Review

Nephron Clin Pract Published online: November 29, 2014

DOI: 10.1159/000368585

Rituximab in Systemic Lupus

Erythematosus and Lupus Nephritis
Hannah Beckwith Liz Lightstone
Imperial AHSC Lupus Centre and Section of Renal Medicine and Vascular Inflammation, Department of Medicine,
Imperial College London, London, UK

Key Words many physicians firmly believe in the value of rituximab in

Systemic lupus erythematosus · Lupus nephritis · SLE/LN treatment and have continued to use it in their clini-
Rituximab · B cell depletion therapy cal practice. Recent work has demonstrated the efficacy of
rituximab as a steroid-sparing agent and as an alternative
therapeutic option for refractory SLE/LN. There are two fur-
Abstract ther rituximab randomised controlled trials planned/started
Treatment options for systemic lupus erythematosus (SLE) in LN – one using a steroid-minimising regimen with ritux-
and lupus nephritis (LN) have high associated morbidity and imab for induction and one evaluating rituximab for LN re-
mortality. Side effects, particularly from long-term cortico- fractory to 6 months standard of care treatment. Rituximab
steroid usage, limit patient adherence, with subsequent im- remains a problematic drug in lupus and LN – it is a biologi-
pacts on treatment efficacy. In addition, a subset of patients cally plausible agent with a huge amount of supportive an-
with SLE/LN fails to respond to current standard immuno- ecdotal clinical data. Yet the completed trials have been neg-
therapy. There is an urgent need to develop steroid-sparing ative to date despite clinical experience strongly suggesting
treatment regimens as well as novel therapies for the man- efficacy. It is hoped that the two new trials will determine the
agement of refractory disease. Rituximab is a chimeric role for rituximab, at least in LN. © 2014 S. Karger AG, Basel
mouse/human monoclonal antibody directed against the B
cell CD20 receptor. It has been used in the treatment of non-
Hodgkin’s lymphoma for over 30 years and has an excellent
safety profile. Recent work has demonstrated a role for B cell Introduction
depletion therapy in the management of autoimmune dis-
ease, and the efficacy of rituximab in many observational B cells play a pivotal role in the development and
studies in SLE and LN has been noted. Unfortunately, two maintenance of autoimmune disease [1]. Systematic lu-
large randomised controlled trials evaluating rituximab for pus erythematosus (SLE) is a prototypic autoimmune dis-
the treatment of renal and non-renal lupus failed to meet order associated with a diverse array of pathogenic auto-
their primary endpoints. Reasons for this have been dis-
cussed extensively within the medical community with a
general consensus that trial design (steroid use, trial size and Biologic Treatment in Glomerular Disease
endpoints used) was the principal reason for the failures. De- D. Jayne, Cambridge
spite the lack of trial evidence, clinical experience means V. Tesar, Prague
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Mount Sinai School of Medicine

