Recent Advances in SLE Treatment Including Biologic Therapies

Abstract

Systemic lupus erythematosus (SLE) is a long-term multisystem autoimmune rheumatic disease that can affect the skin, joints, kidneys, lungs, heart, and central nervous system. Clinical manifestations range from mild to severe and life-threatening diseases, which could be associated with poor outcomes, including morbidity, poor quality of life, and mortality. There is no cure for SLE, and the management is guided by organ system involvement, flare prevention, managing comorbidities, and reducing damage accumulation. Hydroxychloroquine is the most common drug that is used to control lupus disease activity. Anifrolumab is an antibody that inhibits all signaling through the type I interferon receptor and is licensed for the treatment of moderate to severe SLE. Voclosporin is a calcineurin inhibitor approved for the treatment of lupus nephritis. Belimumab as a biologic agent has been approved for the management of individuals with SLE and lupus nephritis. Despite the fact that rituximab has failed to meet its primary endpoints in clinical trials for SLE, rituximab can be used according to ACR and EULAR guidelines and is commonly used off-label for severe lupus flares. There is an unmet need for new biologic and novel therapeutic approaches in the management of SLE.

1. Introduction

Systemic lupus erythematosus (SLE) is one of the most prevalent systemic autoimmune diseases caused by a dysfunctional immune system. In the SLE-affected individuals, autoantibodies are generated against tissue antigens, including nuclear, cytoplasmic, phospholipid-associated, and cell-membrane antigens—major constituents of different cell types residing in tissues and organs of the human body [1]. The binding of autoantibodies with tissue antigens generates immune complexes, which may be deposited inside tissues and organs over time. These immune complexes elicit a cascade of immune responses that result in severe inflammation and destruction of tissue architecture, leading to multiorgan dysfunction and premature mortality [2].

SLE is a long-term multisystem autoimmune rheumatic disease that can affect the skin, joints, kidneys, lungs, heart, and central nervous system. Clinical manifestations range from mild to severe and life-threatening diseases, which could be associated with poor outcomes, including morbidity, poor quality of life, and premature mortality. There is no cure for SLE, and the management is guided by organ system involvement, flare prevention, managing comorbidities, and reducing damage accumulation. The clinical signs and course of the pathology of SLE can be altered through lifestyle alteration, such as avoiding sunlight and diet modifications. The incidence and prevalence of SLE have increased in the last few decades, possibly due to increased awareness and the ability to diagnose milder forms of SLE [3]. Studies indicate that SLE has shown strong ethnicity and gender biases. Certain ethnic groups such as those with African and Asian ancestry are more predisposed to the development of SLE. While the incidence of SLE differs between the different ethnic groups, it is interesting to note that the incidence of SLE is higher in females than in males, across all groups of ethnicities [4, 5]. Pregnant women with SLE have an increased risk of recurrent miscarriages, fetal retardation, and stillbirths especially if they are positive for antiphospholipid antibodies. The babies born to SLE mothers are at a 3% risk of having neonatal lupus especially if they are positive for anti-RO and/or anti-LA antibodies [6].

SLE is a complex disease with poorly defined etiology. Several studies have reported a strong correlation between disease incidence and certain genetic and environmental factors. About 7% of childhood-onset SLE show Mendelian inheritance and is associated with defects in genes involved in the clearance of necrotic and/or apoptotic cell debris, pathways that protect against autoimmune response against autoantigens, and those involved in autoreactive lymphocyte generation and maintenance [7, 8, 9, 10]. Hormones are a significant underlying factor responsible for gender-biased SLE development. Specifically, estrogen and estrogen receptor signaling mediates SLE through positive regulation of CREMα transcription factor, favoring the generation of CD4+ T effector cells and double-negative T cells [11]. Several environmental factors have been associated with an increased risk of SLE. However, the time duration of exposure and dosage is not well-defined [12, 13, 14]. Particulate matter in the air, including cigarette smoke, induces oxidative stress and can damage endogenous DNA, and cellular proteins are known to trigger SLE development [15, 16]. Exogenous hormone uses, such as oral contraceptives and hormone replacement therapy, have been positively linked with SLE onset [17]. The involvement of cardiovascular disease in patients with SLE can increase the risk of mortality [18]. Renal failure and sepsis are the significant causes of mortality in patients with SLE [19]. Furthermore, autoimmune vascular injury increases the risk of atherosclerosis and coronary artery diseases in SLE patients [20].

