Lupus

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Autoimmune Rheumatic Diseases 2
Systemic lupus erythematosus and other autoimmune
rheumatic diseases: challenges to treatment
Grainne Murphy, Larissa Lisnevskaia, David Isenberg
Increased understanding of the molecular mechanisms underlying the pathogenenesis of autoimmune rheumatic
diseases has led to targeted biological treatments that modulate various aspects of the immune response. These new
treatments, together with more judicious use of other immunosuppressive drugs, have resulted in marked
improvements in morbidity and mortality. Although belimumab, an agent that inhibits B-cell survival, is the first drug
to be approved by the US Food and Drug Administration for the treatment of systemic lupus erythematosus in 50 years,
many other immunological targets are under investigation. We discuss the recent advances in the biological treatment
of autoimmune rheumatic diseases, with a particular focus on systemic lupus erythematosus.
Introduction
The prognosis of patients with autoimmune rheumatic
diseases has improved substantially. In the 1950s,
the 4 year survival for patients with systemic lupus
erythematosus was 50%, now 15 year survival is 85%.1
In this part of the Series on autoimmune rheumatic
diseases, we briefly review the treatment of these dis-
orders, focusing mainly on systemic lupus erythemato-
sus, and highlight the recent advances that have been
made in biological treatments.
Pharmacological management
The mechanisms of action and indications for the
drugs used to treat autoimmune rheumatic diseases are
diverse. The table summarises the commonly prescribed
conventional drugs available for the treatment of systemic
lupus erythematosus. The main advances in the past
decade in the conventional management of systemic lupus
erythematosus have included studies showing efficacy for
mycophenolate as an induction agent for lupus nephritis7,10
and the equivalent efficacy of low-dose cyclophosphamide
given every 2 weeks in comparison with the preceding
National Institutes of Health protocol9
(table). Many other
immunosuppressives, such as methotrexate, ciclosporin,
and leflunomide, are used as steroid-sparing agents to
treat systemic lupus erythematosus and the other auto-
immune rheumatic diseases.
New biological treatments
Improved understanding of the immune response and
abnormalities in apoptosis have allowed the recognition
of cells and molecules that are crucial to the development
of systemic lupus erythematosus and other autoimmune
rheumatic diseases. Increased recognition of the multi-
faceted role that B cells have in the pathophysiology of
systemic lupus erythematosus has led to the development
of several novel treatments, notably rituximab and
belimumab. The failure of some other agents targeted at
alternative biological pathways might, partly, be indicative
of the complex interplay of cells and secreted products of
the immune system, highlighting the difficulties asso-
ciated with making the transition from bench to bedside.
The figure shows the immune pathways that have been
the subject of therapeutic trials in systemic lupus
erythematosus.
Until recently, the only drugs approved by the US Food
and Drug Administration (FDA) for the treatment of
lupus were non-steroidal anti-inflammatories, gluco-
corticoids, and hydroxychloroquine. After more than
50 years, the approval of belimumab in 2011 marks the
advent of targeted biological treatments for systemic
lupus erythematosus. In rheumatoid arthritis, the use of
biologics is widespread and has revolutionised the disease
course. Although many patients with lupus or vasculitis
do not respond to conventional treatments, the role of
biologics targeting B cells, T cells, cytokines, or growth
factors is not fully established.
B-cell-depleting treatments
The presence of autoantibodies is a hallmark of systemic
lupus erythematosus. However, B cells are not only
passive producers of antibodies, but are also implicated
in T-cell activation, cytokine secretion, modulation of
dendritic cells, and act independently as antigen-
presenting cells.11
CD20 is a B-lymphocyte specific antigen that is expressed
by pre-B cells and mature B cells. Rituximab is a chimeric
monoclonal immunoglobulin G1 antibody to CD20, the
administration of which results in B-cell depletion, which
Lancet 2013; 382: 809–818
See Editorial page 744
This is the second in a Series of
three papers about autoimmune
rheumatic diseases
Centre for Rheumatology,
Department of Medicine,
University College London
Hospital, London, UK
(G Murphy PhD, D Isenberg MD);
and Oshawa Clinic, Oshawa,
ON, Canada (L Lisnevskaia MD)
Correspondence to:
Prof David Isenberg, Centre for
Rheumatology,The Rayne
Building, University College
London Hospital,
LondonWC1E 6JF, UK
d.isenberg@ucl.ac.uk
Search strategy and selection criteria
We searched PubMed for articles published in English
between Jan 1, 2005, and Feb 27, 2013, and Summon Search
between Jan 1, 2005, and Feb 27, 2013, with the search terms
“systemic lupus erythematosus” and “lupus” in combination
with the terms “management” and “biologics”.We also
searched the references of articles identified by this strategy
and selected those that were relevant.

