The Role of Belimumab in Systemic Lupus Erythematosis: A Systematic Review

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple systems with a range of clinical presentations caused by the production of antibodies, activation of complements, and deposition of immune complexes. The exact cause of SLE is still unknown. The effectiveness of traditional treatment methods for SLE is very little. Nowadays, resistance to conventional therapy, steroids, and immunosuppressants is common among SLE patients. Patients with refractory disease and nephritis generally have severe drug-induced toxicity which contributes to organ dysfunction, despite available therapies. Different biologic agents and therapeutic antibodies have become an alternative and have been under experiment in clinical trials, enrolling patients whose disease is inadequately controlled by conventional treatment. Belimumab is the only targeted therapy approved for SLE treatment. This systematic review discusses one such biological agent for treating systemic lupus erythematosus, namely, belimumab. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies included randomized clinical trials (RCTs) from 2005 to 2021 on adult SLE. patients treated with monoclonal antibodies to assess the efficacy and safety. Methodological quality was assessed using PubMed, PMC, the Cochrane Risk of Bias tool, and the QUality In Prognosis Studies Tool (QUIPS) for RCTs. Two independent reviewers performed an electronic search on MEDLINE, Cochrane Library, SCIELO, Scopus, and ResearchGate. Based on a systematic review of articles we found that belimumab appears to be efficacious and generally well-tolerated in the treatment of SLE as compared to other drugs. The long-term use of belimumab combined with standard therapy showed a low incidence of organ damage. A lower incidence of organ damage was seen after initiating treatment in patients with a high risk for organ dysfunction. Patients who test for antinuclear antibody or anti-dsDNA-positive SLE, with moderate symptoms in the skin and musculoskeletal systems despite immunosuppressants, are treated with belimumab as an adjunct therapy. Patients with severe lupus nephritis or active CNS lupus cannot be treated with belimumab. Belimumab is effective in most races, as a clinical trial done in North-East Asia showed improvement in SLE symptoms and decreased dependence on prednisone. Belimumab also decreased disease activity and severe flares. Belimumab had greater efficacy in children.


Introduction And Background
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple systems with a range of clinical presentations caused by the production of antibodies, activation of complements, and deposition of immune complexes. The exact cause of SLE is still unknown [1]. Still, epidemiologic evidence exists for the associations of silica, cigarette smoking, oral contraceptives, postmenopausal hormone therapy, and endometriosis with SLE incidence [2]. Recent studies have also provided robust evidence of the association between alcohol consumption and decreased SLE risk [3]. The immunology of SLE involves dysregulation of the immune response, including innate immunity and adaptive immunity [4]. B lymphocyte has an essential role in the adaptive immune response of SLE, which involves the production of autoantibodies, presentation of autoantigens, and activation of autoreactive T cells. Furthermore, T lymphocyte plays a role through the co-stimulator-mediated signaling pathway and cytokines secreted by subsets of T cells [5]. The heterogeneous nature of lupus makes it challenging to identify sensitive and specific markers for its diagnosis and monitoring [6].
The effectiveness of traditional treatment methods for SLE is very little. Nowadays, resistance to conventional therapy, steroids, and immunosuppressants is common among SLE patients [7]. Patients with refractory disease and nephritis generally have severe drug-induced toxicity, which contributes to organ dysfunction, despite the available traditional therapies [8]. Different biologic agents and therapeutic antibodies have become an alternative and have been under experiment in clinical trials enrolling patients whose disease is inadequately controlled by conventional treatment regimens [9]. Belimumab is the only targeted therapy approved for SLE treatment, as treatment with many biologic agents has given unsatisfactory results [10]. Several novel biologic agents targeting B cells, T cells, or cytokines are undergoing clinical trials for the treatment of SLE [11]. With a deepening understanding of pathogenesis, targeted therapy has become a more promising treatment, especially for patients who are resistant to conventional therapies [12]. Patients have started developing tolerance toward conventional therapies like steroids and immunosuppressants [13]. At present, moderate and severe SLE are treated with biological agents [14]. In cases where the immunosuppressive agents and hormone therapy are ineffective, biological agents control the disease levels [15].
This systematic review discusses one such biological agent for treating systemic lupus erythematosus, namely, belimumab.