Over the past two decades, the understanding of SLE pathogenesis and treatment has improved. Significant progress has been made in uncovering the molecular events that trigger SLE pathogenesis and exploring novel treatment options, including newly approved biologics. In this chapter, we discuss the advances in the pathogenesis of SLE and emerging treatment options.

2. Therapy with small molecules

Since SLE is an autoimmune disease affecting multiple tissues and organs, the outcome of the disease is mostly unpredictable [21, 22]. The optimum management of SLE is preventing further tissue or organ damage, preventing flares, improving the quality of patients’ life, and ultimately extending the lifespan of SLE patients. However, currently available therapy is mainly focused on treating symptoms, including flares. Antimalarials, glucocorticoids, and other immunosuppressive drugs are among the current treatments [23].

2.1 Hydroxychloroquine

Hydroxychloroquine (HCQ) belongs to the group of antimalarials. Among the oldest drugs used in SLE, chloroquine, and HCQ were introduced between 1953 and 1955 and these drugs are four aminoquinolines that are widely used to manage SLE [22, 24]. Antimalarial drugs are well-absorbed orally, and the half-life of hydroxychloroquine is around 40 or 50 days [25]. Although the mechanisms of action of antimalarial drugs in attenuating inflammation and clinical signs of SLE remain unclear, recent studies suggest a possible action on the lysosomes of the immune cells. Specifically, antimalarials increase the lysosomal vesicle pH, suppressing the antigen presentation and synthesis of inflammatory mediators, such as prostaglandins, cytokines, and chemokines [26]. One of the most beneficial effects of increasing lysosomal pH in antigen-presenting cells by antimalarials is the selective suppression of presentation of autoantigens by decreasing the binding of autoantigenic peptides to class II MHC molecules without affecting the responses against foreign antigens [26].

Similarly, chloroquine and hydroxychloroquine also inhibit Toll-like receptor (TLR) signaling in immune cells leading to reduced immune activation [27]. In addition, chloroquine treatment inhibits the production of pro-inflammatory cytokines, including TNF, IL-6, IFN-γ, IL-1β, and IL-18, in a lysosome-independent manner [28, 29]. Hydroxychloroquine reduces the serum levels of the leukocyte activation markers, including soluble CD8 and soluble IL 2 receptors [30]. Studies suggest that antimalarial agents might work as prostaglandin antagonists and inhibit the enzyme phospholipase A2 by decreasing inflammation [22, 31]. Chloroquine and hydroxychloroquine reduce dermatological manifestations, significantly protecting against skin damage by reducing the production of pro-inflammatory cytokines exposure to ultraviolet light. Moreover, chloroquine treatment also reduces matrix metalloproteinase activity and helps maintain extracellular matrix homeostasis in patients with SLE [32, 33].

HCQ is an inexpensive, well-studied, well-tolerated, and most valuable immunomodulator drug for SLE treatment. Several studies have been published on the efficacy of antimalarials in patients with SLE. Generally, HCQ is prescribed to all SLE patients with minimal contraindications or side effects, especially in patients with lupus nephritis, and is used to treat constitutional, musculoskeletal, and mucocutaneous involvement. Studies indicate that antimalarials reduce mortality in SLE patients of diverse ethnic groups [34, 35, 36, 37, 38]. Administration of HCQ significantly reduces the severity of SLE disease activity, which includes a reduction in active clinical involvements, serum markers, activity scores, and disease flares [39]. Randomized controlled trials (RCT) have demonstrated the benefits of HCQ in SLE, including a reduction in flares [40, 41, 42], improvement in arthralgia [41], cytokine profiles [29, 43, 44, 45], and disease severity [36, 46, 47, 48, 49]. HCQ decreases SLE disease activity, including flares during pregnancy [39, 50]. Despite the fact that HCQ is well tolerated, it has been linked to a variety of side effects, including cardiovascular, hematological, neurological, ocular, and skin concerns [39]. HCQ reduces the recurrence of congenital heart block in anti-SSA/Ro-pregnancies in SLE mothers and can be used as a secondary preventative of fetal cardiac disease [51]. Furthermore, a combination of HCQ and mepacrine has a synergistic effect in refractory musculocutaneous lupus [52].