© 2014 S. Karger AG, Basel Prof. Liz Lightstone, PhD, FRCP

1660–2110/14/0000–0000$39.50/0 Section of Renal Medicine and Vascular Inflammation
Department of Medicine, Imperial College London
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E-Mail karger@karger.com
Hammersmith Campus, Du Cane Road, London W12 0NN (UK)
www.karger.com/nec
E-Mail l.lightstone @ imperial.ac.uk
antibodies directed towards cytoplasmic and nuclear cell Rituximab in SLE
compartments. Multiple systems can be involved, with
subsequent immune complex deposition driving comple- SLE is an archetypal antibody-mediated disease and
ment activation, inflammation and end-organ damage. hence promoting B cell depletion appears to target a plau-
Between 40 and 70% of patients with SLE develop lupus sible critical pathophysiological pathway. Early case re-
nephritis (LN), and the consequences can be devastating ports and then case series suggested benefit in the treat-
[2]. Even with aggressive immunosuppressive therapy, ment of SLE (reviewed in [14]). This led to the develop-
rates of end-stage renal disease over 5–10 years are in the ment of the EXPLORER trial (a randomised, double-blind,
region of 10%, a figure that has disappointingly remained placebo-controlled exploratory phase II/III SLE evalua-
largely unchanged over the last 30 years [3, 4]. Despite the tion of rituximab) [15]. The EXPLORER trial recruited
introduction of newer immunosuppressive agents such as 257 patients aged 16–75 years with moderate and severe
mycophenolate mofetil (MMF), treatment of SLE and LN SLE who met four of the American College of Rheumatol-
remains challenging. Current standard therapeutic regi- ogy (ACR) criteria for SLE including a positive test for
mens are associated with significant side effects and cu- antinuclear antibodies, active disease at screening [de-
mulative toxicity including premature ovarian failure, in- fined as ≥1 domain with a British Isles Lupus Assessment
creased risk of future malignancies and teratogenicity. Group (BILAG) A score (severe activity) or ≥2 domains
Prolonged corticosteroid use is associated with increased with a BILAG B score (moderate disease activity)], and
risk of premature cardiovascular disease and a 2- to 4-fold stable use of one immunosuppressive drug at entry which
increased risk of coronary events in SLE [5]. In addition, was continued throughout the trial (methotrexate, aza-
cosmetic changes associated with prolonged steroid use thioprine or MMF). 57% of participants were corticoste-
may contribute to non-adherence, which is a recognised roid dependent. Exclusion criteria included severe central
cause of treatment failure [6]. Consequently, there has nervous system or organ-threatening lupus, any other ac-
been a strong desire amongst physicians to develop new tive conditions requiring significant use of immunosup-
and innovative treatment regimens to help improve prog- pressives, previous B cell depletion therapy, and deranged
nosis and reduce the burden of iatrogenic morbidity [7]. hepatic or haematological serum parameters. Patients
Given the key role of B cells in the development of a dys- were randomised at a 2: 1 ratio to receive intravenous
regulated immune response, a strong argument exists for rituximab or placebo on days 1, 15, 168 and 182 (in addi-
the use of B cell-depleting agents in the management of tion to prednisolone and baseline immunosuppressive
SLE and LN. therapy). The primary endpoint was the effect of placebo
versus rituximab in achieving and maintaining clinical
response at week 52, assessed using the BILAG index or-
Rituximab gan system scores.
Unfortunately the EXPLORER trial failed to meet its
Rituximab is a chimeric mouse/human monoclonal primary endpoint. Potential reasons for this include in-
antibody directed against the CD20 receptor of the B cell. adequate trial size, concomitant background immuno-
CD20 is expressed on immature, mature and activated B suppressive/high-dose corticosteroid usage and appor-
cells, but not plasma cells, stem cells or pro-B cells. Ritux- tion of endpoints which were unable to discriminate
imab acts via antibody-dependent cell-mediated cytotox- between minor disease fluctuations and meaningful
icity, complement-dependent cytotoxicity and apoptosis clinical response [16]. However, on further examina-
to effectively deplete B cells for 6–9 months in over 80% tion, a post hoc analysis of this trial suggested rituximab
of patients [8]. Importantly, rituximab has been exten- reduced the risk of a subsequent first severe flare and
sively used in the treatment of non-Hodgkin’s lymphoma lowered mean severe flare rates [17]. In addition, effi-
[9] and has an excellent safety record. Adverse events fol- cacy signals were detected in subsets of patients includ-
lowing rituximab use are minimal and include infusion- ing African Americans and Hispanics [15].
related reactions and increased risk of infection [7, 10]. It is worth briefly reviewing the contrasting fate of the
Hence, there was confidence in transferring its use to au- anti-BLys antibody, belimumab. B lymphocyte-stimulat-
toimmune diseases, and rituximab has been successfully ing factor (BLyS) is a cytokine produced predominantly
used in the treatment of rheumatoid arthritis, ANCA-as- by myeloid cells. BLyS is necessary for B cell maturation,
sociated systemic vasculitis and primary immune throm- survival and immunoglobulin production [16]. Belu-
bocytopenic purpura [11–13]. mimab, a soluble anti-BLyS monoclonal antibody was
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Mount Sinai School of Medicine

