Abstract
Although the use of corticosteroids and immunosuppressive agents such as cyclophosphamide and mycophenolate has led to reduced mortality in systemic lupus erythematosus (SLE), there is a need for development of new biologic agents to improve outcomes further. The pathogenesis of SLE involves many components of the immune system, notably B cells, T cells, cytokines and innate immunity, which are potential targets for the new biologic therapies. In this study, the rationale for the development of new therapies in SLE and the progress that has been made in each direction of therapy are described. Most progress has been made with agents directed against B cells, especially rituximab and belimumab and the latter has been the subject of two successful randomised clinical trials (RCTs). Anti-T-cell and anti-cytokine therapies are further back in the development process, but promising advances can be anticipated over the next decade.
Introduction
Systemic lupus erythematosus (SLE) is a multisystem autoimmune rheumatic disease that can affect every organ system. The disease is characterised by deposition of autoantibodies and immune complexes, leading to widespread tissue damage. Over the last half century, the 5-year survival rate of patients with SLE has improved significantly from <50% in the 1950s to >90% more recently . Despite this, there is still an increased risk of mortality compared to the general population . The use of corticosteroids revolutionised the treatment of SLE in the 1950s and remains the mainstay of treatment but carries with it multiple long-term side effects contributing to disease morbidity. Unlike the targeted biological therapies that have been propelled to the forefront of disease management in rheumatoid arthritis (RA), the movement in SLE has been at a much slower pace. The mortality from lupus nephritis has improved in the last 30 years, but the improvements have slowed with virtually no difference in outcome observed in the last decade compared to the one before , thereby suggesting that we may have reached the limits of current therapy. Therefore, there is a clear void to fill in the development of targeted biological therapy in SLE. Developing an increasing understanding of the complex pathophysiology of SLE is pivotal for the development of new drugs targeting the key molecules in disease pathogenesis. The key biological agents are studied in association with the targeted immunological pathways and the key trial data are summarised (see Fig. 1 ).
Rationale for targeting B cells in SLE
B cells are proposed to play a central role in the pathogenesis of SLE with B-cell hyperactivity and loss of tolerance being hallmarks of this process. The failure in check points peripherally and centrally (within the bone marrow) results in the loss of B-cell tolerance, which occurs early in disease . Defects in apoptosis, resulting in an abnormal programmed cell death, have been demonstrated in SLE. An increased apoptotic rate in lymphocytes is accompanied with an impaired clearance of the apoptotic material. Macrophages from patients with SLE have been shown to engulf less apoptotic material in vitro compared to those from the healthy controls . This apoptotic material includes blebs consisting of cellular material exposed on the surface of dying cells during apoptosis and incorporating antigens that are normally intracellular. Thus, the failure of macrophages in removing this material implies that these antigens are exposed to the immune system, leading to the activation of innate immune cells and the B-cell receptor (BCR) of autoreactive B cells, leading to B-cell activation and expression of the B-cell survival molecule receptor (BAFF) and APRIL (a proliferation-inducing ligand) . BAFF and APRIL, cytokines of the tumour necrosis factor (TNF) ligand family, are thought to play a pivotal role in the development and maintenance of SLE .
Polyclonal B-cell activation results in the production of autoantibodies directed against many nuclear, cytoplasmic and plasma membrane antigens. At least 95% of the SLE patients have anti-nuclear antibodies (ANAs). Many of the clinical manifestations of lupus result from an immune complex deposition in tissues and subsequent multi-organ damage. The immune complexes are formed as anti-nuclear antibodies that bind to the nuclear material. B cells also perpetuate the inflammatory response by presenting autoantigens to T cells and producing pro-inflammatory cytokines .
Many B-cell-based therapies have been developed with the ongoing clinical trials. Some of the B-cell-targeted therapies have been tested in clinical trials in lupus have been reviewed.
