B lymphocyte stimulator (BLyS), often referred to as B-cell-activation factor (BAFF), is a member of the tumor necrosis factor (TNF) cytokine superfamily and is essential for B-cell survival and development (Figure 1) (Blair and Duggan, 2018). SLE is associated with B-cell hyperactivity, autoantibodies, and increased concentrations of BLyS (Zhang et al., 2001).

Belimumab, a fully humanized anti-BAFF monoclonal antibody, has been the first biologic drug to receive a license for the treatment of SLE to date. This medication binds to BAFF and prevents soluble BAFF from attaching to B cell receptors, thereby preventing B cell survival, differentiation, and activation (Blair and Duggan, 2018). Belimumab was formally approved for the treatment of SLE through a phase III randomized controlled trial (RCT) in 2011. And its efficacy is demonstrated by four large double-blinded phase Ⅲ RCT (Furie et al., 2011; Navarra et al., 2011; Stohl et al., 2017; Zhang et al., 2018). In the RCT, this medicine was shown to be effective in reducing SLE disease activity and severe flares and delaying the onset of lupus in addition to standard therapy (Furie et al., 2011; Navarra et al., 2011). And according to the findings of a prospective cohort trial, belimumab may have clinical benefits for people with acute and subacute cutaneous lupus erythematosus by decreasing the frequency of flares and slowing the progression of skin lesions in patients with active SLE (Iaccarino et al., 2017). In a 104-week trial conducted at 107 sites in 21 countries, the probability of kidney-related events, morbidity, and mortality was all lower in the trial group compared to the control group, which demonstrates the utility of belimumab with standard therapy (Furie et al., 2020). The effectiveness, safety, and pharmacokinetics of intravenous belimumab were assessed in a Phase-2, randomized, placebo-controlled, double-blind research for children with systemic lupus erythematosus (cSLE). The results show that belimumab was well tolerated by paediatric patients, and the pharmacokinetics, pharmacodynamics and safety profiles were similar to those of adults with SLE (Brunner et al., 2020). A 28-week open-label study found that increases occurred in the proportions of patients achieving primary efficacy renal response and complete renal response from open-label baseline to week 28. Additionally, no new safety signals were identified, and efficacy was generally maintained throughout the open-label phase (Furie et al., 2022).

Similar to belimumab, tabalumab is a fully human IgG4 monoclonal antibody against soluble and membrane BAFF. Two phase Ⅲ randomized, multicenter, double-blinded, placebo-controlled trials (ILLUMINATE-1 and ILLUMINATE-2) were taken to assess efficacy and safety of subcutaneous tabalumab in patients with SLE. The results of the study demonstrated that the key clinical efficacy endpoints of ILLUMINATE-1 failed to achieve statistical significance, and the safety profile of tabalumab was similar to placebo (Isenberg et al., 2016). However, ILLUMINATE-2 met the primary endpoint of SLE response index 5 in the cohort receiving tabalumab 120 mg every 2 weeks (Merrill et al., 2016).

Although both studies noted that there were no serious safety signals, LUMMINATE-2 revealed that more patients (8.5%) receiving tabalumab than placebo reported depression and 3 patients in the tabalumab cohort attempted suicide while on treatment (Merrill et al., 2016). Although the results of the two phase Ⅲ trials of tabalumab were unsatisfactory, they did not indicate little or no efficacy. That may be a result of tabalumab’s researchers skipping a phase Ⅱ clinical trial and going directly to a phase Ⅲ trial.

Blisibimod is a potent and selective inhibitor of BAFF and has a unique tetravalent, ‘peptibody’ structure features. The results of randomized, double-blind phase 1a and phase 1b trials demonstrated that the safety and tolerability profile of blisibimod in SLE was comparable with that of placebo (Stohl et al., 2015). Subsequently, a phase 2 RCT in patients with moderate-to-severe SLE was taken. In this RCT, SLE responder index 5 response rates were not significantly improved in the pooled blisibimod groups compared with placebo; however, reductions in proteinuria, changes in anti-double standard DNA antibody, complement C3 and C4, and reductions in B cells were observed significantly with blisibimod (Furie et al., 2015). Therefore, the phase Ⅲ RCT of blisibimod enrolled patients with high disease activity. Although the SLE responder index 6 was not met in the study, blisibimod was well-tolerated and was associated with steroid reduction, decreased proteinuria and biomarker responses (Merrill et al., 2018a).

