Systemic lupus erythematosus (SLE), a complex autoimmune disease with multisystem involvement, is characterised by recurring flares and remissions throughout the course of illness. The agents currently being used for management include corticosteroids, antimalarials and various immunosuppressants. Belimumab, a B lymphocyte stimulator (BLyS) inhibitor has been recently approved for the treatment of SLE. This review aims to discuss the role of belimumab in the treatment of SLE and the trials leading to its FDA approval. Belimumab demonstrated high degree of activity in patients with autoantibody-positive active SLE disease on a stable treatment regimen. There was a significantly greater response compared to placebo as assessed with the SLE Responder Index (SRI) in two randomized, double-blind, phase III trials (BLISS-52 and BLISS-76). The treatment was well tolerated. Additional studies are required to evaluate belimumab in special populations and assess its long-term safety. This therapy could change the focus of management from symptomatic treatment to targeting an important step in the disease pathogenesis. It could enable development of treatment which could halt long-term progression, minimize target organ damage and thus provide a better quality of life for these patients.
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder that is characterized by considerable morbidity and mortality. As many as 300 000–4 million persons are afflicted by this disease in US alone. It commonly affects women in the age group of 15–45 years. Patients exhibit varied symptoms ranging from mild fever, rash, mucocutaneous ulcerations and arthralgias to multiorgan toxicities (renal, cardiac, pulmonary and hematopoietic systems). This disease undergoes a variable clinical course with remissions and exacerbations throughout the course of the illness. Despite extensive understanding of the disease, and its pathophysiology, progress in pharmacological treatment has been quite slow. The drugs approved for use in SLE are corticosteroids, antimalarials, aspirin and hydroxychloroquine. More than half a century has passed since any drug has been approved for the treatment of lupus. In the last year, two phase III randomized placebo-controlled trials of rituximab plus conventional immunosuppressive therapy failed to demonstrate superiority over placebo, for the treatment of moderately active non-renal SLE (EXPLORER) or class III/IV lupus nephritis (LUNAR). Recently, belimumab (Benlysta; Human Genome Sciences, Rockville, MD, USA/Glaxo Smith Kline, Uxbridge, UK), a B lymphocyte stimulator (BLyS) inhibitor demonstrated a high degree of activity in patients with autoantibody-positive active SLE. There was a significantly greater response compared to placebo as assessed with the SLE Responder Index (SRI) in two multicentre, randomized, double-blind, placebo-controlled phase III trials (BLISS-52 and BLISS-76).[6-8] Belimumab also prevented flares, improved serologic activity, reduced corticosteroid use and was well tolerated. The favorable results of these two trials paved the way for approval of belimumab for the treatment of SLE by the US Food and Drug Administration (FDA) in March 2011. Subsequently, in July 2011, the European Commission granted a marketing authorisation for Benlysta valid throughout the European Union.
This review aims to discuss the role of belimumab in the treatment of SLE and the trials leading to its FDA approval. We elucidate how belimumab effectively targets B-cells (BLyS) and induces apoptosis of autoreactive clones resulting in diminished production of autoantibodies. We critically discuss the preclinical studies and clinical trials (including phase III BLISS-52 and BLISS-76) of belimumab and the need for further studies to assess its long-term safety in varied population groups.
BLyS Biology in SLE and Action of Belimumab
BLyS (also known as B-cell-activating factor [BAFF], tumor necrosis factor [TNF] homologue that activates apoptosis, nuclear factor-κb [NF-κb], and c-jun NH2-terminal kinase (THANK), TNF- and ApoL-related leukocyte expressed ligand 1 [TALL-1]) is a 285-amino acid cytokine and plays an important role in B-cell homeostasis and survival. BLyS and its closely related homologue APRIL (a proliferation-inducing ligand) are members of the TNF superfamily. It is expressed by a variety of cell types, mainly innate immune cells, like neutrophils, dendritic cells, macrophages, and monocytes and some T and B lymphocytes. The activated BLyS (soluble form) when enzymatically cleaved from the cell membrane, attaches to three receptors: BR3 (BAFF receptor 3), TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), and BCMA (B-cell maturation antigen). BR3 binds solely to BLyS, whereas TACI and BCMA ligate both BLyS and APRIL. All three receptors signal through TNF receptor-associated factors (TRAFs), activating the NF-κB and other pathways. BR3 is a potent stimulator of the alternative NF-κB pathway, in contrast to TACI and BCMA, which stimulate the classic NF-κB pathway. When bound to these receptors, BLyS results in inhibition of apoptosis and allows the proliferation and differentiation of B lymphocytes into immunoglobulin (Ig)-producing plasma cells.