Rituximab
Rituximab is a chimeric monoclonal antibody against CD20, a surface molecule present on pre-B and mature B cells. The drug was approved for use in RA in 2006 by the Food and Drug Administration and has been used off-label in the treatment of SLE patients with refractory disease . The first open uncontrolled study of rituximab for SLE patients was published by Professor Isenberg’s group at the University College London, which showed improvements in the clinical and laboratory features, and these findings were replicated in many similar uncontrolled studies . However, disappointingly two phase III randomised controlled trials (RCTs) involving patients with moderate to severe lupus (EXPLORER) and patients with class III or IV lupus nephritis (LUNAR) did not meet their primary end points of significant reduction of disease activity compared to placebo. These two trials have been further detailed in the next section.
EXPLORER study
The EXPLORER study compared the efficacy and safety of rituximab versus placebo in patients with moderately to severely active (≥1 BILAG A (British Isles Lupus Assessment Group) score or ≥2 BILAG B score) SLE without renal involvement. This was a randomised, multicentre double-blinded trial involving 257 patients from North America. The inclusion criteria for this study are shown in Table 1 .
| EXPLORER | LUNAR |
|---|---|
| Age range: 16–75 years with a history of meeting four American College of Rheumatology (ACR) criteria for SLE | Age range: 16–75 years with a history of meeting four American College of Rheumatology (ACR) criteria for SLE |
| Severe disease activity at screening : ≥1 organ system with a British Isles Lupus Assessment (BILAG) A score or Moderate disease activity : ≥2 organ systems with a BILAG B score | Biopsy proven (within 12 months) Class III, IV or V Lupus Nephritis and proteinuria. An active urinary sediment was required if the biopsy was performed >3 months before screening. |
| The stable use of one immunosuppressive drug at entry, which was continued during the trial | All patients had a background treatment of MMF up to 3 mg/day by week 4 |
Patients were randomised at a ratio of 2:1 to receive intravenous rituximab (1-g doses) or placebo on days 1, 15, 168 and 182 which was added to prednisone (given according to the protocol) and to the baseline immunosuppressive regimen. Corticosteroids were given at an initial dose of 0.5, 0.75 or 1 mg/kg depending on severity (by BILAG score) and the type of disease manifestation, followed by a taper regimen.
Patients were evaluated monthly with the BILAG index and the lupus quality-of-life index. The primary end points were recorded as achieving a major clinical response (MCR), a partial clinical response (PCR) or no clinical response at week 52 assessed using each of the eight BILAG index organ system scores. A major clinical response was defined as BILAG C scores or better in all organs at week 24 without experiencing a severe flare, and maintaining this response without a moderate or severe flare to week 52. The primary and secondary outcomes are summarised in Table 2 .
| Trial | Primary end points | Secondary end points |
|---|---|---|
| EXPLORER | Major Clinical Response (MCR) : BILAG C or D scores in all organ systems without a severe flare at 6 months, and maintaining this response without a moderate or severe flare at week 52. Partial Clinical Response (PCR) : Defined as meeting one of the following criteria:
Those who failed to reach MCR or PCR |
|
| LUNAR | Complete Renal Response (CRR) : At week 52; serum creatinine improving from abnormal to normal level or from normal to ≤115% of baseline normal; a fall in the urine protein-creatinine ratio to <0.5; and urine sediment containing <5 red blood cells in a high powered field without casts. Partial Renal Response (PRR) : Serum creatinine reduced to ≤115% of abnormal baseline; red blood cells ≤50% above baseline and without red blood cell casts; and a reduction in urine protein-creatinine ratio from ≥3.0 to ≤3.0 or <1 from ≤3.0. No Renal Response (NRR) : Those who failed to reach CRR or PRR |
|
Findings of EXPLORER
Approximately 70% of patients completed the study in both arms and the safety and tolerability were similar in both groups. There was no significant difference between the rituximab and placebo groups in terms of the primary and secondary end points. Interestingly in a post hoc analysis of subgroups, a beneficial effect of rituximab on the primary end point was observed in Afro-Caribbean and Hispanic subgroups. In the rituximab group, 20% achieved MCR and 13.8% PCR, compared to the placebo group with 9.4% MCR and 6.3% PCR ( p = 0.041).