Review Methods
The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Screening of Articles
Inclusion criteria included papers from 15 years, published in English, an adult population whose age ranged from 18 to 65 years, female, and randomized clinical trials (RCTs).
Exclusion criteria were pediatric population, geriatric population, unpublished papers, and gray literature.

Search Strategy
Studies included RCTs from 2005 to 2021 on adult SLE patients treated with monoclonal antibodies to assess the efficacy and safety of clinical responses like arthritis, mucocutaneous and renal response, relapse, and side effects. RCTs included for methodological quality were assessed using PubMed, PubMed Central, the Cochrane Risk of Bias tool, and the QUality In Prognosis Studies Tool (QUIPS) for RCTs. The quality of subgroup analyses testing predictors of differential treatment response was also evaluated. The best evidence synthesis was performed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.

Results
This systematic review initially identified 2964 articles; 500 duplicate records were deleted and another 2464 were removed since their outcome was not of interest. Due to the difference in exclusion criteria, another 72 records were not considered. The remaining 78 articles were further filtered after reading the complete text, and 38 articles were eventually considered in this systematic review ( Figure 1).

FIGURE 1: Search Strategy and Screening of Articles
The total number of patients included in trials involved in this systematic review is 6598. Even though most studies had belimumab as the primary intervention compared to control, other studies included other monoclonal antibodies such as ustekinumab, anifrolumab, epratuzumab, AMG, sifalimumab, and other monoclonal antibodies. The upper limit of age was not available in all the studies we discuss, but the lower age limit is five years. Different indicators were used to assess the efficacy of most interventions with some similarities, including an improvement of several SLE scores, making a unified systematic review difficult. Therefore, we will discuss several studies separately, especially those using other monoclonal antibodies than belimumab.

Goals of Treatment of SLE
The objectives of treatment for lupus are to maintain a very low disease activity and avoid triggers known to cause disease flare-ups, prevent damage to organs from disease activity, and decrease the secondary complications of lupus and its treatment [16]. Initiating treatment early and having a partnership with the patient toward the above-mentioned goals, is essential. This includes avoidance of known triggers that cause flares, the need for sun protection, avoiding the use of prednisone for maintenance therapy, and controlling active disease with immunosuppression or biologics [17].

Drugs Commonly Used to Treat SLE
a) Immunomodulators: The various immunomodulatory drugs used in SLE are: Hydroxychloroquine is commonly used in every patient, as it modulates the immune response by inhibiting B cell receptors, TLR signaling, intracellular TLR-3, and -7 activation, which plays a very important role in nucleic acid-sensing. It also interferes with the lysosomal pH and MHC-antigen binding, which is the reason for it being the cornerstone of treatment for lupus [18].
Vitamin D has to be used as a supplement in all SLE patients because of its modulatory role in the immune system and anti-fibrotic effects [19].
Dehydroepiandrosterone (DHEA) is used in the treatment of SLE because of its regulatory effects on proinflammatory cytokines like interleukin (IL)-2, IL-1, IL-6, and tumor necrosis factor-alpha (TNF-a). It also causes a reduced antibody production in mice [20].
Corticosteroids are used to rapidly ablate the autoimmune response in organ-threatening manifestations such as nephritis, vasculitis, central nervous system lupus, myocarditis, or alveolitis. In lupus patients, 80% of organ damage after diagnosis is attributable to prednisone use. Lower doses can increase the risk of cataracts, osteoporosis, fractures, and coronary artery disease. Doses above 6 mg increase the risk of organ damage by 50% and doses of 10 to 20 mg daily increase the risk of cardiovascular events [21]. b) Cytotoxic drugs: The various cytotoxic drugs used in SLE are: Cyclophosphamide is an alkylating agent that acts by depleting T and B cells and producing antibodies. It is widely used to induce and maintain lupus nephritis and central nervous system lupus. It has been replaced by immunosuppressive medications that are less toxic [22].
Azathioprine has been commonly used in renal and extrarenal lupus. Two randomized studies that compared treatment with azathioprine to corticosteroids alone showed a reduction in mortality and flares, especially in patients with severe renal or central nervous system disease. Given its inferiority to cyclophosphamide, its use has decreased over time [23].
Methotrexate is an antimetabolite used in the treatment of SLE, as it interferes with DNA synthesis, repair, and replication by irreversibly binding to dihydrofolate reductase. Methotrexate reduces disease activity in SLE, especially in joint and skin diseases. It also facilitated anti-dsDNA and complement levels. Methotrexate showed modest steroid-sparing activity in a randomized controlled trial [24].
Mycophenolate is used in the treatment because it acts by preferentially depleting guanosine nucleotides in T and B cells, which inhibits their proliferation. Mycophenolate is effective for the induction and maintenance of lupus nephritis [25].
Calcineurin inhibitors are used in the treatment of SLE, as it targets T cells by preventing the inhibition of calcineurin. Multiple small RCTs showed that the induction of lupus nephritis cyclosporine or tacrolimus is equally effective as cyclophosphamide or mycophenolate [26]. c) Monoclonal antibodies: The various monoclonal antibodies used in SLE are: Rituximab is used in the treatment of SLE, as it is an anti-CD20 monoclonal antibody that leads to the depletion of peripheral B cells [27]. Several observational studies showed that rituximab was beneficial in renal and non-renal lupus [28]. There were two large randomized placebo-controlled trials with rituximab in renal and non-renal lupus that failed to meet their primary outcomes. In the EXPLORER non-renal trial with rituximab, the primary endpoint, which was the proportion of patients achieving complete or partial remission based on the BILAG score, was not met. B-cell depletion was seen in about 90% of SLE patients treated with rituximab. Rituximab did reduce anti-dsDNA titers and improved C3 and C4 levels [29]. The LUNAR renal trial showed that rituximab did reduce proteinuria better than mycophenolate alone at 18 months. Hence, the above-mentioned clinical trials clearly show that the use of rituximab in the treatment of SLE is still controversial [30].