2.2 Glucocorticoids

Glucocorticoids are well known for their rapid action, potent anti-inflammatory, and immunosuppressive effects. They are part of treatment regimens for many autoimmune rheumatic diseases, including SLE. Glucocorticoids exert their action via genomic and nongenomic pathways [53]. The genomic pathway of glucocorticoids is mediated by the cytoplasmic glucocorticoid receptor, which binds to the glucocorticoids in the cytoplasm. After binding, the GC-cGR complex translocates inside the nucleus and binds to the glucocorticoid response elements present in the promoter of several target genes. The GC-GC complex decreases the transcription of inflammatory cytokines via the process known as transrepression and increases the transcription of anti-inflammatory genes by transactivation [53, 54]. The nongenomic pathway is mediated via the membrane glucocorticoid receptor, inhibition of the enzyme phospholipase A2, and alterations in the cell membranes leading to decreased lymphocyte proliferation and function [55]. While genomic mechanisms require 30 minutes for activation after administration of glucocorticoids, nongenomic mechanisms work within minutes after administration. Generally, activation of the genomic and nongenomic pathways depends on the dose of glucocorticoids. While low doses of glucocorticoids induce genomic pathways, very high doses induce nongenomic pathways of action. Specifically, the nongenomic pathway is activated at doses of more than 100 mg/day of glucocorticoids and it is sensitive to glucocorticoids, such as methylprednisolone and dexamethasone, which have five times more potent nongenomic effects than genomic ones [56]. Interestingly, the use of glucocorticoids in lupus dramatically improved the survival of patients [56, 57]. Glucocorticoids are considered primary therapy in achieving rapid control of active lupus. Studies indicate that pulse intravenous methylprednisolone reduces moderate to severe disease activity [58]. Oral prednisone at a dose of less than 30 mg/day initially and then tapering dose between 2.5 and 5 mg/day over a few weeks successfully treated SLE [59, 60, 61, 62, 63]. Specifically, pulses of methylprednisolone combined with other immunosuppressive drugs and HCQ were helpful in achieving rapid and prolonged lupus disease control [58, 64], resulting in the reduction of cardiovascular and global damage [58]. Glucocorticoids are the best therapeutic strategy during pregnancy in the case of lupus flares as their potent anti-inflammatory effect is not associated with teratogenicity but may increase maternal morbidity [65]. Although glucocorticoids have significantly reduced acute mortality in severe SLE, the high-dose treatment regimen for long periods has markedly increased adverse events and systemic infections, causing long-term damage. Extensive observational studies support that GC-mediated toxicity is mainly dependent on the dose and the duration of exposure [66]. It appears that doses lower than 7.5 mg/day (prednisone equivalent) may be relatively safe for long-term maintenance therapy for glucocorticoids [66, 67, 68]. In contrast, using a high dose of glucocorticoids has been associated with the development of osteonecrosis, infectious complications, and even death [69, 70, 71, 72, 73].

2.3 Azathioprine

Azathioprine (AZA) has been one of the oldest immunosuppressants. It is used in treating conditions, such as chronic inflammatory diseases [74], organ grafts, malignancies, and rheumatologic diseases [75]. It is a heterocyclic carbon–nitrogen aromatic compound belonging to the purine family of analogs. It is the only purine analog used in treating SLE [76]. Though its mechanism of action in immunosuppression is controversial, AZA and its metabolite 6-mercaptopurine (6-MP) inhibit the enzymatic conversion of inosinic acid to xanthylic acid and of adenylosuccinate to adenylic acid and are known to interfere with DNA replication and de novo synthesis of nucleotides. This inhibits the replication of T-lymphocytes, as they are deprived of salvage pathways [77]. A previous study reported that AZA could induce T-cell apoptosis by inhibiting the costimulatory signaling mechanism that results in T-cell anergy, thus mitigating the effects of autoimmune cells [78]. Azathioprine is used in SLE for the management of multiple active nonrenal manifestations and renal complications, such as lupus nephritis, and is safe for use during pregnancy. AZA alone has shown encouraging results in the treatment of SLE when combined with steroids to reduce SLE mortality and morbidity [79]. Although AZA and 6-MP have been evidenced to cross the placenta [80], several studies show that when AZA is given at a lower dose, it can effectively treat SLE without affecting the fetus or creating congenital abnormalities [81].