2 Nephron Clin Pract Beckwith/Lightstone

DOI: 10.1159/000368585
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shown to lead to superior results when added to standard imab was again used as an add-on to standard of care with
of care, compared to standard of care alone, in two large MMF and corticosteroids. Unfortunately, the LUNAR
randomised controlled trials in patients with active SLE trial also failed to meet its primary endpoint of 20% supe-
(n = 865 and 819) [18, 19]. These results led to belimum- riority in the proportion of patients achieving complete
ab being granted regulatory approval for the treatment of or partial remission at 52 weeks [21].
patients with antibody-positive SLE with active disease Trial design is again likely to have contributed to its
despite treatment with standard drugs. lack of success. The use of corticosteroids as well as MMF
These trials were designed slightly differently to the as background in both the rituximab and control group
EXPLORER trial; they used large numbers of patients and may have masked any incremental benefit of rituximab.
aimed for a smaller delta. A composite endpoint was In addition, the LUNAR trial was powered for a compos-
used, the SLE Responder Index (SRI) response rate at ite endpoint of complete renal remission (CR) and partial
week 52 [which is largely driven by the SLE Disease Activ- renal remission (PR), but weighted towards a greater pro-
ity Index (SLEDAI) score], and inclusion criteria were portion of CR rather than PR (powered at 90% to detect
narrower – only seropositive patients were included and a 20% increase in CR and a 5% increase in PR). This
they had to have evidence of activity as judged by a meant the study was underpowered to detect the 15% in-
SLEDAI score of at least 6. Key exclusions were central crease in the proportion of PR actually seen or doubling
nervous system lupus or active LN. Participants were of the number of rituximab-treated patients who achieved
again continued on previous immunosuppressive thera- a PR compared to standard therapy (31 vs. 15%). Ironi-
py, but adjustments to background immunosuppressants cally, the overall delta was 11%, which was larger than that
were more strictly controlled and time limited, including seen in the belimumab trials but in a much smaller trial –
increases to corticosteroid doses in the first 6 months and so the difference was not significant. However, there are
increases to other immunosuppressants in the first 16 reasons to consider that the rituximab arm showed ben-
weeks. efit. The data at 78 weeks of follow-up strongly suggest
Interestingly, a post hoc analysis of the belimumab that rituximab was having a beneficial effect as there were
studies demonstrated that belimumab is most effective in significant differences in the proportion of patients who
the subset of patients with high disease activity (e.g. high achieved proteinuric remission and who did not require
titres of anti-dsDNA antibodies and low complement lev- additional immunosuppression (reviewed in [24]). Re-
els) [20]. Rituximab also reduces anti-dsDNA levels and peat renal biopsies, had they been done, might have dem-
increased complement levels [15, 21], suggesting that the onstrated histological remission at 1 year which we have
problem might not be the drug, but instead the trial de- suggested may precede biochemical remission which can
sign. take a long time as suggested by these data. What is clini-
cally important is that despite the failure of these two
rituximab randomised controlled trials to achieve their
Rituximab in LN primary endpoint, many clinicians continue to use ritux-
imab in daily practice, based on their personal experience,
Given the many case series and registry reports of use the large case series and registry data, and the long-term
in refractory LN, it was reasonable to evaluate rituximab outcome data in the LUNAR trial [1, 14, 25]. This con-
in a clinical trial setting for the treatment of LN. LN is trasts with the clinical reality for belimumab, where de-
classified according to the ISN/RPS criteria [22]. Treat- spite the positive trial data there has been relatively slow
ment is generally reserved for those with proliferative LN uptake of use of this drug in lupus, possibly because of
(class III-a or a/c or class IV-S a or a/c or class IV-G a or difficulty in knowing which patients would benefit most
a/c where a = active, c = chronic, S = segmental and G = and due to the lack of data on use in LN.
Global – all referring to glomerular lesions), and some We have developed an alternative way of using ritux-
guidelines recommend treatment for class V LN only if imab – we chose to use rituximab as an ‘instead of’ drug
associated with nephrotic range proteinuria [23]. rather than an add-on and (more radically) opted to omit
Following the failure of the EXPLORER trial (non-re- oral steroids. The rationale was based on experience in
nal SLE) to meet its primary endpoint of reduced clinical renal transplantation where the introduction of biologi-
activity without subsequent flares [15], guidelines for ste- cal agents at induction has led to the development of ste-
roid use in the LUNAR trial (Lupus Nephritis Assessment roid-avoiding regimens. Importantly, in transplantation
with Rituximab) were more stringent. However, ritux- such an approach has led to better outcomes both in
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Mount Sinai School of Medicine