Belimumab Effects on SLE Disease Activities
Belimumab mechanism of action in SLE: One of the pathogenic mechanisms of SLE is the overexpression of B Lymphocyte Stimulator (BLyS), which promotes B cell survival, especially autoreactive B cells. BLyS inhibition results in apoptosis of autoreactive B-cell. BLyS plays an important role in the pathogenesis of SLE. SLE patients generally have elevated circulating BLyS levels compared to healthy individuals. Higher levels of BLyS correlate with increased disease activity. Higher levels of BLyS also correlate with increased anti-double-stranded DNA (dsDNA) antibody titers. Therefore, the biological activity of BLyS has to be inhibited, which is necessary for the treatment of the disease. Belimumab acts by binding to soluble BLyS [31].
Belimumab is a complete human monoclonal antibody against BLyS, a B-cell survival factor. It was licensed in 2011 for the treatment of autoantibody-positive SLE. Belimumab plays a very important role in B cell survival and function, as it belongs to the TNF superfamily.
Belimumab is the first biological agent to be approved by the Food and Drug Administration (FDA) for SLE. Early multicenter phase III clinical trials have shown that the long-term use of high doses continuously improved serological indicators, reduced hormone dosage, and reduced the risk of severe recurrence in SLE [32].
The BLISS-52 and BLISS-76 Phase III trials successfully demonstrated that once-a-week therapy with belimumab (10 mg/kg) with standard therapy significantly decreased disease activity in SLE patients both clinically and statistically compared to placebo with standard treatment. Both the clinical trials mentioned here met their primary outcomes in SLE [33].

Belimumab Effects on Lupus Nephritis
The design of the clinical trials mentioned above did not involve treating a frequent cause of SLE-associated morbidity and mortality, which was lupus nephritis because of the heterogeneous definitions of treatment response, clinical presentation, and renal involvement, which made it practically impossible for a comparison of the results using a single outcome parameter. Based on emerging evidence, there seems to be a potential therapeutic role for agents that target BLyS.
However, most of these above-mentioned studies and clinical trials defined the clinical response in renal flare and renal remission rates, which may gradually reduce the risk of proteinuria. Despite the limitations of the studies included, the data available seems to be promising by providing preliminary support for targeting BLyS, which will induce or maintain a renal response [34].
Recently, a randomized, double-blind, placebo-controlled phase 3 trial of intravenous belimumab in patients with active lupus nephritis, which was called the BLISS-LN trial showed that patients with lupus nephritis, who received belimumab plus standard therapy (MMF or AZA) had a better renal response when compared to those who received standard therapy alone.
As there is no data available on whether belimumab plays a role in patients who failed induction therapy or relapse, it is still not yet recommended as the only primary treatment for lupus nephritis [35].