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typically lasts between 6 and 12 months. This effect is
probably caused by antibody dependent cell-mediated
cytotoxicity, lysis mediated by the complement cascade,
and apoptosis. The absence of CD20 expression on early
pro-B cells allows the regeneration of B cells from the
marrow, and its absence on mature plasma cells minimises
the reduction in the amount of immunoglobulin, which is
produced mainly by longlived plasma cells. Notably, in
systemic lupus erythematosus, the auotantibodies that
correlate with disease activity are secreted by short-
lived plasma cells, indicative of B-cell hyperactivity.
These disease-associated antibodies are susceptible to
depletion by rituximab.12
This drug has been approved for
the treatment of non-Hodgkin lymphoma and rheumatoid
arthritis. Rituximab has also been used off-label for
diseases including antineutrophil cytoplasmic antibody-
associated vasculitis, cryoglobulinaemia, dermatomyositis,
and Sjögren’s syndrome. Many descriptions also exist of
the use of rituximab in patients with systemic lupus
erythematosus who have refractory disease.13–19
Up to now, two large double-blind trials20,21
have
assessed the efficacy of rituximab in patients with active
systemic lupus erythematosus, both of which have
disappointed, failing to reach their primary endpoints.
The EXPLORER trial20
assessed rituximab in 257 patients
with moderate to severe systemic lupus erythematosus.
The primary endpoint was to achieve and maintain
clinical response using the British Isles Lupus
Assessment Group (BILAG) index at week 24 and to
avoid moderate or severe flare up to week 52. No overall
difference was recorded in primary and secondary
endpoints, but beneficial effects were noted in African–
American and Hispanic patients.20
Additionally, findings
from a post-hoc analysis of data from the EXPLORER
trial showed that patients given rituximab had decreased
amounts of anti-double-stranded DNA and anticardio-
lipin antibody and increased complement component
C3.22
Thus, although clear evidence existed of biological
benefit of rituximab in patients with systemic lupus
erythematosus, this benefit had not translated into
clinical advantage.22
The LUNAR trial,21
a randomised, double-blind, placebo-
controlled trial, included 144 patients with class III/IV
lupus nephritis concomitantly given mycophenolate
and glucocorticoids. The primary endpoint (rituximab
superiority) was not achieved. The reasons why the
EXPLORER and LUNAR studies failed to reach their
endpoints are discussed later. However, many reports
documenting the off-label efficacy of rituximab in the
treatment of active systemic lupus erythematosus are
available.23–27
In this real-world scenario, a systematic
review28
of 27 studies including 456 patients given
rituximab reported a 61% mean decrease in the global
BILAG score (14·7–7·0) and a decrease of 59% in the
mean Systemic Lupus Erythematosus Disease Activity
Index (SLEDAI) score (14·8–5·4). Specifically, in the
Mode of action Typical usage Other
Glucocorticoids Changes gene expression, decreases
pro-inflammatory cytokines and adhesion
molecules, and induces anti-inflammatory
cytokines
Rapid onset of action, dose dependent on degree of organ
involvement (typically 5–60 mg daily)
Substantial long-term side-effects including
osteoporosis, diabetes, and hypertension; major
predictor of damage accrual in systemic lupus
erythematosus at 15 year follow-up2
Hydroxychloroquine Changes lysosomal pH3
and has
immunomodulative action through changing
activation of toll-like receptor 7 and toll-like
receptor 94
Effective for control of articular, cutaneous, and constitutional
symptoms (eg, fatigue), usual dose 200–400 mg per day
Findings from a recent systematic review5
showed improved disease activity, reduced
mortality, and a modest effect on thrombotic risk
and damage accrual, potential beneficial effect on
lipid profile and cardiovascular disease,5
safe for
use in pregnancy
Azathioprine Purine analogue, inhibits synthesis of
xanthylic and adenylic acids
Used for active systemic disease including maintenance treatment
of lupus nephritis, selective use as induction treatment for lupus
nephritis, usual dose 1–3 mg/kg per day
Data from trial6
suggest similar efficacy to
mycophenolate as maintenance treatment for
lupus nephritis after induction with low-dose