Atacicept, a fusion protein of the transmembrane activator calcium moderator and cyclophilin lingand interactor (TACI) receptor and IgG, inhibit both BAFF and a proliferation-inducing ligand (APRIL). APRIL is another cytokine that has been identified as an important B-cell regulator. BAFF and APRIL levels are increased in patients with SLE, which indicates that dual blockade by atacicept may be more effective than blockading BAFF alone (Bag-Ozbek and Hui-Yuen, 2021).

A phase Ⅱ b RCT of 24-week, multicenter, randomized, double-blind, placebo-controlled, parallelism was taken to evaluate the safety and efficacy of atacicept in patients with SLE. The results of the study showed that there was a trend toward an improved SLE responder index 4 response rate with atacicept 75 mg and 150 mg as compared with placebo. Additionally, the risk of serious adverse events and serious or severe infection was not increased with atacicept as compared with placebo (Merrill et al., 2018b). The post hoc analyses of phase Ⅱ b RCT demonstrated that low disease activity (LDA) and lupus low disease activity state (LLDAS) were attainable at week 24 in the patients with high disease activity (HDA) receiving atacicept 150 mg compared to placebo (Morand et al., 2020b). Additionally, patients on continuous 150 mg atacicept had a reduced risk of first severe flare and a longer time to first severe flare. The study has drawn the conclusion that long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile and durable efficacy (Wallace et al., 2021).

Rituximab (RTX) is a chimeric monoclonal antibody that targets the B-cell CD20 (Figure 1) (Durcan et al., 2019). CD20 is a cell-surface antigen expressed on most B cells, except plasma cells, the majority of plasmablasts, and lymphoid stem cells (Gelfand et al., 2017; Payandeh et al., 2019). RTX was initially developed and approved by the Food and Drug Administration (FDA) for the treatment of non-Hodgkin’s lymphoma and has successfully entered rheumatology with benefits in the treatment of rheumatoid arthritis (RA) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (Stone et al., 2010; van Vollenhoven et al., 2015). RTX was first used in SLE in 2002, and 5/6 patients with refractory lupus erythematosus had a clinical response to the combination of RTX, CYC, and high-dose corticosteroids (Leandro et al., 2002). Subsequently, RTX is successful in treating refractory SLE symptoms such as nephritis and neuropsychiatric illness (Gottenberg et al., 2005; Leandro et al., 2005; Roccatello et al., 2011).

For the treatment of SLE, the combination of RTX and belimumab has undergone substantial research and appears to be a valuable potion for several clinical situations. Although RTX has a greater capacity to deplete B cells compared to belimumab, RTX’s SLE RCT has not achieved its primary clinical endpoint (Wise and Stohl, 2020). A randomized controlled trial was taken to evaluate the effectiveness of belimumab after RTX in SLE patients. In this study, patients were treated with RTX and then 4–8 weeks later were randomized (1:1) to receive belimumab or placebo for 52 weeks. The result of this study showed that belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced the risk of severe flare in SLE patients who are refractory to conventional therapy at 52 weeks (Shipa et al., 2021). The efficacy of the combination of RTX and belimumab is theoretically plausible but requires more clinical studies and case reports to confirm it.

The main side event of RTX is allergic response because it is a chimeric anti-CD20 antibody. Therefore, other anti-CD20 antibodies, like ofatumumab, are investigated in SLE. Ofatumumab is a fully humanized anti-CD20 monoclonal antibody and is a safe, well-tolerated and effective alternative for B cell depletion (Cinar et al., 2021). Ofatumumab has recently received permission for treatment in individuals with chronic lymphocytic leukemia (Sandhu and Mulligan, 2015) and multiple sclerosis (Hauser et al., 2020). In a single-center retrospective case series of 16 patients treated with ofatumumab, 14/16 patients were well-tolerated. In this study, B cell depletion was achieved in 12 patients and was associated with improvement in serological markers of disease activity including ANA, anti-dsDNA antibody, and complement levels. Additionally, half of the patients with LN achieved renal remission by 6 months (Masoud et al., 2018). In an endogamous Pakistani kindred with monogenic SLE, 2/3 of the siblings had severe infusion-related reactions to RTX. Therefore, ofatumumab has been used and resulted in marked clinical improvement in both patients (Lei et al., 2018). A study of single-center retrospective case series for juvenile SLE found that significant clinical improvement was observed in all cases after using ofatumumab, mirrored by improved laboratory markers of disease activity including anti-dsDNA antibody, complement levels, and proteinuria (Cinar et al., 2021).