An additional subgroup analysis of patients on background methotrexate (MTX) showed that patients in the rituximab group had improved mean BILAG global scores at week 52 compared with the placebo group ( p = 0.007). However, none of the primary or secondary end points were met in this subgroup.
Although no significant clinical improvements were found with rituximab treatment, those treated with the drug had significant improvements in serology-reduced anti dsDNA antibody ( p = 0.006), increased C3 ( p = 0.0029) and C4 levels ( p = 0.0045) at the completion of the trial.
LUNAR trial
The LUNAR study , a double-blind RCT, investigated the efficacy and safety of rituximab in patients with lupus nephritis who were being treated with MMF (mycophenolate mofetil) and corticosteroids. The inclusion criteria for the study are summarised in Table 1 .
In total, 144 patients were randomised to receive either rituximab (1 g IV) or placebo on days 1, 15, 168 and 182. Apart from MMF therapy, (3 g/day) no other immunosuppressive drugs were allowed during the study and IV methyl prednisolone (1 g) was administered within the first 3 days of the trial. The primary end point was defined as a complete, partial or no renal response at week 52 (defined in Table 2 ). The secondary end points are also shown in Table 2 .
Findings of LUNAR
This study did not show any difference between the treatment and placebo groups for either primary or secondary end points. An improved response rate, though non-significant, was observed in Afro-Caribbean subjects treated with rituximab. A statistically significant serological improvement in the treatment group was found with a decreasing level of anti-dsDNA antibodies ( p = 0.007) and increasing C3 levels ( p = 0.03).
Possible reasons for failure of the EXPLORER and LUNAR studies
Before concluding that the above two trials fail to demonstrate clinical effectiveness of rituximab in SLE, it is important to critique the study designs of these trials. Both studies have the following drawbacks.
Populations recruited
Patients recruited in both trials had moderate-to-severe disease with aggressive use of immunosuppressants as background treatments in both placebo and rituximab groups. Thus, clinical improvements would be expected in both groups and improvements due to the use of high-dose steroids for instance may have masked the full extent of the efficacy of rituximab. Probably, a study in a larger number of subjects could have shown statistically significant differences between groups. The belimumab studies, which involved large numbers, have been discussed later.
The positive experience of rituximab from open studies and in clinics was demonstrable in patients who had mostly failed conventional therapy. Rituximab was used successfully in combination with cyclophosphamide (CYC) in open-label trials; however, CYC was not used in both these RCTs, thus potentially negating any synergistic effect of both treatments being used together .
Treatment protocols
Patients were retreated with rituximab halfway through the study. This may have caused depletion in regulatory B cells that suppress immune responses by production of IL-10 and might also be relevant to rituximab resistance in some patients .
It is difficult to understand how rapidly the steroids should be tapered during trials in patients with severe disease. However, the trials designed in the future that extend beyond 12 months may have a better success at demonstrating the effect of rituximab if steroids are reduced to low levels at 6 months .
Subgroup responders
Both trials suggested that Afro-Caribbeans may respond better to rituximab who typically have more refractory disease, and therefore may be more beneficial in certain types of patients. EXPLORER also seemed to suggest that patients on MTX and rituximab maintained adequate disease control for a longer duration. Hence, there may be a subset of patients who respond better to rituximab; however, future studies are required to confirm this and explore the potential mechanisms.
Use of rituximab in early disease to avoid corticosteroids
Despite the clinical data for the use of rituximab in SLE nephritis being less than favourable, the use of the drug is recommended in resistant patients by both American College of Rheumatology and European League against Rheumatism. However, rituximab use early in the course of lupus nephritis as a steroid-sparing drug is currently being investigated in a large multicentre RCT called the RITUXILUP trial . In a small prospective study, 50 SLE patients with biopsy-proven active SLE nephritis (class III, IV or V) were treated with rituximab (two doses of 1 g rituximab with methyl prednisolone 500 mg 2 weeks apart) and maintenance treatment of MMF without oral steroids. A total of 45 (90%) patients achieved complete or partial remission by 37 weeks. By 1 year, 52% ( n = 26) had reached complete remission and just over one-third (34%, n = 17) had a partial remission. Only 12 renal relapses occurred in 11 patients, at a median time of 61.5 weeks from remission. Of the 45 responders, only two patients required >2 weeks of oral steroids . This protocol is currently being studied in RITUXILUP.