2.4 Mycophenolate

Mycophenolate is an antiproliferative immunosuppressant drug. As an inhibitor of inosine monophosphate dehydrogenase (IMPDH) that is both uncompetitive and selective, mycophenolic acid (MPA) does not incorporate into the DNA while inhibiting the guanosine nucleotide synthesis de novo pathway. It is cytostatic on lymphocytes as mycophenolic acid inhibits the critical dependency of the de novo pathway of purine synthesis, through which T- and B-lymphocytes proliferate. It is typically administered orally in the form of tablets, whether coated, delayed-release, or as a suspension, and as lyophilized or powder for injection. Similar to AZA, MPA’s mechanism of action interferes with the de novo synthesis pathway of nucleotides, with a cytostatic effect on lymphocytes. Mycophenolic acid has a mean half-life of 8–16 hours and an MPAG metabolite half-life of 13–17 hours, but its route of elimination is not understood. It was introduced as a new drug in patients with lupus nephritis and renal problems who were unresponsive to conventional immunosuppressants [82]. MPA is available as a prodrug mycophenolate mofetil (MMF) and mycophenolate sodium (Myfortic) that increases MPA bioavailability and lessens gastrointestinal side effects, respectively [83]. MPA treatment has been reported to lessen the SLE complications combined with other immunosuppressive drugs, such as corticosteroids and antimalarials, when the disease was inadequately controlled with the previous non-MPA treatment regimens. Mycophenolate mofetil is most frequently used for induction or maintenance therapy of lupus nephritis and is effective in treating nonrenal symptoms as well. Typical symptoms of adverse effects include leukopenia, neutropenia, abdominal pain, diarrhea, nausea, vomiting, and dyspepsia. Mycophenolate has a potential teratogenic effect. Pregnancy case studies show that mycophenolate consumption during pregnancy causes major adverse effects including early, spontaneous, and elective terminations and abortions, fetal malformations and congenital defects, and premature and low-birth-weight newborns, [84]. As a result, female SLE patients have been prescribed AZA instead of mycophenolate when they become pregnant [85].

2.5 Cyclophosphamide

Cyclophosphamide (CP) is an inactive prodrug that requires enzymatic activation, which occurs by the hepatic cytochrome P-450 [86]. Cytochrome P-450 hydroxylates the oxazaphosphorine ring of cyclophosphamide, thereby generating 4-hydroxycyclophosphamide, which coexists with its tautomer aldophosphamide. Upon decomposition, this aldophosphamide yields phosphoramide mustard, which acts as the alkylating effector, thereby exhibiting the cytotoxicity of CP. Interestingly, immunosuppression with cyclophosphamide has been identified as effective against life-threatening autoimmune disorders, such as SLE. SLE is characterized by B-cell hyperactivation and subsequent autoantibody production, often accompanied by T-cell abnormalities [87]. Under these conditions, cyclophosphamide has been beneficial as it effectively suppresses B-cell activity and antibody production [86]. Clinical studies in murine and human models showed that cyclophosphamide was more effective than prednisone in stabilizing renal function when given orally or intravenously. Standardization of medication revealed that long-term courses of cyclophosphamide alone or in combination with high doses of corticosteroids had a lower probability of doubling serum creatinine and renal function preservation [86]. A 6-month treatment regimen with cyclophosphamide significantly improved renal function and complement activity. Over the last years, IV cyclophosphamide is one of the standards of care for induction of remission therapy that is used in severe lupus nephritis due to its ability to slow the progression to end-stage renal failure and it has been shown to be also effective for the treatment of severe nonrenal symptoms, such as vasculitis and myocarditis. While cyclophosphamide is beneficial, it should be noted that its administration is associated with significant adverse effects, including nausea and vomiting [88]. Cyclophosphamide, like other cytotoxic medicines, has teratogenic side effects. Among the most acute toxicities of CP are cytopenias, infections, gonadal failure, and malignancies [86]. Some infections, including herpes zoster, are more common than others in these patients; hence regular vaccinations are recommended. While the overall standardized incidence ratio of cancer is higher in SLE patients, administration of CP has been shown to increase the incidence of cancers, particularly those of the urinary tract, bone marrow, and skin, prompting the use of combination therapy to prevent these side effects [89]. A recent randomized clinical trial in Chinese SLE patients comparing cyclophosphamide and tacrolimus has shown that tacrolimus has a marginally higher rate of complete response and faster recovery of kidney function [90]. In contrast to this, another trial showed that combination therapy of cyclophosphamide with rituximab followed by belimumab not only lowered the maturation of transitional to naive B cells during B-cell reconstitution but also improved the negative selection of autoreactive B cells, thereby proving beneficial over the conventional cyclophosphamide and belimumab combination [91]. When cyclophosphamide is contraindicated due to a previous severe reaction or malignancy, or there is a concern for drug toxicity, mycophenolate mofetil or rituximab or belimumab is recognized as an alternative immunosuppressive agent to cyclophosphamide for the treatment of lupus nephritis.