Ocrelizumab is another fully humanized anti-CD20 antibody. The CD20 epitopes binding ocrelizumab and RTX are overlapping. The result of a phase Ⅲ study showed that overall renal response rates with ocrelizumab were numerically superior to those with placebo. However, ocrelizumab in SLE patients with class III/IV LN was terminated prematurely due to a high rate of serious infections in the cohort treated with ocrelizumab (Mysler et al., 2013). Anyhow, initial results suggested ocrelizumab may have some efficacy in treating LN. And ocrelizumab was shown to have great efficacy in treating multiple sclerosis in several phase Ⅲ trials (Lamb, 2022).

CD19 is a transmembrane protein on the surface of B lymphocytes and is an important co-receptor for B cell antigen receptor (BCR) signaling. It is closely related to the activation, signal transduction, and growth of B cells. CD19 co-linked with BCR synergistically enhances calcium release, mitogen-activated protein kinase activity and cell proliferation (Li et al., 2017). CD19 has been widely used in the diagnosis and prognosis of leukemia, lymphoma, and immune system diseases, and is an important target for immunotherapy. Fcγ receptor (FcγR) IIB is a low-affinity IgG receptor expressed on the surface of B cells, which, when combined with the Fc segment of IgG, crosslinks with the BCR, raises the threshold of B cell activation, reduces antibody production, and thus plays a negative feedback regulatory function in humoral immunity (Espéli et al., 2016).

XmAb5871 (also known as obexelimab), a monoclonal antibody targeting CD19 and FcγRIIb, was found to inhibit calcium transport, proliferation, and co-stimulatory molecule expression in B cells in SLE patients and healthy volunteers, thereby suppressing humoral immunity and reducing IgM, IgG and IgE levels (Horton et al., 2011). The result of a phase Ⅱ study showed that XmAb5871 was well-tolerated, the infection rate was low, and flares were similar to other trials, which supports further evaluation of XmAb5871 in SLE (Merrill et al., 2018c).

CD22 is expressed in mature B cells and modulates activation and migration of B cells by acting as an inhibitory co-receptor of the B-cell receptor. Epratuzumab is a humanized antibody binding to the glycoprotein CD22 of the cell surface of mature B cells (Clowse et al., 2017).

Initially, two phase Ⅲ study (ALLEVIATE-1 and -2) was taken to evaluate the efficacy and safety of epratuzumab in patients with moderate/severe flaring SLE. However, both initial ALLEVIATE studies were discontinued prematurely because of the drug supply (Wallace et al., 2013). Subsequently, phase Ⅲ study (EMBLEM) with 227 patients showed that proportion of responders was higher in all epratuzumab groups than with placebo (Wallace et al., 2014). An open-label extension study indicated that open-label epratuzumab treatment was well tolerated for up to 3.2 years, and associated with sustained improvements in disease activity along with a reduction of corticosteroid dose (Wallace et al., 2016). This result has been confirmed in several other studies (Strand et al., 2014; Tsuru et al., 2016). On the contrary, results from two phase Ⅲ trials showed that patients treated with epratuzumab + standard therapy did not result improvements in response rates over that observed in the placebo + standard therapy group (Clowse et al., 2017).

Abatacept is a fusion protein composed of cytotoxic T-associated protein 4 (CTLA-4) (a leukocyte differentiation antigen) and the Fc region of IgG1 (an immunoglobulin fused to extracellular structures). This medicine could regulate T cell costimulatory molecules by interrupting the interaction between CD80/CD86 and CD28 (Figure 1) (Pimentel-Quiroz et al., 2016). Two signals are required for T cells to activate and attack antigens to produce an immune response. For the first signal, antigen-presenting cells (APCs) bind to major histocompatibility complex (MHC) molecules and be presentd to T cell receptors on the T cell surface; for the second signal, APCs present B7 protein on their cell surface to CD28 protein on the T cell surface. Abatacept binds to B7-1 and B7-2 and blocks the signaling 2 pathway, preventing T cells from being activated.

However, a study showed that the phase II b clinical study of abatacept failed to meet the primary/secondary endpoints measured by the British Isles Lupus Assessment Group (BILAG) (Merrill et al., 2010a). In another clinical trial, a total of 298 patients were treated for 52 weeks to compare the efficacy and safety of intravenous (IV) abatacept. The result showed that although the primary endpoint was not met, abatacept showed evidence of biological activity (greater improvements in anti-double-stranded DNA antibody, C3, and C4 levels and a 20%–30% greater reduction in mean urinary protein-to-creatinine ratio compared with placebo) and was well tolerated in patients with active class III or IV lupus nephritis (Furie et al., 2014).