Belimumab (Human Genome Sciences/GlaxoSmithKline) is a fully human Ig G1-λ monoclonal antibody that has been approved for patients with active, autoantibody-positive SLE who are receiving standard therapy. Belimumab, a 147 kDa molecule has been produced by recombinant DNA technology in a mammalian cell expression system. Belimumab selectively targets and binds to the soluble form of BLyS with high affinity; inhibiting the interaction of this receptor with BR3, TACI and BCMA and the resultant signal transduction pathways. This in turn inhibits B lymphocyte proliferation and differentiation into Ig-producing plasma cells and induces apoptosis of the autoreactive B cells (Fig. 1).
Circulating BLyS levels have been found to be elevated in patients with SLE, rheumatoid arthritis and other systemic immune-based rheumatic diseases.[14, 15] Among 185 patients with various systemic autoimmune diseases, 21% had significantly elevated plasma BLyS levels compared to healthy controls, and levels of BLyS correlated with IgG levels and anti-double-stranded DNA (anti-dsDNA) titers. In addition, there was no correlation between serum BLyS levels and patients' age, sex, race or medications. A large-scale study involving a total of 245 SLE patients of varied ethnicity (67% white, 31% African American, and 2% Asian) were evaluated prospectively over a 2-year period. It was found that BLyS concentrations related to disease activity, as measured by Safety of Estrogen in Lupus Erythematosus National Assessment – SLE Disease Activity Index (SELENA-SLEDAI) across all study sites. The authors suggested that elevated BLyS can serve as a biomarker for disease activity and BLyS is a potential target for drug development in SLE.
Preclinical and Phase 1 Trials
The preclinical trials of belimumab began as early as 2000–2001. It was observed that selective blockade of BLyS in New Zealand black/white (NZB/W) F1 mice, the prototypical model of SLE nephritis, effectively depleted splenic B cells, sparing B1 and T1 cells. In lupus-prone mice, selective or non-selective BLyS blockade attenuated inflammation and even induced remission of nephritis in some strains. In accordance with observations in mice, multiple in vivo studies of belimumab were performed in monkeys. Administration of belimumab for 26 weeks in cynomolgus monkeys, resulted in almost 75% reduction in the number of lymphoid tissue and peripheral blood CD20+ B cells and CD21+ plasmacytoid cells. The effects of belimumab appeared to be dose-dependent after 13 weeks of treatment and maximal in all dose groups by week 26. In addition there was a decrease in the size of splenic lymphoid follicles. On discontinuation of belimumab in cynomolgus monkeys, the numbers of peripheral blood CD20+ B cells recovered to normal levels within 3–5 months. Intravenous doses of up to 50 mg/kg delivered every 2 weeks over 6 months were well tolerated in cynomolgus monkeys. In this 26-week multiple-dose toxicology study, belimumab demonstrated the expected pharmacologic activity of specifically decreasing B lymphocytes both in tissues and in peripheral blood.
The phase 1 dose-escalating trial of belimumab was undertaken in 70 patients of SLE with mild to moderate disease activity (Table 1). The patients were randomized to receive either the drug in a dose of 1, 4, 10 or 20 mg/kg or placebo. The treatment was administered as a single infusion or as two infusions separated by 21 days. The primary safety end-point for dose escalation was the incidence of grade 3 (severe) or 4 (life-threatening) adverse events (AEs). The majority of events were mild to moderate in severity (except one patient in the placebo and nine in the belimumab group had a severe AE; and one patient in the belimumab group had a grade 4 AE). There were no significant differences in the incidence of AEs in the placebo and belimumab treatment groups and most of the events were not related to the study drug. The most common AEs were arthralgia, headache, rash, diarrhoea and nausea in patients treated with the study agent. Two patients receiving belimumab developed a human anti-human antibody (HAHA) response. Neutralizing HAHA was detected on days 14–56 in one patient (1 mg/kg single dose group) on concomitant prednisone and non-neutralizing HAHA on day 77 in another patient (20 mg/kg double-dose group) on concomitant mycophenolate mofetil and prednisone.