Belimumab Effects on Serological Markers of SLE
Treatment with belimumab resulted in a 63-71% reduction of naive, activated, and plasmacytoid CD20+ B cells and a 29.4% reduction in anti-dsDNA titers (P = 0.0017) by Week 52. The adverse and severe events rates were similar in the belimumab and placebo groups.
Belimumab was biologically active and well-tolerated. The effect of Bbelimumab on reducing SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab and standard therapy than standard therapy alone [36]. SLE patients who were treated with Bbelimumab experienced a significant and sustained reduction in immunoglobulin G (IgG), autoantibodies, and an improvement in C3/C4 levels. This resulted in positive-tonegative conversion rates for IgG anti-dsDNA, anti-Sm antibodies, anticardiolipin antibodies, and antiribosomal P autoantibodies. This also led to the normalization of hypergammaglobulinemia and low C3/C4 levels. There was a significant decrease in naive and activated B cells and plasma cells. There was no decrease in memory B cells and T cell population.
Belimumab causes a normalization of serologic activity and reduces BLyS-dependent B cell subsets in SLE patients who are serologically and clinically active. Better treatment response to belimumab is predicted by greater serological activity.

Belimumab Effects on the Clinically Significant Disease Activities of SLE
A post hoc analysis showed that there were significant reductions in SLE disease activity. There was a decrease in the risk of severe flares in patients who were anti-dsDNA positive and had low C3/C4 levels at baseline treated with belimumab 10 mg/kg (P≤0.01). The serum levels of C3 and anti-dsDNA were back to the normal range by eight weeks, which was irrespective of therapy. This predicted a reduced risk of severe flares over 52 weeks [37].
A pooled post hoc analysis of phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline. The analysis was also done to explore whether belimumab provided additional renal benefit to patients receiving mycophenolate mofetil at baseline.
In the clinical trial that treated patients with SLE with belimumab for over 52 weeks, the rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment -Systemic Lupus Erythematosus Disease Activity Index and the British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity was assessed. The results of the trial favored belimumab.
Among the 267 patients with renal involvement at baseline, a more remarkable renal organ disease improvement with belimumab was seen than in those receiving mycophenolate mofetil. The limitations of this analysis were the small patient population and the post-hoc nature of this pooled analysis. The results suggest that SLE patients with renal involvement benefited from belimumab therapy [38].
In the following  worsening.
There was a low incidence of organ damage accrual in patients with SLE who were treated with long-term Belimumab plus SoC.
There was also a low accrual in patients who were at high risk with pre-existing organ damage which suggested a favorable effect.

Future thrust
The following aspects of belimumab that are yet to be explored are the fact that the efficacy of belimumab as monotherapy is still to be proved, the safety and efficacy of Belimumab in lupus nephritis patients have not been established yet, the risk of developing neuropsychiatric manifestations of belimumab is a concern, especially in patients with CNS lupus, the safety and efficacy of belimumab in children and pregnant patients is yet to be established, the long-term safety of belimumab is still not established, and clinical and economic studies are to be done yet to know its feasibility.

Conclusions
Based on a systematic review of the literature and clinical trials on the role and effect of belimumab on SLE, we can confidently say that belimumab appears to be efficacious and generally well-tolerated in the treatment of SLE as compared to other drugs. The long-term use of belimumab combined with standard therapy showed a low incidence of organ damage; patients who had a high risk for organ damage had a lower incidence of organ damage after initiating the treatment. Patients who test for antinuclear antibody or anti-dsDNA-positive SLE with moderate symptoms in the skin and musculoskeletal systems despite immunosuppressants are treated with belimumab as an adjunct therapy. Patients with severe lupus nephritis or active CNS lupus cannot be treated with belimumab. Belimumab is effective in most races, as a clinical trial done in North-East Asia showed improvement of SLE symptoms and decreased dependence on prednisone. Belimumab also decreased disease activity and severe flares. Finally, belimumab had greater efficacy in children.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.