2.6 Voclosporin

The use of calcineurin inhibitors (CNIs) voclosporin is an effective therapy against lupus nephritis, a common and serious consequence of SLE. CNIs bind to and inhibit calcineurin, a calcium-dependent phosphatase, preventing T-cell activation, and T-cell-mediated immune response leading to attenuation in the inflammatory process in lupus nephritis [92]. Voclosporin has a modified functional side chain and was found to have a fourfold increase in potency by inducing structural changes in calcineurin. The modification increased the effectiveness of this drug and improved the clearance of metabolites from the system. Thus, voclosporin was effective against lymphocyte proliferation, T-cell antigen presentation, and cytokine production [92]. According to the results of phase II clinical trial, females treated with voclosporin exhibited a 25% reduction in urine protein creatinine ratio after 8 weeks of treatment, as well as better complement activity after 24 weeks of treatment [93]. Interestingly, by the end of 24 and 48 weeks, the majority of patients had achieved remission, indicating that voclosporin was well tolerated in SLE patients. Another randomized double-blind placebo-controlled multicenter trial called AURA-LV, found that both low-dose and high-dose voclosporin administration promoted complete remission much more than the placebo group in a heterogeneous population [94, 95, 96]. Moreover, these patients had reduced anti-dsDNA antibody levels by 48 weeks, indicating the effectiveness of the medication. However, the study reported that patients receiving voclosporin experienced at least one adverse effect. Infection was the most common, under low-dose and high-dose administration, with a mortality of 5% [94]. Common adverse effects of the people who died in the low dose administration group include acute respiratory distress syndrome, infection, and thrombosis. Infection and pulmonary embolism were both common adverse outcomes in the high-dose administration deaths, showing that this medicine could have safety concerns [94]. Furthermore, the AURORA1 clinical trial in lupus nephritis patients found that adding low-dose voclosporin to a regimen of MMF given with low-dose corticosteroids significantly improved the therapeutic effects, with stable kidney function and no increase in the incidence of adverse effects [97].