Table 1. The clinical development of belimumab
BILAG, British Isles Lupus Assessment Group; PGA, Physician's Global Assessment; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment – Systemic lupus erythematosus Disease Activity Index; SF-36 PCS, Short Form 36 Physical Component Score; SRI, Systemic lupus erythematosus Responder Index.
Belimumab (1 mg/kg; n = 15, 4 mg/kg; n = 14, 10 mg/kg; n = 14, 20 mg/kg; n = 14), placebo (n = 13)
Belimumab demonstrated linear pharmacokinetics across 1–20 mg/kg dose range with long terminal elimination half-life. Adverse events and laboratory abnormalities were similar among the belimumab and placebo groups. Significant reductions in CD20+ B cells were observed, although disease activity remained unchanged after one or two doses of belimumab.
Phase II trial
Belimumab (1 mg/kg; n = 114, 4 mg/kg; n = 111, 10 mg/kg; n = 111), placebo (n = 113)
No significant differences between belimumab and placebo groups were attained for the primary endpoint. However, in the serologically active patient subgroup, belimumab resulted in significantly better responses at week 52 than placebo for SELENA-SLEDAI, PGA and SF-36 PCS scores.
Exploratory analyses of phase II trial
Belimumab (1 mg/kg; n = 114, 4 mg/kg; n = 111, 10 mg/kg; n = 111), placebo (n = 113)
Evidence-based exploratory analyses of this trial led to the development of a novel responder index, SLE Responder Index (SRI) which could be used as a primary endpoint in further trials and also define a clinically meaningful change in disease activity. In serologically active patients, belimumab resulted in a significantly greater SRI response at week 52 compared with placebo.
Phase III (BLISS-52)
Belimumab (1 mg/kg; n = 288, 10 mg/kg; n = 290), placebo (n = 287)
Belimumab 1 mg/kg and 10 mg/kg plus standard therapy resulted in significantly higher SRI rates than with placebo at week 52. A dose–response relation was observed, with belimumab 10 mg/kg resulting in greater response in all three SRI components (SELENA-SLEDAI, BILAG domain scores and PGA) compared to 1 mg/kg which improved outcomes in two components (SELENA-SLEDAI and PGA). Belimumab reduced disease activity, severe flares and was well tolerated.
Phase III (BLISS-76)
Belimumab (1 mg/kg; n = 271, 10 mg/kg; n = 273), placebo (n = 275)
Belimumab 10 mg/kg plus standard therapy met the primary efficacy end point (significantly greater SRI response) at week 52, reduced SLE disease activity and severe flares, and was well tolerated. Patients with higher SELENA-SLEDAI score thresholds achieved a significantly better discrimination at weeks 52 and 76 compared to placebo.
Belimumab exhibited linear pharmacokinetics in the dose range of 1–20 mg/kg. The mean steady state volume of distribution was 69–112 mL/kg. The distribution phase half-life was 1–2.2 days while the terminal half-life was 8.5–14.1 days. After a single dose administration, the clearance was 7 mL/kg/day. There were no significant differences in the clearance, half-life and volume of distribution between the patients who received the drug either singly or as two infusions. Belimumab resulted in reductions in CD20+ B lymphocytes and anti-dsDNA antibody, exhibiting promise for further trials. The results of this study demonstrated that treatment with belimumab was safe and well tolerated in patients with mild to moderate SLE.
