectedly high placebo response rate (42.3%) [103].

Atacicept

Atacicept is a fully human, recombinant, soluble fusion protein composed of the extracellular domain of TACI receptor fused to the Fc portion of human IgG1. This molecular design enables atacicept to function as a circulating decoy receptor that neutralises both BAFF and APRIL. In addition, atacicept can neutralise BAFF/APRIL heterotrimers [104]. In the Phase Ib dose-escalating trial in SLE patients, atacicept induced dose-dependent and sustained reductions in circulating immunoglobulin levels (IgG, IgM, and IgA) and mature and total B cells [81]. The Phase IIb ADDRESS II trial investigated atacicept in patients with active SLE. Although the primary endpoint (SRI-4 at Week 24) was not formally met, both weekly SC doses (75 mg and 150 mg) yielded a trend toward improved responses [105]. A post hoc analysis in the serologically active (anti-dsDNA and low complement) disease subgroup showed greater SRI-4 and SRI-6 response rates with atacicept 150 mg compared with placebo [106] whereas over longer-term follow-up (median 83.8 weeks), atacicept 150 mg showed an acceptable safety profile and sustained SRI-4 and SRI-6 responses [107].

The APRIL-SLE Phase II/III trial evaluated the efficacy and safety of atacicept in preventing flares in patients with moderate to severe SLE. The 150-mg arm was terminated early after two infection-related deaths, and the primary endpoint was not met for the 75-mg group. However, a post hoc analysis of the 150 mg arm suggested a significant benefit in reducing flare rates (OR 0.48, p = 0.002) [108]. Additional post hoc analyses indicated that patients with elevated baseline BAFF (≥ 1.6 ng/mL) and APRIL (≥ 2.2 ng/mL) levels experienced greater benefit. In this subgroup, atacicept 150 mg reduced flare rates from 75.7 to 32.0% [109]. More pronounced safety concerns arose in the APRIL-LN trial, a Phase II/III study in LN, which was discontinued after enrolment of six patients due to rapid and profound declines in serum IgG levels and the occurrence of severe infections [110].

Telitacicept

Telitacicept is a recombinant fusion protein composed of the extracellular domain of the TACI receptor fused to the Fc fragment of human IgG (TACI-Fc) [111]. A Phase III trial in China reported an SRI-4 response rate of 67.1% at Week 52 with weekly SC telitacicept 160 mg, compared with 32.7% with placebo [112]. In a retrospective study conducted in China, 30 patients with LN received SC telitacicept at a weekly dose of 160 mg. Treatment was associated with favourable clinical outcomes, with 86.67% of patients achieving an SRI-4 response [113].

Telitacicept promotes significant reductions in IgM, IgG, and IgA levels, decreases anti-dsDNA autoantibodies, and reduces CD19⁺ B cells and short-lived plasma cells [80]. In this study, the absolute counts of Bregs (CD19⁺CD20⁺CD24^hiCD27⁺) showed an increase during the telitacicept therapy compared with baseline, without a statistically significant difference. Notably, IL-10 levels did not change significantly [80].

Povetacicept

Povetacicept (ALPN-303; TACI vTD-Fc) is a Fc-fusion protein containing an engineered variant of the TACI extracellular domain. The TACI domain was optimised to generate a variant (vTD) with markedly enhanced binding affinity for both BAFF and APRIL [114]. Povetacicept uses a CRD2-optimised design incorporating three key amino-acid substitutions (K77E, F78Y, Y102D) required for optimal activity. It is fused to a modified human IgG1 Fc lacking effector function avoiding Fc receptor binding and complement activation [114, 115].

In vitro, povetacicept showed substantially greater potency than selective inhibitors, being 5.7-fold more potent than specific antibodies against APRIL and 3.4-fold more potent than belimumab in reporter assays [114]. Also, it demonstrated superior neutralisation of BAFF 60-mers and BAFF/APRIL heterotrimers [114]. In murine models of lupus (NZB/NZW and bm12), povetacicept reduced proteinuria, anti-dsDNA antibodies, and clinical disease activity [114]. In a placebo-controlled trial assessing the safety of povetacicept in 72 healthy adult volunteers, povetacicept induced dose-dependent reductions in IgG, IgM, IgA, with a pronounced suppression of IgE isotypes [116].