2.7 Tacrolimus

Tacrolimus is a calcineurin inhibitor studied for its effects against SLE [98]. Tacrolimus has been recognized for its immunosuppressive effects and has found extensive use as a post-transplant drug. Mechanistically, tacrolimus binds to FK-binding proteins in the cytoplasm, forming a complex associated with the calcium-dependent calcineurin/calmodulin complexes to inhibit calcium-dependent signal transduction lymphocytes and resultant cytokine production [98]. The initial report on tacrolimus’ efficacy against SLE came from a patient study in which cyclophosphamide and cyclosporine treatment was shown to be ineffective. Tacrolimus treatment reduced creatinine levels and eliminated digital vasculitis and gangrene in these patients [99]. Furthermore, tacrolimus had a significant impact on treatment-resistant cutaneous lupus erythematosus [100]. Another study in mice with spontaneous lupus nephritis found that tacrolimus reduced proteinuria slowed nephropathy progression and increased the lifespan of the lupus mice. Moreover, tacrolimus reduced the elevation in anti-ds DNA antibodies seen in SLE patients [101, 102]. A previous patient study showed that patients administered with tacrolimus for a year had a significant decrease in the SLEDAI (SLE Disease Activity Index) compared to nontreated patients [103]. Moreover, patients exhibited decreased anti-dsDNA antibodies and increased C3 concentration, indicating improved complement activity. While these patients developed minor adverse effects, such as tremors and headaches upon tacrolimus administration, the effects subsided gradually, indicating the medication’s effectiveness and safety [103]. In addition to its efficacy in SLE patients without renal involvement, tacrolimus was effective in pediatric SLE patients with lupus nephritis who had persistent disease activity despite conventional immunosuppressive therapy [104]. Subsequently, multiple studies showed the effectiveness of tacrolimus in SLE patients through its improvements in renal function and targeted immunosuppression [98], thereby proving it as an effective therapeutic agent that functions against SLE through multiple mechanisms. In a meta-analysis of several randomized controlled trials, case-control studies, and cohort studies, it was found that tacrolimus in combination with glucocorticoids resulted in higher total remission rates, lower proteinuria levels, and a lower SLE activity index than cyclophosphamide, indicating that tacrolimus is a safe and effective therapy against SLE [105]. Another trial indicated that tacrolimus is as effective as and non-inferior to mycophenolate mofetil in reaching a complete renal response rate, demonstrating its value as a lupus nephritis induction therapy [106]. Combination therapy has demonstrated encouraging results in the treatment of patients with refractory lupus nephritis, with the potential to improve disease control and prevent lupus nephritis flares. Both mycophenolate mofetil and tacrolimus combination have synergistic efficacy and favorable adverse event profile; therefore, they can be utilized to treat refractory lupus nephritis.

3. Therapy with biologics

During the past decade, a new class of therapeutics called biologics has been introduced, and their use led to successful treatment outcomes for lupus and several other inflammatory diseases. Biologics are proteins capable of binding to specific receptors present in immune cells and modulating the functions of immune cells. Overall, biologics are now being developed against several types of immune cells to modulate the functions of the immune system to treat the disease (Figure 1). Belimumab, a biologic that targets B cells, has been approved for the treatment of SLE. A number of biologics are now being studied in clinical trials (Table 1).

Figure 1.

Mechanism of action of belimumab and rituximab. Belimumab competitively inhibits BAFF binding to the BAFF receptor required for B-cell survival and maturation. Similarly, rituximab inhibits CD-20 on the surface of B cells, which inhibits B-cell maturation into plasma cells.

Drugs	Type	Target cell/molecule	Mode of action	Clinical trial	Side effects	References
Obinutuzumab	Humanized anti-CD20 monoclonal antibody	CD20 on B-cell	Binding to CD20 on B-cell which causes complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity	Phase III	Neutropenia, Anemia, Pyrexia, Musculoskeletal disorders, Cough, Infusion reactions, Thrombocytopenia,; Hepatitis B virus reactivation
Daratumumab	Humanized anti-CD38 mAb	CD38 marker on plasmablasts	Binds to CD38 and causes apoptosis by triggering ADCC, complement-dependent cytotoxicity	Phase II	Infusion-related reactions (IRRs), face swelling, skin rashes
Ustekinumab	Human monoclonal antibody against p40 subunit of IL-12 and IL-23	p40 subunit of IL-12 and IL-23	Prevent these molecules from binding to their receptors	Phase II discontinued during phase III	Dizziness, joint pain, headaches, sore throat	[21]
Obexelimab	Humanized Fc-engineered anti-CD19 mAb	CD19 on B-cell	Co-engages BCR and FcγRIIb on B-cell and inhibits B-cell activation	Phase II	Not known
Lulizumab	Humanized PEGylated anti-CD28 dAb (Domain antibody)	CD28 on T-cell	Binds to CD28 receptor and inhibits T-cell proliferation and cytokine production	Phase II	Not known
VIB7734	Anti-1LT7 Monoclonal antibody	Plasmacytoid dendritic cells	Deplete pDCs through ADCC	Phase II	Not known
BIIB059	Humanized IgG1 monoclonal antibody	BDCA2 (blood dendritic cell antigen 2) receptor pf pDCs	Causes rapid BDCA2 internalization and impedes IFN production by plasmacytoid dendritic cells which leads to IFNGS (Type I interferon gene signature) expression in blood	Phase II	Risk of infection because of diminished pDC-mediated antiviral response	[21]
Telitacicept	Recombinant TACI-Fc (transmembrane activator and calcium modulator and cyclophilin ligand interactor) fusion protein	BLyS (B-lymphocyte stimulator) and APRIL (a proliferation-inducing ligand)	Binds and neutralizes the activity of BLyS and APRIL, thereby, inhibiting the development and survival of mature B cells and plasma cells	Phase II	Upper respiratory tract infection, reactions at the injection site	[21]

Table 1.