Phase 2 Trials
The double-blind, placebo-controlled safety efficacy trial of belimumab was undertaken in patients with active disease, as defined by SELENA-SLEDAI score ≥ 4. The patients were allowed standard stable treatment, including prednisone 4–50 mg/day, antimalarial or other immunosuppressive medications for at least 60 days prior to the study. Patients were randomized to receive intravenous belimumab (1, 4, or 10 mg/kg) (n = 336) or placebo (n = 113) on days 0, 14, 28 and then every 28 days for a duration of 52 weeks. The primary outcome was the percent change in the SELENA-SLEDAI score from baseline at 24 weeks and the time to first flare of the disease (defined by the SELENA-SLEDAI flare index) during the study period. The SELENA-SLEDAI is a cumulative, weighted index of lupus disease activity. The total score falls between 0 and 105, with higher scores representing increased disease activity and 0 indicating inactive disease at a certain timepoint. The SLEDAI has been shown to be a valid and reliable disease activity measure in multiple patient groups. The disease flares are classified as mild/moderate flare if there is a change in SLEDAI > 3 points and severe flare if the change in SLEDAI > 12 points. No significant differences were reported in the treatment group compared to placebo in the modified intent-to-treat analysis for the primary endpoints. However, it was observed that time to flare during weeks 24 through 52 was 154 days in the belimumab group compared to 108 days in the placebo group (P = 0.0361). As early as week 4, significant changes in Physicians Global Assessment (PGA) was observed in the combined belimumab group and by 52 weeks, there was a 31% decrease in mean PGA score in the combined belimumab group compared to 14% decrease in the placebo group (P = 0.0019). This index assesses the disease severity based on a 10-cm visual scale, with an increase of 2.5 cm between visits representing a disease flare. Apart from symptomatic improvement, there were decreases in the B cell populations (CD 19+, CD20+, activated B cells and plasmacytoid B cells) as well in the combined belimumab group at week 52. The adverse events were similar in all the treatment groups, including placebo. Serious events were reported in 16.1% of patients on belimumab compared to 19.5% on placebo. The most common serious infections were pneumonia and cellulitis, similar across all the groups. One patient discontinued belimumab due to severe infusion reaction. Additionally, an uncontrolled, open label extension of this study demonstrated that seropositive patients had sustained improvements in disease activity with decreased frequency of flares. Furthermore, serious adverse events and infections stabilized or decreased during this 5-year period.
In post hoc analysis, in a subset of autoantibody-positive/serologically active (antinuclear antibody [ANA] titer ≥ 1 : 80 and/or anti-dsDNA antibody level ≥ 30 IU/mL) patients (71.5% of the original cohort), belimumab significantly reduced disease activity at week 52 (greater reductions in SELENA-SLEDAI scores: −28.8% in the combined belimumab group vs. −14.2% in the placebo group; P = 0.0435). In addition, significant improvements in both the PGA (−32.7% in the combined belimumab group vs. −10.7% in the placebo group; P = 0.0011) and Short Form 36 Physician Component Score (SF-36 PCS) (3.0-point increase in the combined belimumab group vs. 1.2-point increase in the placebo group; P = 0.041) were reported. Belimumab thus demonstrated beneficial effects in serologically active SLE patients. This exploratory analysis formed the basis for the development of the SLE Responder Index (SRI), a robust responder index that reflects improvement in disease activity using a global scoring system without concomitant worsening of the disease in any organ system. This SRI was evaluated as the primary efficacy endpoint at 52 weeks for two large phase III trials.[6, 7]
Phase III Trials
Following favorable results of belimumab in phase II trials, phase III studies (BLISS-52 and BLISS-76 trials) were undertaken (Table 2).[6, 7] These trials evaluated belimumab (1 and 10 mg/kg) against placebo in autoantibody-positive active SLE patients on standard therapy with the SRI at week 52 as the primary endpoint. The SRI assessment consists of the SELENA-SLEDAI score to determine global improvement; British Isles Lupus Assessment Group (BILAG) domain scores to ensure no significant worsening in unaffected organ systems; and PGA to reflect that improvements in disease activity do not impact the patient's overall condition. A patient is identified as a responder if there is a ≥ 4-point reduction in SELENA-SLEDAI score and no new BILAG A organ domain scores or ≥ 2 new BILAG B organ domain scores and no worsening in PGA (< 0.3-point increase) (all scores compared with baseline).
Table 2. Baseline demographic characteristics, disease activity/severity, efficacy parameters and adverse events in phase III trials of belimumab (BLISS-52 and BLISS-76)
Placebo (n = 287)
Belimumab 1 mg/kg (n = 288)
Belimumab 10 mg/kg (n = 290)
Placebo (n = 275)
Belimumab 1 mg/kg (n = 271)
Belimumab 10 mg/kg (n = 273)
Data are number (%) or n/N (%) or mean ± standard deviation. *, **, *** indicates P-values < 0.05, < 0.01 and < 0.001 for pairwise comparison of the placebo group with the belimumab 1 mg/kg or 10 mg/kg group. AE, adverse event; ANA, antinuclear antibody; BILAG, British Isles Lupus Assessment Group; C3, C3 complement; C4, C4 complement; PGA, Physician's Global Assessment; SELENA-SLEDAI, Safety of Estrogens in Lupus Erythematosus National Assessment – Systemic lupus erythematosus Disease Activity Index; SFI, Systemic lupus erythematosus Flare Index; SRI, Systemic lupus erythematosus Responder Index; VAS, Visual Analog Scale.