Rituximab in SLE and LN Nephron Clin Pract 3

DOI: 10.1159/000368585
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terms of lower rates of rejection and of fewer side effects Houssiau and colleagues, is aiming to evaluate the addi-
such as new-onset diabetes [26]. We have reported our tion of rituximab in patients who have had 6 months of
single-centre observational cohort study of 50 consecu- standard of care but failed to achieve a complete remis-
tive patients with biopsy-proven LN, not on oral steroids sion. This trial will formally assess whether rituximab is
and who were treated with our ‘Rituxilup’ regimen: meth- effective in refractory LN.
yl prednisolone (500 mg) and rituximab (1 g) on days 1 So, several years after the first reports of rituximab as
and 15 and with just MMF as maintenance, and no oral the new ‘wonder’ drug for lupus and LN, it remains unli-
steroids [27]. The results were very encouraging – 52% of censed but quite widely used – in that respect it is no dif-
patients achieved complete renal remission at 1  year, ferent from MMF, cyclophosphamide or azathioprine.
there were few extrarenal flares and of the 45 patients who Guidelines on the management of LN suggest it can be
stayed on the regimen, only 2 required longer than 2 used (added in) where standard of care with MMF or cy-
weeks of oral steroids over a median follow-up of 163 clophoshphamide has failed in the treatment of prolifera-
weeks. Colleagues have used this approach in new pa- tive LN [29–31].
tients with lupus (not specifically renal lupus) and have
also demonstrated efficacy and steroid sparing [28].
There has been great excitement in the renal and rheuma- Conclusion
tology communities over a steroid-sparing approach.
This work is now being taken forward in a large, open- Whilst no randomised controlled trial presently ex-
labelled, randomized, controlled, multicentre trial (the ists demonstrating the efficacy of rituximab in treating
RITUXILUP trial, NCT01773636 at www.clinicaltrials. SLE and LN, it is clear that clinicians and scientists have
gov). The trial is designed as a non-inferiority trial to a strong belief in its potential role based on biological
demonstrate that the Rituxilup regimen (Rituximab, plausibility (the key role of B cells in lupus pathogene-
methyl prednisolone and MMF, but no oral steroids) is sis), the influence on serology and surrogate markers of
not inferior in inducing CR at 1 year compared to stan- disease activity, and numerous cohort and registry re-
dard of care with methyl prednisolone, MMF and taper- ports. Part of the drive to use rituximab is that it has a
ing oral steroids. It is also powered to show superiority of strong and long safety profile and that current treat-
the Rituxilup regimen compared to standard of care for ment options have a high associated morbidity and
serious adverse events and serious infections. Patients mortality, and side effects experienced by patients limit
(n = 252) will be followed for a minimum of 2 years. The adherence and treatment efficacy. There is an unmet
estimated completion date is 2018, and if the trial is a suc- need for both steroid-sparing treatment regimens and
cess it will mark a paradigm shift in the management of new novel therapies to treat refractory cases: rituximab
LN as it will be the first time in 66 years that steroids are is an exciting therapeutic option which has demonstrat-
not deemed necessary for treatment. ed success in both of the above. Further work is needed
RING (Rituximab for Lupus Nephritis with Remission to elucidate the real value of B cell depletion through
as a Goal, NCT01673295), another ongoing trial led by rituximab.

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Rituximab in SLE and LN Nephron Clin Pract 5

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