Belimumab
B-lymphocyte stimulator (BLys) and its closely related homologue, APRIL, are cytokines of the TNF superfamily. Data from several animal and in vitro studies have suggested that the BLyS/APRIL axis is a key pathway for the development of autoreactive B cells. They promote B-cell maturation, proliferation and immunoglobulin production. Patients with SLE, in comparison with serum from healthy individuals, have higher serum concentrations of BlyS . Belimumab is a fully humanised monoclonal antibody that binds to soluble human BLys and was the first new drug for SLE approved by the FDA in 50 years.
The efficacy of belimumab in addition to the standard-of-care (SOC) therapy has been successfully demonstrated in two large multicentre RCTs at separate geographic sites in patients with active SLE (BLISS-52 ( n = 865) and BLISS-76 ( n = 819)), which led to its approval by the American Food and Drug Administration as an add-on therapy for moderate-to-severe SLE . These trials were performed in patients with active disease (defined by an SLE Disease Activity Score Index of ≥6), and the majority of patients entered with active arthritis and/or a rash. Patients were randomised to receive placebo plus or intravenous infusions of belimumab at 1 or 10 mg/kg at 2 and 4 weeks, and then every month until 48 weeks.
Results of belimumab trials (BLISS-52 and BLISS-76)
Both of these RCTs met the primary end points for efficacy. These end points were defined in terms of a novel composite responder index, the SLE responder index (SRI), which incorporated the systemic lupus erythematosus disease activity index (SLEDAI), BILAG and a physician’s global assessment (PGA). To be defined as a responder, the patient must show an improvement in SLEDAI by at least 4 points, no worsening in BILAG and no worsening in PGA. There was a modest but significant excess of SRI responders in patients receiving belimumab 10 mg/kg over placebo at 52 weeks; in BLISS-52, 58% achieved this in the belimumab 10 mg/kg group versus 44% in placebo group ( p = 0.0006), and in BLISS-76, 43% in the belimumab versus 33% placebo ( p = 0.017) group. As in the LUNAR and EXPLORER studies, the fact that both treatment groups received corticosteroids and immunosuppression meant that there was a large response in the placebo group. Unlike LUNAR and EXPLORER, however, this did not prevent detection of a significant difference between the treatment groups. This is probably because the BLISS trials included larger numbers or due to the use of the composite responder index (which might be more sensitive to improvements than either SLEDAI or BILAG alone) or perhaps belimumab genuinely is more effective than rituximab in this group of patients.
The significantly reduced rates of disease flares allowing for lower corticosteroid doses and decreased serologic activity in the belimumab group versus placebo with SOC treatment was shown in a post hoc analysis of both trials. In addition, a greater therapeutic benefit with belimumab may be observed in patients with more active disease, prednisolone use on enrolment, higher anti-double-stranded DNA levels and lower complement levels .
Other biologic therapies directed at B cells
Please refer to Table 3 for information on other B-cell pathway-targeting agents in development.