cyclophosphamide
Mycophenolate Inhibits monophosphate dehydrogenase and
blocks synthesis of guanosine nucleotides and
proliferation ofT cells and B cells
Used for induction and maintenance treatment of lupus nephritis,
also useful agent for other systemic features of systemic lupus
erythematosus, usual dose 0·5–3 g per day
Findings from ALMS (370 patients) study7
showed no significant difference between
cyclophosphamide and mycophenolate as
induction agents for lupus nephritis;7
more
beneficial than cyclophosphamide in
African–American and Hispanic populations;8
more beneficial than azathioprine as
maintenance treatment in ALMS
Cyclophosphamide Forms active alkylating metabolites in liver
and other tissues and prevents cell division by
crosslinking DNA and suppressing DNA
synthesis
Used as induction treatment of lupus nephritis (orally or
intravenously); Euro-lupus project showed equivalent efficacy of
low-dose intravenous cyclophosphamide (six fortnightly pulses of
500 mg) to the National Institutes of Health protocol (750 mg/m²
monthly intravenous cyclophosphamide for 6 months followed by
quarterly infusions for 2 years)9
Also used for other organ or life-threatening
manifestations
ALMS=Aspreva Lupus Management Study.
Table: Conventional drugs used in the treatment of systemic lupus erythematosus

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setting of lupus nephritis, treatment with rituximab
resulted in a complete response rate of 27% and partial
response rate of 39%.
Rituximab has mainly been used when conventional
drugs have failed. However, Pepper and colleagues29
used
the drug at diagnosis in patients with lupus nephritis
instead of oral glucocorticoids because glucocorticoids
have long-term side-effects that are strongly associated
with damage and increased mortality. A further small
study30
compared eight patients who underwent B-cell
depletion at diagnosis with three matched controls
(treated conventionally). Patients were given azathioprine
(Pepper and coworkers used mycophenolate) after
rituximab. The mean reduction of global BILAG score
for the patients who underwent B-cell depletion was
12·0 points compared with 13·2 for the patients given
conventional treatment (non-significant). However, the
mean cumulative prednisolone doses at 6 months were
1287·3 mg for the patients with B-cell depletion lupus
versus 2834·6 mg in the control group.30
Although
rituximab is generally well tolerated and has an acceptable
safety profile, questions remain about its use in the
treatment of systemic lupus erythematosus. Additionally,
the appropriate indications for the use of rituximab in
patients with systemic lupus erythematosus, definition of
response, and use of concomitant immunosuppressives
(especially cyclophosphamide, which might be especially
effective when used in combination), are still being
investigated. Although some data suggest more profound
B-cell depletion when cyclophosphamide is combined
with rituximab, a small study (n=19) by Li and colleagues
in 2009,31
reported no difference in clinical response rates
or the achievement of complete B-cell depletion in patients
given rituximab monotherapy in comparison with a
regimen combining rituximab and cyclophospha-
mide. Guidelines from both the American College of
Rheumatology (ACR)32
and European League against
Rheumatism (EULAR)33
support the use of rituximab in
the treatment of refractory lupus nephritis. Furthermore,
findings from a recent study by Condon and coworkers34
showed that B-cell depletion is of benefit in patients with
lupus nephritis at the time of diagnosis. The researchers
gave rituximab intravenously to 50 patients with lupus
nephritis followed by low-dose mycophenolate to avoid
the use of oral steroids. After 2 years of follow-up, only two
patients have needed regular oral steroids, and marked
histological improvement was seen in most of the patients
at second biopsy.34
The use of B-cell depletion in other autoimmune rheu-
matic diseases is beneficial. The RAVE trial,35
a double-
blind, randomised trial in patients with antineutrophil
cytoplasmic antibody-associated vasculitis, compared
remission induction in 197 patients given oral cyclophos-
phamide or rituximab. The primary endpoint was to stop
prednisone at 6 months; rituximab was non-inferior to
cyclophosphamide and was superior at induction of
remission in patients with relapsing disease.