36·2 ± 11·8
35·0 ± 10·6
35·4 ± 10·8
40.0 ± 11.9
40.0 ± 11.4
40.5 ± 11.1
Women, no. (%)
SLE disease activity at baseline
Disease duration, years
5·9 ± 6·2
5·0 ± 4·6
5·0 ± 5·1
7.4 ± 6.7
7.9 ± 7.1
7.2 ± 7.5
9·7 ± 3·6
9·6 ± 3·8
10·0 ± 3·9
9.8 ± 4.0
9.7 ± 3.7
9.5 ± 3.6
SELENA–SLEDAI score ≥ 10, no. (%)
≥ 1 BILAG A or 2 BILAG B scores, no. (%)
PGA score (0–3 VAS)
1.4 ± 0.5
1.4 ± 0.5
1.4 ± 0.5
1.5 ± 0.5
1.4 ± 0.5
1.4 ± 0.5
Medications at baseline
Daily prednisone > 7.5 mg/day at baseline, no. (%)
Prednisone dose, mg/day
11.9 ± 7.9
12.9 ± 8.6
13.2 ± 9.5
9.4 ± 8.9
8.7 ± 7.6
8.4 ± 7.9
Mycophenolate mofetil, no. (%)
Azathioprine, no. (%)
Methotrexate, no. (%)
Antimalarial (aminoquinolone) use, no. (%)
Biomarkers at baseline
BLyS above limit of detection (0.5 ng/mL), no. (%)
BLISS-52 trial was conducted in 90 centres in 13 countries (primarily in Asia, South America and Eastern Europe) to assess the efficacy, safety and tolerability of belimumab with standard of care in seropositive SLE patients. The study population included patients with active disease (score ≥ 6 at screening on SELENA-SLEDAI), positive ANA titre ≥ 1 : 80 or anti-ds DNA antibody ≥ 30 IU/mL. They were randomized to receive intravenous belimumab infusion over 1 h (1 mg/kg; n = 288) or (10 mg/kg; n = 290) or placebo (n = 287) on days 0, 14, 28 and then every 28 days for a duration of 48 weeks, with standard of care. Improvement in SRI at 52 weeks was the primary efficacy endpoint. Belimumab resulted in significantly higher SRI rates (1 mg/kg; 51% responders, P = 0.0129), (10 mg/kg; 58% responders, P = 0.0006) compared to placebo (44% responders). The onset of clinical improvement was observable at 16 weeks and there was an overall reduction in the risk of flares with belimumab. Additionally, there was a significant reduction in anti-dsDNA and IgG concentrations with hypergammaglobulinemia (P < 0.001 at week 52) and low complement levels (P < 0.001 at weeks 12–52) returning to normal. There was a ≥ 50% reduction in the prednisone dose in a significant proportion of patients on 10 mg/kg dose during weeks 24–52 (P = 0.0122 at week 52). There were no significant differences in the rates of adverse events (including serious adverse events: infections, death, spontaneous abortions, stillbirths, laboratory abnormalities, or discontinuation attributable to adverse events) in the three groups. The most common adverse effect was infection followed by headache, upper respiratory tract infection, arthralgia, influenza, diarrhoea, nasopharyngitis and hypertension. Infusion reactions requiring medical intervention were reported in 7%, 9% and 8% of patients on belimumab at 1 mg/kg, 10 mg/kg or placebo, respectively. Nine deaths were reported in the study; three were due to infections in the belimumab groups. The trial showed a superior safety efficacy profile compared to placebo in controlling the disease in a large segment of population.