| Drug | Mechanism/target | Key trials | Results of trial |
|---|---|---|---|
| Atacicept | Human fusion protein that inhibits both BLyS/APRIL. | Phase II/III RCT in Lupus Nephritis. Atacicept in combination with corticosteroids and MMF. Double-bind placebo-controlled trial patients with moderate-to-severe SLE were randomised to atacicept 75 mg or atacicept 150 mg subcutaneously or placebo | Trial prematurely terminated due to significant decline in serum IgG levels and development of serious infections . Enrolment in the atacicept 150 mg arm was discontinued prematurely due to two deaths. No difference between atacicept 75 mg and placebo for flare rate or time to first flare. Analysis of atacicept 150 mg suggested benefit . |
| Ocrelizumab | Humanised anti-CD20 monoclonal antibody | Phase III trial (BELONG) for LN, was added to SOC (MMF/CYC) with course of high dose corticosteroids | Prematurely terminated due to increased risk of opportunistic infections (mainly Oriental patients) . |
| Epratuzumab | Targets CD22 on B cells. CD22 is a regulatory molecule with effects of B-cell activation | Two RCTs (ALLEVIATE 1 +2) in patients with severe SLE to assess efficacy. Corticosteroids were increased at baseline and other immunosuppressants continued. Further RCT with different doses of Epratuzumab in moderately active to severe SLE. | Trials were discontinued prematurely due to drug availability. Results based on intention to treat population. Improved BILAG scores in treatment group at week 12 . Treatment with epratuzumab 2400 mg cd was well tolerated in patients with moderately to severely active SLE, and associated with improvements in disease activity . Has led to further ongoing Phase III trials. |
| Tabalumab | Fully human IgG4 monoclonal antibody with high affinity to soluble and membrane-bound BLyS | Phase III RCT | Significant improvement in SRI, anti-dsDNA and complement levels but key clinical efficacy end points did not reach statistical significance. No issues with safety . |
| Blisibimod | BLyS pathway-binds to BAFF and inhibits interaction with receptor on B cells, decreasing B-cell survival and proliferation. | Phase II trials | Improved SRIs, proteinuria, anti-dsDNA and complement. Phase III trials are ongoing . |
| Bortezomib | Nonselective proteasome inhibitor resulting in plasma cell depletion | Efficacy in a phase I trial with proliferative nephritis . | |
| Edratide, Abetimus Sodium | Tolergens- induce B-cell tolerance | Efficacy in murine models. Failed in clinical trials . | |
Challenging areas for the future of B-cell-targeted therapies
The above-discussed trials show that there still remain many unanswered questions regarding B-cell depletion in SLE. In addition to being better designed as highlighted by the deficiencies of LUNAR/EXPLORER trials, future trials must address the questions regarding the types of B cells that are suppressed (depleting short-lived plasma cell and non-pathogenic longer-lived plasma cells), the dosage and timing of repeating B-cell depletion to achieve disease remission and disease heterogeneity, which may result in certain groups showing a greater response to therapy.
Rationale for targeting B cells in SLE
B cells are proposed to play a central role in the pathogenesis of SLE with B-cell hyperactivity and loss of tolerance being hallmarks of this process. The failure in check points peripherally and centrally (within the bone marrow) results in the loss of B-cell tolerance, which occurs early in disease . Defects in apoptosis, resulting in an abnormal programmed cell death, have been demonstrated in SLE. An increased apoptotic rate in lymphocytes is accompanied with an impaired clearance of the apoptotic material. Macrophages from patients with SLE have been shown to engulf less apoptotic material in vitro compared to those from the healthy controls . This apoptotic material includes blebs consisting of cellular material exposed on the surface of dying cells during apoptosis and incorporating antigens that are normally intracellular. Thus, the failure of macrophages in removing this material implies that these antigens are exposed to the immune system, leading to the activation of innate immune cells and the B-cell receptor (BCR) of autoreactive B cells, leading to B-cell activation and expression of the B-cell survival molecule receptor (BAFF) and APRIL (a proliferation-inducing ligand) . BAFF and APRIL, cytokines of the tumour necrosis factor (TNF) ligand family, are thought to play a pivotal role in the development and maintenance of SLE .
Polyclonal B-cell activation results in the production of autoantibodies directed against many nuclear, cytoplasmic and plasma membrane antigens. At least 95% of the SLE patients have anti-nuclear antibodies (ANAs). Many of the clinical manifestations of lupus result from an immune complex deposition in tissues and subsequent multi-organ damage. The immune complexes are formed as anti-nuclear antibodies that bind to the nuclear material. B cells also perpetuate the inflammatory response by presenting autoantigens to T cells and producing pro-inflammatory cytokines .