As in systemic lupus erythematosus, although many
off-label successes with rituximab in patients with
refractory myositis have been reported, a large double-
blind, placebo-controlled trial of rituximab yielded
disappointing results.36
The RIM trial36
of 200 patients
(adult and children) with refractory polymyositis or
dermatomyositis compared the efficacy of rituximab
given early (week 0) or late (week 8) from the start of
enrolment. This unusual design allowed a placebo group
to be introduced in the 0–8 week phase. No significant
difference in the time-to-improvement between the early
and late treatment groups was recorded. Both groups had
a high response rate in what was previously believed to be
refractory disease. Some aspects of the study design,
including the use of a short 8 week placebo phase, in
Figure:Targeted biological agents available and in present or previous clinical trials of systemic lupus erythematosus
pDC=plasmacytoid dendritic cell. BLys=B-lymphocyte stimulator.TNFα=tumour necrosis factor α. APC=antigen-presenting cell.
Belimumab
Atacicept
Peptide
Antibodies
TocilizumabAbatacept Epratuzumab Abetimus
Infliximab
Anti-interleukin 10
Ruplizumab
Toralizumab
Interleukin 10
Interleukin-6
receptor
CD22
CD20
Immune stimulation
Immune
complexes
containing
nucleic acids
Rituximab
Ocrelizumab
Veltuzumab
Ofatumumab
Interferon α
Rontalizumab
Sifalimumab
pDC
APC T cell B cell
TNFα
Apoptotic
material
BLy S

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addition to a higher than expected placebo response
and longer than anticipated time-to-rituximab-response
(which decrease the power of the study to detect a
rituximab-specific response) were suggested by the
investigators as potential reasons for the absence of an
apparent benefit for rituximab; further trials are awaited.
Some evidence suggests that rituximab is effective for
the treatment of some aspects of Sjögren’s syndrome.
Dass and colleagues37
reported the results of the first
randomised controlled trial of rituximab in 2008, finding
marked improvements in fatigue and quality of life in
patients given the drug. More recently, Meijer and
colleagues38
reported efficacy of rituximab in comparison
with placebo in 30 patients with primary Sjögren’s
syndrome. Stimulated salivary flow, fatigue, and lab-
oratory parameters (rheumatoid factor and B-cell concen-
trations) were substantially improved. Findings from
observational studies including data from the Auto-
Immune and Rituximab registry support a benefit on
disease activity, including peripheral neuropathy.39
The detection of a human antichimeric antibody
response, which might have a negative effect on thera-
peutic efficacy, in patients given rituximab has led to
the development of fully humanised monoclonal anti-
bodies that target CD20. These antibodies have less
complement-dependent cytotoxicity and increased
antibody-dependent cellular cytotoxicity. Although
several such agents are available—eg, ocrelizumab,
ofatumumab, and veltuzumab—large phase 3 studies in
the specific setting of systemic lupus erythematosus
and other autoimmune rheumatic diseases are awaited.
A phase 3 trial40
of ocrelizumab for the treatment of
lupus nephritis in patients receiving concomitant cyclo-
phophamide, prednisolone, and azathioprine or myco-
phenolate, was terminated early because of concerns
about high rates of serious or opportunistic infections.