Biologics currently under clinical trial for the treatment of SLE.

3.1 Anifrolumab

Anifrolumab, a type I interferon receptor antagonist, was recently approved in 2021 for the treatment of SLE in patients with moderate to severe symptoms [107]. Previous studies have indicated that type I IFN plays a key role in the pathophysiology of SLE and increased type I IFN signaling causes increased disease activity. Previous studies have demonstrated that type I interferon plays a key role in the pathophysiology of SLE and increased type I interferon signaling results in increased disease activity [108, 109]. The efficacy and safety data were obtained from the two TULIP phase III trials, and the MUSE phase II trial led to the approval of Anifrolumab [108, 110, 111, 112, 113]. These trials were randomized, double-blinded, and placebo-controlled trials involving patients with moderate to severe SLE, who were under standard therapy with glucocorticoids, antimalarials, or immunosuppressants. In these trials, SLE patients treated with Anifrolumab experienced an overall reduction in disease activity in almost all organs, especially in skin and joints, and achieved a considerable reduction in the requirement of corticosteroids [107]. Further data suggest that Anifrolumab prevents organ damage occurring due to SLE or by chronic medications, including steroids, and thus, it improves the quality of life of SLE patients. The major adverse effects of Anifrolumab usage are mostly respiratory tract associated, including nasopharyngitis, bronchitis, and upper respiratory tract infections [107, 108, 110, 111, 112].

3.2 Rituximab

Rituximab (RTX) is a monoclonal antibody targeting CD20, a membrane receptor present on the surface of B-lineage cells, as a transmembrane protein excluding plasma cells and pro-B cells [114, 115, 116]. The interaction between CD20 and RTX results in the inaccessibility of CD20 for its ligand, leading to the inhibition of distinct cell survival pathways and B-cell maturation signals. Furthermore, the binding of rituximab with this membrane receptor results in the induction of both antibody and cell-mediated cytotoxicity, which causes the reduction of CD20⁺ cells [116]. The FDA initially approved RTX for non-Hodgkin’s lymphoma; it has also provided promising results in rheumatoid arthritis (RA) treatment. Based on recent studies, RTX may have a beneficial role in inflammatory diseases [117]. In 2002, RTX was used to treat SLE; RTX was used in combination with steroids and cyclophosphamide; five out of six patients developed significant improvement in response to this treatment [118, 119]. RTX showed significant beneficial results in phase I and phase II clinical trials; another retrospective clinical trial performed on 45 patients showed the beneficial effects of RTX [120]. Phase II and phase III trials, known as the EXPLORER trial, were conducted based on the positive outcomes of RTX treatment in SLE. The main aim of this trial was an extensive analysis of RTX efficacy in nonrenal SLE. This trial comprised 257 patients who were kept on a stable dose of one immune-suppressive drug were included in this study; these participants were treated by following a standard care of treatment, along with either two intravenous RTX 1 g doses (one at 14 days following the start of the trial and the other at 6 months) or placebo. The use of methotrexate, azathioprine, mycophenolate mofetil (MMF), and corticosteroids was allowed for continuation under the supervision of treating medical specialists. The primary endpoint of this study was to achieve and maintain a robust clinical response or a partial clinical response by the 52nd week. The secondary endpoint was to assess the clinical response of patients at 52 weeks, along with the improvement in quality of life. The steroid-sparing benefit of RTX was also evaluated as a secondary endpoint. No difference between the primary and secondary endpoints was observed in the RTX and placebo groups for this EXPLORER trial. Another trial, known as LUNAR, was conducted in SLE patients to investigate the efficacy of RTX in lupus nephritis [121]. It was a double-blind RCT with 144 participants, and the amount of RTX dosage and other standards of care treatments were similar to the EXPLORER trial. There was no significant difference between the RTX and placebo cohorts’ primary and secondary endpoints [121]. Although the endpoints of phase II and phase III RCTs for rituximab failed, this does not necessarily mean that the drug failed; trial design can be considered as a possible potential reason for this failure. RTX has some adverse effects. RTX use is contraindicated in advanced heart failure (New York Heart Association Class IV) [122]. Since RTX is an immunosuppressant, infection is a significant concern with rituximab treatment. Several studies have shown that repeated use of RTX can be associated with decreased immunoglobulin levels. Patients who already have low immunoglobulins or are already taking other immunosuppressant medication have a higher rate of infection while taking RTX treatment [123].