Many B-cell-based therapies have been developed with the ongoing clinical trials. Some of the B-cell-targeted therapies have been tested in clinical trials in lupus have been reviewed.
Rituximab
Rituximab is a chimeric monoclonal antibody against CD20, a surface molecule present on pre-B and mature B cells. The drug was approved for use in RA in 2006 by the Food and Drug Administration and has been used off-label in the treatment of SLE patients with refractory disease . The first open uncontrolled study of rituximab for SLE patients was published by Professor Isenberg’s group at the University College London, which showed improvements in the clinical and laboratory features, and these findings were replicated in many similar uncontrolled studies . However, disappointingly two phase III randomised controlled trials (RCTs) involving patients with moderate to severe lupus (EXPLORER) and patients with class III or IV lupus nephritis (LUNAR) did not meet their primary end points of significant reduction of disease activity compared to placebo. These two trials have been further detailed in the next section.
EXPLORER study
The EXPLORER study compared the efficacy and safety of rituximab versus placebo in patients with moderately to severely active (≥1 BILAG A (British Isles Lupus Assessment Group) score or ≥2 BILAG B score) SLE without renal involvement. This was a randomised, multicentre double-blinded trial involving 257 patients from North America. The inclusion criteria for this study are shown in Table 1 .
| EXPLORER | LUNAR |
|---|---|
| Age range: 16–75 years with a history of meeting four American College of Rheumatology (ACR) criteria for SLE | Age range: 16–75 years with a history of meeting four American College of Rheumatology (ACR) criteria for SLE |
| Severe disease activity at screening : ≥1 organ system with a British Isles Lupus Assessment (BILAG) A score or Moderate disease activity : ≥2 organ systems with a BILAG B score | Biopsy proven (within 12 months) Class III, IV or V Lupus Nephritis and proteinuria. An active urinary sediment was required if the biopsy was performed >3 months before screening. |
| The stable use of one immunosuppressive drug at entry, which was continued during the trial | All patients had a background treatment of MMF up to 3 mg/day by week 4 |
Patients were randomised at a ratio of 2:1 to receive intravenous rituximab (1-g doses) or placebo on days 1, 15, 168 and 182 which was added to prednisone (given according to the protocol) and to the baseline immunosuppressive regimen. Corticosteroids were given at an initial dose of 0.5, 0.75 or 1 mg/kg depending on severity (by BILAG score) and the type of disease manifestation, followed by a taper regimen.
Patients were evaluated monthly with the BILAG index and the lupus quality-of-life index. The primary end points were recorded as achieving a major clinical response (MCR), a partial clinical response (PCR) or no clinical response at week 52 assessed using each of the eight BILAG index organ system scores. A major clinical response was defined as BILAG C scores or better in all organs at week 24 without experiencing a severe flare, and maintaining this response without a moderate or severe flare to week 52. The primary and secondary outcomes are summarised in Table 2 .
| Trial | Primary end points | Secondary end points |
|---|---|---|
| EXPLORER | Major Clinical Response (MCR) : BILAG C or D scores in all organ systems without a severe flare at 6 months, and maintaining this response without a moderate or severe flare at week 52. Partial Clinical Response (PCR) : Defined as meeting one of the following criteria:
Those who failed to reach MCR or PCR |
|
| LUNAR | Complete Renal Response (CRR) : At week 52; serum creatinine improving from abnormal to normal level or from normal to ≤115% of baseline normal; a fall in the urine protein-creatinine ratio to <0.5; and urine sediment containing <5 red blood cells in a high powered field without casts. Partial Renal Response (PRR) : Serum creatinine reduced to ≤115% of abnormal baseline; red blood cells ≤50% above baseline and without red blood cell casts; and a reduction in urine protein-creatinine ratio from ≥3.0 to ≤3.0 or <1 from ≤3.0. No Renal Response (NRR) : Those who failed to reach CRR or PRR |
|
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