Ofatumumab was effective in the treatment of patients
with rheumatoid arthritis who inadequately responded
to methotrexate; the drug resulted in significantly
improved ACR-20 response at week 24 with no
detectable immunogenicity.41
B-cell modulating treatment
The activation of B cells by interaction with antigen is
helped by several costimulatory molecules including
CD19, and might be inhibited by other receptors—eg,
CD22 and Fcγ receptor IIB. CD22 is a B lymphocyte-
specific transmembrane sialoglycoprotein and links
α-2,6-sialic acid residues in many glycoproteins. The
protein is found in the cytoplasm of pro-B cells and
pre-B cells, but is absent on memory and plasma cells.42
Functionally, CD22 downregulates B-cell receptor sig-
nalling by reducing calcium efflux in B cells. Epratu-
zumab, a monoclonal antibody that results in rapid
internalisation of CD22, causes a partial depletion of
peripheral B cells (especially naive and transitional
subsets) and can also act via inhibition of proliferation
and activation of B cells. Findings from an initial open-
label clinical trial43
of epratuzumab in 14 patients with
moderately active systemic lupus erythematosus showed
that epratuzumab was well tolerated and improved
BILAG scores by more than 50% in 77% of patients at
week 6. Findings from a phase 2b study44
of epratuzumab
in 227 patients with moderate to severe lupus showed
an improvement in disease activity, especially for
cardiorespiratory or neuropsychiatric disease. A further
randomised, double-blind trial of epratuzumab in non-
renal systemic lupus erythematosus is in progress
(NCT01262365).
Inhibition of B-cell survival
To support proliferation, activation, and matura-
tion, B cells rely on several different cytokines, notably,
B-lymphocyte stimulator (or B-cell activating factor).
B-lymphocyte stimulator is a cytokine of the tumour
necrosis factor family and binds three receptors on the
B-cell surface: B-lymphocyte stimulator receptor 3,
transmembrane activator and calcium modulator and
cyclophilin ligand interactor (TACI), and B-cell
maturation antigen. Suppression of the binding of
B-lymphocyte stimulator to B-lymphocyte stimulator
receptor 3 causes apoptosis and inhibition of B-cell
maturation.45
Belimumab is a monoclonal human
antibody that inactivates B-lymphocyte stimulator.
Belimumab is approved by the US FDA and European
Medicines Agency (EMA) for the treatment of patients
with antibody-positive systemic lupus erythematosus
with active disease who are recieving standard treatment.
Two belimumab trials, BLISS-5246
and BLISS-76,47
met
the primary endpoints (decrease in Safety of Estrogens in
Lupus Erythematosus National Assessment [SELENA]–
SLEDAI score of >4 without new BILAG A score in any
organ system and <1 new BILAG B score in any organ
system) with a belimumab dose of 10 mg/kg. These trials
were done in different regions and included patients
with skin or joint disease. Many patients were taking
glucocorticoids (67–71% of patients took prednisone
>7·5 mg in BLISS-52 and 44–48% in BLISS-76) and some
also took other immunosuppressants. A steroid-sparing
effect of belimumab46
was noted in BLISS-52, but not in
BLISS-76. The success of this drug, which might also
help fatigue, encourages other studies of molecules
blocking B-cell activating factor.
The biological effect of atacicept is also mediated
through modulation of B-cell function. Atacicept is a so-
calleddecoyreceptorconsistingofTACI-immunoglobulin
that inhibits the interaction of B-lymphocyte stimulator
and a proliferation-inducing ligand (APRIL) with their
receptors. Like B-lymphocyte stimulator, APRIL acts as a
B-cell survival factor through interaction with receptors
(B-cell maturation antigen and TACI) on B cells. In
isolation, APRIL probably has low biological activity.
Through inhibition of these associations, atacicept
suppresses the differentiation (to plasma cells) and

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survival of B cells and can also inhibit the survival of
longlived plasma cells. Although this process results in a
modest fall in the number of B cells, a comparatively
greater decrease in immunoglobulin G concentrations
arises because of increased inhibition of plasma cells.