BLISS-76 recruited 819 adults with autoantibody-positive (2 positive ANA or anti-dsDNA test results with ANA titer ≥ 1 : 80 and/or anti-dsDNA antibody level ≥ 30 IU/mL) active (SELENA–SLEDAI score ≥ 6 at screening) SLE disease (diagnosis of SLE by American College of Rheumatology criteria) on a stable treatment regimen (prednisone [or equivalent] alone [7.5–40 mg/day] or combined [0–40 mg/day] with antimalarial drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or immunosuppressive therapies for ≥ 30 days before the first study dose) from Central and Eastern Europe, Latin America and Asia Pacific. Patients with serious intercurrent illness or severe disease (active lupus nephritis/central nervous system manifestations) or prior treatment with a B cell-targeted agent were excluded. In this phase III, multicenter, double-blind, placebo-controlled trial, patients were randomized in a 1 : 1 : 1 ratio to receive either placebo or belimumab (1 or 10 mg/kg) by intravenous (IV) infusion over 1 h on days 0, 14, and 28 and every 28 days through to week 72. The primary endpoint was the SRI response rate at week 52. All subjects who were randomized and received at least one dose of study agent were included in the analysis. There was a significant difference in the percentage of participants achieving SRI response rate at 52 weeks in the belimumab 10 mg/kg group versus placebo (43.2% vs. 33.5%, P = 0.0167). However, at 76 weeks, SRI response rate was no longer significant in the belimumab-treated groups compared to placebo (belimumab 10 mg/kg 38.5% vs. placebo 32.4%, P = 0.1323) (belimumab 1 mg/kg 39.1% vs. placebo 32.4%, P = 0.1050). No statistically significant improvement was seen with belimumab versus placebo with regard to health-related quality of life (HRQOL) as assessed by the SF-36, PGA scores or reductions in the average prednisone doses. More than 90% of patients reported at least one AE in all the groups; with almost 20% having a serious AE in each group, including placebo.
In post hoc sensitivity analyses, a more stringent response criteria; higher SELENA–SLEDAI score thresholds (≥ 5-point reduction to a ≥ 10-point reduction) were used to evaluate the effect of belimumab. Belimumab treatment demonstrated a significant difference from placebo at both weeks 52 and 76, with 10 mg/kg achieving better discrimination for every SELENA–SLEDAI threshold at weeks 52 and 76 (P ≤ 0.05). These results demonstrating the safety and efficacy of belimumab paved the way for approval of this drug, enabling a suitable treatment option for patients with SLE.
Ongoing Trials and Further Studies
In addition to these trials, studies are ongoing to assess the long-term safety (continuation studies), efficacy and tolerability of subcutaneously administered belimumab and immune response to vaccination in patients of SLE.[24-28] A global BENLYSTA Pregnancy Registry has been set up to collect data on pregnancies and pregnancy outcomes (birth defects) in mothers who received belimumab 4 months prior to and/or during pregnancy. Trials are also underway to evaluate the efficacy of belimumab in various other conditions: symptomatic Waldenstrom's macroglobulinemia, myasthenia gravis, chronic immune thrombocytopenia, renal transplantation and primary Sjögren's syndrome.
Belimumab has not been adequately evaluated in children or in adults more than 65 years of age. Caution is advised with the use of this drug in the elderly. There is a need to carry out drug interaction studies of belimumab with commonly concomitantly administered drugs. However, co-administration with corticosteroids, antimalarials, immunomodulatory and immunosuppressive agents (including azathioprine, methotrexate and mycophenolate), angiotensin pathway antihypertensives, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors (statins) and NSAIDs did not result in any clinically meaningful effect on belimumab pharmacokinetics in clinical trials of patients with SLE.
Numerous agents are still being developed for the treatment of this disease. The drugs which are currently in phase III include epratuzumab (monoclonal antibody against CD22), atacicept (blocks BLyS and APRIL), LY2127399 (targets BLyS) and ocrelizumab (monoclonal antibody against CD20).
SLE patients exhibit a variable pattern of flares and remissions over a long timespan. An ideal drug for the treatment of this disease should halt long-term progression and minimize target organ damage, enabling a better quality of life for these patients. However, there is a long way to go before such a drug is approved for this disease. The approval of belimumab has been a landmark in the management of SLE and could help in minimizing the toxicity associated with the use of corticosteroids and other immunosuppressants. A combination therapy targeting multiple factors/pathways affecting the pathogenesis of SLE could help achieve a cure for this disease.
We thank Mr. Gurpreet Singh Chugh for his assistance.
Dr. Preeta Kaur Chugh has made substantial contributions to the conception and acquisition of data. She also drafted the manuscript.
Dr. Bhupinder Singh Kalra was involved in definition of intellectual content, editing and reviewing the manuscript and has given final approval of the version to be published.