Ianalumab

Ianalumab (VAY736) is a fully human IgG1/κ monoclonal antibody targeting BAFF-R. Ianalumab operates through two simultaneous mechanisms. First, it induces direct B cell lysis via antibody-dependent cellular cytotoxicity (ADCC); the Fc region is defucosylated to enhance affinity for Fcγ receptors, thereby maximising ADCC capacity. Second, by binding BAFF-R, ianalumab blocks BAFF-mediated survival and maturation signals [117].

In SLE, a randomised, double-blind, placebo-controlled Phase II study assessed a monthly SC ianalumab dose of 300 mg in patients with moderate to severe disease despite standard therapy. The study met its primary endpoint, defined as achievement of SRI-4 together with glucocorticoid tapering at Week 28; 44.1% of patients receiving ianalumab met the endpoint compared with 9.1% in the placebo group [118]. Ianalumab also reduced the incidence of moderate or severe flares during the double-blind period (8.8% with ianalumab vs 30.3% with placebo). Increases in complement C3 and C4 were observed from Week 8 and persisted through Week 68. Greater reductions in serum autoantibodies, including anti-dsDNA, anti-C1q, anti-U1-RNP, and anti-Sm were seen with ianalumab compared with placebo. Ianalumab induced a rapid and sustained depletion of circulating CD19⁺ B cells with an increase in sBAFF levels consistent with ianalumab-targeted BAFF-R blockade [118].

Future Perspectives

Although the combination of biologic agents with standard immunosuppressive therapies remains the current standard of care, sequential combination of biologic agents has been explored. In studies such as BEAT-LUPUS and CALIBRATE, rituximab (anti-CD20) was administered first, followed by belimumab, with the aim of neutralising post-B-cell–depletion BAFF rise and delaying re-emergence of autoreactive B cells. BEAT-LUPUS, a Phase IIb, double-blind, multicentre, randomised controlled trial, compared belimumab with placebo following rituximab induction in patients with refractory SLE and met its primary endpoint, demonstrating a reduction in anti-dsDNA IgG antibody titres at 52 weeks. In contrast, CALIBRATE, an open-label Phase II trial that enrolled 43 patients with active proliferative LN, found that add-on belimumab as a part of the remission maintenance part of the therapy did not result in significant improvements in kidney function [73, 119–121]. The BLISS-BELIEVE trial evaluated SC belimumab during 52 weeks with a single cycle of rituximab at Week 4, based on the hypothesis that BAFF inhibition mobilises memory B cells from tissue niches into the circulation, rendering them more susceptible to CD20-mediated depletion. The primary endpoint was the proportion of patients achieving disease control at Week 52, defined as a SLEDAI-2K score of ≤ 2, no concomitant immunosuppressant use, and a prednisone-equivalent dose of ≤ 5 mg/day. The proportion of patients meeting this composite endpoint did not differ significantly between the belimumab/rituximab and the belimumab/placebo groups; hence, the primary endpoint was not met [122]. These approaches aim to overcome the limitations of biologic monotherapy. Future therapeutic approaches may incorporate BAFF ligand-based CAR-T cells targeting BAFF-R, TACI and BCMA to enable more profound depletion of B cells and CD138⁺ plasma cells [123].

Rather than a quantitative impairment, the predominant feature of Breg dysregulation in SLE appears to be a loss of effective suppressive capacity [53]. Some cytokines such as IL-21 and IFN-α, known for supporting pathogenic B cell responses in SLE, have been implicated in Breg development highlighting a paradoxical role that may depend on co-stimulatory context or cytokine concentration [66, 124, 125]. The proposed Breg imbalance during belimumab treatment suggests a potential regulatory role of BAFF. Similar to other cytokines, BAFF-mediated induction of Bregs may depend on relative soluble levels or specific co-stimulatory signals [47, 66]. Although in vitro studies have shown that BAFF can promote IL-10 and IL-35 production in CD5⁺CD1d^hi B cells [47, 58], further investigation is required to determine whether BAFF directly supports suppressive Breg function in SLE or whether BAFF inhibition disrupts Breg homeostasis.

Concluding Remarks

Although the role of BAFF supporting the survival of autoreactive B cells and T-independent responses has been widely explored in SLE [28, 30], the reports of BAFF inducing the production of anti-inflammatory cytokines increases the complexity of this axis [47, 58]. Given that human Bregs share surface markers with transitional B cells (a population highly dependent on BAFF for survival) [53, 66], it is plausible that BAFF similarly supports Breg survival. Whether the BAFF-induced IL-10 production comes from regulatory or CD11c⁺ B cells needs to be explored. In concordance with the regulatory role of BAFF, the observed reduction in IL-10 levels [96] and the occurrence of de novo LN during belimumab treatment [91, 93] suggest that belimumab may provide insufficient protection in certain clinical contexts (Fig. 4). This highlights an important challenge: selecting patients for belimumab therapy based on serological activity may inherently identify individuals at increased risk of developing (de novo or relapse of) LN. Notably, these observations have been reported exclusively in the context of belimumab treatment, suggesting either a BAFF-specific effect or a context-dependent phenomenon. Whether this lack of protection during BAFF inhibition is related to a Breg imbalance or not remains unclear.