Although preliminary evidence for tolerability of
atacicept was recorded in a small trial (n=24) of patients
with systemic lupus erythematosus,48
a more recent phase
2 trial49
was terminated early. In this study phase 2 trial of
patients with renal lupus, atacicept was used in con-
junction with mycophenolate and glucocorticoids and was
stopped after the enrolment of six patients because of
serious infections; two of four patients treated with
atacicept developed infections during the study period and
one further during the safety follow-up. These infections
were mainly attributable to hypogammaglobulinaemia
induced by mycophenolate. The efficacy of atacicept was
not assessed.49
Atacicept could be an encouraging thera-
peutic agent in the treatment of systemic lupus erythema-
tosus, and results of a major trial in patients with
non-renal lupus are eagerly awaited (NCT00624338).
Other potential B-cell targeting strategies
Abetimus is a tetrameric synthetic oligonucleotide
that reduces the number of anti-double-stranded DNA
antibodies. The interaction with anti-double-stranded
DNA antibodies leads to the rapid clearance of this
complex from the circulation. Additionally, abetimus can
deplete self-reactive B cells via apoptosis through binding
to B-cell receptors that are specific to anti-double-
stranded DNA. Despite the serological effect on anti-
double-stranded DNA antibodies, findings from two
large trials50,51
in patients with lupus nephritis failed to
show a significant therapeutic effect.
An alternative approach to B-cell treatment is to target
plasma cells. Findings from murine studies have shown
that the proteasome inhibitor bortezomib is effective in
the treatment of lupus nephritis.52
This agent inhibits the
proteasome within plasma cells, which results in failure to
degrade misfolded proteins and resultant apoptosis. Trials
in human beings with systemic lupus erythematosus have
not yet been done. However, some open-label evidence
exists and suggests a therapeutic effect. In 2012, Hiepe
and colleagues53
reported a small series (n=13) of patients
with active systemic lupus erythematosus refractory to
cyclophosphamide, mycophenolate and rituximab, or
both, who were given bortezomib. A significant reduction
in disease activity and antibody concentrations with
increased complement concentrations was reported;
however, three of 13 patients had reversible poly-
neuropathy.53
Immature plasma cells (plasmablasts) are
also targeted by CD19 inhibition, expressed from
pre-B cells to the plasmablast stage resulting in an
increased depletion of B cells. One such CD19-specific
antibody MDX 1342 is in early phase trials in patients with
rheumatoid arthritis;54
no specific trial in patients with
other autoimmune rheumatic diseases has been done.
Inhibition ofT-cell function
Although pathogenic autoantibodies in systemic lupus
erythematosus are derived from B cells, evidence suggests
that T-cell dysfunction exists in systemic lupus erythema-
tosus. T-cell infiltration has been noted in biopsy samples
of individuals with lupus nephritis, and circulating T cells
have abnormal activation and proliferation.55,56
The main
target of T-cell-directed treatment has been the inhibition
of costimulation of T cells. To achieve full activation,
T cells need two signals: the first comes from the antigen–
MHC complex and the second comes from the interaction
of a costimulatory molecule on antigen receptor cells with
its cognate receptor on T cells. The interaction of CD40 on
B cells with CD40L on T cells and CD28 on T cells with
CD80/86onantigen-presentingcellsaretwocostimulatory
pathways that have been targeted therapeutically in
patients with systemic lupus erythematosus.