These unsatisfactory results may be related to a flawed study design that requires continuous optimization at a later stage. The safety profile of abatacept in patients with SLE suggests that abatacept may be considered as an alternative in refractory cases.

Interaction between the CD40 ligand (CD40L, CD154; mainly expressed on activated T cells and platelets) and the CD40 receptor (expressed on a variety of cells, including antigen-presenting cells and B cells) is essential for the activation of the adaptive immune system and drive the pathological process in SLE, including B cell differentiation and proliferation (Furie et al., 2021).

In human SLE, CD40L has long been a desirable therapeutic target. Dapirolizumab is a polyethylene glycol-conjugated Fab’ fragment that targets CD40 ligand (Narain et al., 2020). Since then, two phase Ⅰ clinical studies have investigated dapirolizumab. The first study showed predictable pharmacokinetics in both healthy individuals and patients with SLE and was well tolerated, with no safety signals of concern (Tocoian et al., 2015). The second study showed that multiple doses of dapirolizumab were well-tolerated, and there were no thromboembolic events during the study (Chamberlain et al., 2017). A phase Ⅱ study was taken to investigate the dose response, efficacy, and safety of dapirolizumab. The result of the study showed that although the primary objective was not met, dapirolizumab appeared to be well tolerated, and patients exhibited improvements across multiple clinical and immunological measures of disease activity after 24 weeks relative to placebo (Furie et al., 2021). Further research is necessary to determine the clinical benefit of dapirolizumab.

Spleen tyrosine kinase (Syk) and calcium/calmodulin kinase IV (CaMKIV), small molecule inhibitors of kinases, are aberrantly expressed in immune cells of SLE patients and may present novel treatment prospects.

Syk is implicated in membrane-mediated signal transduction in a variety of cells and overexpressed in T cells of patients with SLE (Krishnan et al., 2008; Grammatikos et al., 2013). In the MRL/lpr mouse model, the Syk inhibitor, R788, avoided the onset of skin disease and dramatically reduced established skin disease, with clinical effects lasting at least 1 month after discontinuation of the drug. Syk inhibitor also decreased the growth of spleen and lymph nodes and inhibited kidney disease progression (Deng et al., 2010).

When the combination of T cell receptor and CD3 is activated, CaMKIV, which is expressed at high levels in SLE T cells, translocates to the nucleus and results in aberrant T cell function. A study using the CaMKIV inhibitor KN-93 to treat MRL/lpr mice found that CaMKIV inhibitor in MRL/lpr mice significantly suppressed nephritis and dermatosis, reduced the expression of co-stimulatory molecules CD86 and CD80 on B cells, and prevented the generation of inhibition of interferon (IFN)-γ and TNF-α. In human SLE T cells, the silence of CaMKIV results in the inhibition of IFN-γ production, which confirms the rationality of developing small molecule CaMKIV inhibitors for the treatment of SLE patients (Ichinose et al., 2011).

Anifrolumab, a monoclonal antibody that targets the type I IFN receptor, successfully treated individuals with SLE in a phase 3 randomized trial in 2020 (Morand et al., 2020a). The results showed that adverse events in patients in the anifrolumab group included respiratory infections, nasopharyngitis, and infusion-related reactions. The number of adverse outcomes was lower than that in the placebo group, as well as better GC tapering and severity of skin disease than with the placebo (Morand et al., 2020a). A phase Ⅱ study was taken to assess the efficacy and safety of anifrolumab. Although the result showed that the primary endpoint was not met, anifrolumab intensified regimen was associated with numerical improvements over the placebo acrossing endpoint, including complete renal response (CRR), urine protein-creatinine ratio, CRR with inactive urinary sediment, and sustained glucocorticoid reductions (Jayne et al., 2022). Still, more studies are required to confirm the effectiveness and safety of this drug.

Sifalimumab is a human-derived anti-IFN-α antibody. A recent phase II b clinical trial demonstrated that Sifalimumab has an inhibitory effect on IFN gene expression in patients with moderately to severely active SLE, resulting in remission of disease activity and joint injury (Takeuchi et al., 2020). Therefore, it is important to further explore the role of the type I IFN signaling pathway in autoimmune diseases to develop more effective and safe therapies approaches.

Cytokines play a role in the pathogenesis of SLE, for example, IL-4, IL-5, IL-6, IL-10, and IL-15 are increased in the serum of SLE patients. The pathogenesis of SLE is still unclear, and multi-level analysis of relevant cytokines is beneficial to provide a basis for new target therapy for SLE in the future.