Fig. 4.

Dual role of BAFF. A Neutrophils and apoptotic cells release nuclear material (NETs and cell-free nucleic acids) that engage TLRs on pDCs producing large quantities of IFN-I, which promote the maturation of mDCs and enhance their capacity to present autoantigens to T cells. Concurrently, activated DCs upregulate BAFF expression and release it at elevated levels. Acting in concert, BAFF, IL-21, and cognate antigen presentation lower the activation threshold of autoreactive B cells, promoting their differentiation into autoantibody-secreting plasma cells and perpetuating the inflammatory pathology of SLE. B Elevated BAFF levels (right) promote the survival and maturation of conventional B cells and their differentiation into autoantibody-secreting plasma cells, contributing to the pathogenic humoral response in SLE. BAFF may also support the development of IL-10-producing Bregs and IL-10-secreting plasma cells (left), exerting anti-inflammatory effects that may limit disease progression. Three receptors mediate BAFF signalling (bottom) BAFF-R binds BAFF exclusively and is required for B cell survival. TACI and BCMA recognise both BAFF and the related TNF family ligand APRIL. C Breg development is depicted as dependent on direct T-B cell contact, as well as TLR9 signalling. Anti-BAFF therapy interrupts BAFF signalling, thereby reducing autoreactive B cell survival and pathogenic autoantibody production. However, this blockade raises an important question regarding collateral suppression of the Breg compartment whether BAFF inhibition concurrently impairs IL-10-mediated regulatory responses and potentially worsening end-organ injury such as in lupus nephritis. APRIL a proliferation-inducing ligand, BAFF B-cell activating factor, BAFF-R BAFF receptor, BCMA B cell maturation antigen, Bregs regulatory B cells, CAML calcium-modulator and cyclophilin ligand, IFN-I type I interferons, mDCs myeloid dendritic cells, NETs neutrophil extracellular traps, pDCs plasmacytoid dendritic cells, SLE systemic lupus erythematosus, TACI transmembrane activator and CAML interactor, TLR toll-like receptor

Funding

Open access funding provided by Linköping University. D.A. is supported by funding from the Ingrid Asps Foundation, Region Östergötlands Forsknings- och Stiftelseförvaltning (RÖ-1013485), familjerna Carl och Albert Molins i Motala minne Foundation (2023) and the Renal Foundation (F2025-0124). I.P. is supported by grants from Region Stockholm (FoUI-977096), Karolinska Institutet (FoUI-964139), the Swedish Rheumatism Association (R-1013624), King Gustaf V’s 80-year Foundation (FAI–2023–1055), Swedish Society of Medicine (SLS-974449), Nyckelfonden (OLL–1023269), Professor Nanna Svartz Foundation (2021–00436), and Ulla and Roland Gustafsson Foundation (2024–43). C.S. received grants from the Swedish Research Council for Medicine and Health (2023−02256), Ulla and Roland Gustafsson Foundation (2023−36), Swedish Rheumatism Association (R−993724), Region Östergötland ALF Grants (RÖ−981263), King Gustaf V’s 80-year Foundation (FAI–2022–0877), and King Gustaf V and Queen Victoria’s Freemasons’ Foundation (2022). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Declarations

Conflict of interest

I.P. has received research funding and/or honoraria from Amgen, Argenx, AstraZeneca, Aurinia, Biogen, Bristol-Myers Squibb (BMS), Elli Lilly, Gilead, GlaxoSmithKline (GSK), Janssen, Novartis, Otsuka, Roche, UCB, and Viatris. C.S. has received speaker’s honoraria from AstraZeneca, Novartis, Fresenius Kabi and BMS; and since April 2024, CS in an employee of BMS. The other authors declare no competing interests.

Availability of Data and Material

Not applicable.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Code Availability

Not applicable.

Author Contributions

CS and IP conceived the idea for the article. JAAG performed the literature search and drafted the article. IP, CS, DA and TW revised and edited the manuscript. All authors have read and approved the final manuscript.