Abatacept is a fusion protein consisting of the
T-lymphocyte-associated antigen-4 (CTLA-4) and modified
Fc portion of human immunoglobulin.57
CTLA-4 competes
with CD28 for binding to CD80/86; thus, abatacept down-
regulates T-cell activation. A phase 2, double-blind,
placebo-controlled trial58
investigated outcomes of
118 patients with non-renal lupus given abatacept. The
primary endpoint was the proportion of new flares after
steroid tapering. The study did not meet the primary
endpoint, but treatment differences were recorded in
individuals with arthritis. Additional post-hoc analyses
showed a reduced rate of physician-assessed flares and
improved functional outcomes (Short Form 36 [SF-36]
health survey, sleep, and fatigue) in patients given
abatacept. 19·4% of the patients were negative for
antinuclear antibody and double-stranded DNA anti-
bodies, a higher proportion than expected. Further trials
with abatacept are in progress, including ACCESS
(NCT00774852),59
in which patients with lupus nephritis
are receiving a combination of abatacept and low-dose
cyclophosphamide (Euro-lupus regimen) followed by
maintenance treatment with azathioprine. In view of the
efficacy of the combination approach with abatacept and
cyclophosphamide in animal models of lupus nephritis,
whether this effect can be replicated in human beings will
be interesting to study.60
Few studies have investigated
abatacept in the context of the other autoimmune
rheumatic diseases. An open-label study61
of patients with
mild polyangiitis granulomatosis, most of whom received
concomitant immunosuppression, showed improved
disease activity in 90% of patients, with clinical remission
in 80% of patients at a median time of 3·75 months after
treatment initiation. Studies of abatacept in patients with
myositis are also scarce. Potential efficacy is suggested by a
positive effect in case reports;62
a single-blind clinical trial
of this agent in patients with refractory polymyositis and
dermatomyositis is in progress (ARTEMIS; NCT01315938).
The CD40/40L pathway has also been targeted by
drugs. Two monoclonal antibodies that act by targeting
CD40L—ruplizumab and toralizumab—have shown

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moderate clinical efficacy in early trials of systemic lupus
erythematosus with improvements in proteinuria and
haematuria, and decreasing anti-double-stranded DNA
titres. However, these trials have been stopped because of
increased thromboembolic complications.63
An alternative method to modulate T-cell function is
restoration of tolerance to self-antigens, a property that is
lost in many autoimmune diseases. Several attempts have
been made to develop tolerogens, synthetic molecules
that crosslink autoantibodies on the surface of B cells,
subsequently leading to B-cell depletion or inactivity.
Edratide is a peptide that was designed based on the first
complementarity-determining region of a supposedly
pathogenic human monoclonal anti-DNA antibody. Edra-
tide was effective in disease prevention and amelioration
of established disease in murine models of systemic
lupus erythematosus.64
The drug has been suggested to
alter the expression of tumour necrosis factor α (TNFα)
and transforming growth factor β, and thereby reduce
T-cell apoptosis.64,65
Although findings from a double-
blind controlled trial66
of edratide in patients with systemic
lupus erythematosus showed no significant improvement
in the SLEDAI score at 24 weeks, data from a more recent
smaller study67
in patients with non-renal lupus suggest
that edratide might improve disease and alter cytokine
expression in circulating leucocytes.
Cytokine inhibition
Systemic lupus erythematosus is described as a T-helper-
2-driven disease with increases in the serum concen-
tration of interleukins 4, 6, and 10. Other cytokines such
as the type 1 interferon pathway are also implicated in
systemic lupus erythematosus. In-vivo cytokines can have
diverse roles, complicating matters. Thus, many cytokines
can have dual functions and affect both pro-inflammatory
and anti-inflammatory pathways, dependent on several
different factors including the receptor with which they
interact. Therefore, the ultimate biological effect of their
inhibition can be difficult to predict.
Interleukin 6
Tocilizumab is a monoclonal humanised antibody that
inhibits the interleukin-6 receptor. In addition to its
upregulation in serum, interleukin 6 has been associated
with disease activity, anaemia, and anti-double-stranded
DNA antibodies in systemic lupus erythematosus.68,69
Moreover, urinary interleukin-6 concentrations have been
associated with the activity of lupus nephritis.70
Two early
phase clinical trials of tocilizumab in systemic lupus
erythematosus have been done; findings from the first
study71
in 14 patients with mild to moderate systemic lupus
erythematosus showed an improvement in acute phase
markers and activated lymphocytes. The second study72
in
which 16 patients were given one of three escalating (2, 4,
or 8 mg/kg) doses of tocilizumab over 12 weeks reported
an improvement in disease activity (especially arthritis)
and serological activity (decreased anti-double-stranded
DNA antibody titres). A reversible decrease in neutrophil
counts was recorded.72
Larger scale studies of systemic
lupus erythematosus have not yet been done.