3.3 Belimumab

Belimumab (BEL) is a monoclonal antibody that targets BAFF [124] and is referred to as a B lymphocyte stimulator (BLyS); these factors are secreted by myeloid-lineage cells. The binding of BAFF with BAFF-R (receptor present on B naïve cells) leads to the activation of specific signaling, promoting survival and differentiation of the naïve B cells [125]. BEL binds with these soluble stimulatory factors, resulting in the inhibition of BLyS binding with BAFFR [124, 126]. BEL was first approved for adult SLE in 2011, with remarkable success in adult SLE treatment. A study performed on mice models has demonstrated the importance of BAFF in SLE progression, where deletion of the Baff gene prevented SLE progression in diseased mice [127]. Neutralizing BAFF with specific immunogenic approaches in mice has shown a significant reduction in disease progression [128, 129]. Patients suffering from SLE have shown a higher level of BAFF than healthy controls, and the level of BAFF was found to be increased in the correlation with SLE progression [130, 131, 132]. Efficacy of BEL against SLE was initially studied in a large double-blind phase III RCTs [133, 134]. In this study, 10 mg/kg intravenous BEL was given in addition to the background standard of care therapy with a 2-week interval between the first three doses and then every 4 weeks. SLE patients who had active CNS involvement or lupus nephritis were excluded. Participants were kept on stable doses of corticosteroids, antimalarials, nonsteroidal anti-inflammatory drugs, and immunosuppressive drugs for 30 days before this trial. The primary endpoint was the SLE responder index-4 at week 52. This accounted for ≥4-point depletion in the SLE disease activity index (SELENA-SLEDAI) score. The significant difference between the patient and placebo arm of the trial study has given promising results for BEL use against SLE. Consistently, BEL effectively improved SLE in all the trials compared to placebo. BEL has also shown steroid-sparing effects in these patients [135, 136]. Moreover, in the ongoing international observational clinical studies, BEL is being used as a part of the treatment routine in more than 700 patients and has shown remarkable beneficial effects [137, 138, 139]. Despite being a remarkable drug against SLE, and being an immunosuppressor drug, BEL also has some contraindications along with minor side effects. Major infections have been observed in the patients treated with belimumab. Appropriate precautions and medical advice should be taken by the patient suffering from chronic infection before the BEL treatment [124]. In patients with refractory LN, studies showed that adding belimumab to a therapy regimen that included rituximab/CYC was safe and effective [140]. Moreover, BEL, despite being a safe drug, not all the patients treated with BEL show significant improvement in their disease. This suggests the involvement of other vital pathways playing a role in SLE development which challenges the generalized use of BEL against SLE.

4. Conclusion and future directions

SLE is a complex and devastating disease. Without a possible cure in sight, patients with SLE rely on treatment based on symptoms to improve their quality of life. In recent years, there have been an increasing number of clinical trials with novel biologics that give hope to further improvements in the therapy of SLE. However, a knowledge gap exists in the current understanding of the molecular basis of SLE. Understanding the basis of susceptibility to SLE could open avenues to treat the disease at an early stage before it progresses to severe systemic disease. Primary research is needed to uncover the cause of the disease and, specifically, the reason for the development of autoantibodies, immune system dysfunction, and chronic inflammation. The determinants of disease severity are unknown, challenging current treatment regimens. The existing treatments for SLE usually include immunosuppression, which predisposes patients to infection, the primary cause of premature mortality in SLE patients. From the therapy point of view, it is essential to identify the underlying genetic and epigenetic profiles, immune mechanisms, and the severity of the disease to deliver personalized therapy.

Conflict of interest

The authors declare no conflict of interest.