Tocilizumab might also be useful in the inflammatory
myopathies in view of the importance of interleukin 6 in
the pathogenesis of myositis. In one study,73
two patients
with refractory disease given interleukin-6 inhibition had
normalisation of creatine kinase, although information
about muscle strength was not provided.
Inhibition of interleukin 10
Interleukin 10 has also been proposed as a relevant
therapeutic target in systemic lupus erythematosus in view
of its increased serum concentration in active disease and
its ability to activate B cells.68
Although data from a pre-
liminary study74
with a monoclonal anti-interlukin-10
murine antibody suggested improved disease in six
patients who were dependent on glucocorticoids, in an
open-label trial, all patients developed antibodies against
B-N10, the antibody in question.74
Inhibition ofTNFα
The potential role of TNFα in the pathogenesis of
systemic lupus erythematosus is controversial. Although
serum concentrations are increased and TNFα has been
reported histologically in biopsy samples of individuals
with lupus nephritis,75,76
TNFα inhibitors (used in
rheumatoid arthritis) can induce antinuclear antibody
and, rarely, drug-induced lupus.77
Findings from several
small studies78,79
have shown efficacy of TNFα inhibitors,
in particular infliximab, in patients with systemic lupus
erythematosus. In one study,78
six patients with lupus
nephritis and arthritis or both were given infliximab and
azathioprine or methotrexate with a resultant marked
improvement in proteinuria and arthritis. A less mean-
ingful response was reported in a further study of nine
patients with polyarthritis associated with systemic lupus
erythematosus, in which only one of three patients had a
clinical improvement.79
TNFα inhibition has also been used in the treatment of
other autoimmune rheumatic diseases. In the inflam-
matory myopathies, the results have been variable. Data
from a 2011 double-blind trial80
suggested some benefit
in the facilitation of glucocorticoid tapering. In this
study, 16 patients with dermatomyositis were randomly
assigned to receive etanercept (11 patients) or placebo
(five patients) and followed a standardised steroid
tapering as tolerated over 24 weeks. The average daily
prednisone dose at the time of completion was 1·2 mg
per day in the etanercept group and 29·2 mg per day in
the placebo group. Moreover, all patients in the placebo
group were so-called treatment failures by contrast with
five of the 11 in the group given etanercept who were
successfully weaned off glucocorticoids. The use of
etanercept in vasculitis (eg, polyangiitis with granulo-
matosis) remains contentious; a particular concern is
safety.81
Infliximab might be a more relevant alternative.

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Type 1 interferon
In systemic lupus erythematosus, serum concentrations
of interferon α are increased in association with a distinct
interferon signature (a pattern of genes induced by
interferon) in peripheral blood cells that is associated
with disease activity.82,83
Several biologics targeting the
interferon pathway are being investigated in patients
with systemic lupus erythematosus. Most work is being
done on interferon α.84
Sifalimumab and rontalizumab
are monoclonal antibodies that target interferon α and
are in early phase trials for patients with systemic
lupus erythematosus. The results from a preliminary
phase 1 trial85
(n=60) in which sifalimumab was given to
patients with mild to moderately active systemic lupus
erythematosus with cutaneous involvement also showed
an effect on normalisation of the aberrant interferon
signature, in addition to changing interferon expression
in skin biopsy samples. In view of encouraging find-
ings from phase 1 mechanistic studies, a multicentre
phase 2 trial86
of rontalizumab in patients with moderate
to severe active systemic lupus erythematosus is under-
way. Other targets under investigation in systemic lupus
erythematosus include interferon γ (NCT00818948) and
an immunisation strategy with interferon-α kinoid with
the aim of inducing a polyclonal anti-interferon antibody
response (NCT01058343).
Complement inhibition
Deficiency in the early components of the complement
system predispose to the development of a lupus-like
disease. Activation of the complement pathway mediated
by immune complexes is central to the pathogenesis of
disease. Thus, attempts to target components of the com-
plement cascade have been proposed in systemic lupus
erythematosus. One example is eculizumab, a mono-
clonal anti-C5 antibody, approved for the treatment of
paroxysmal nocturnal haemoglobinuria. Whether such
agents will be of benefit in the treatment of systemic
lupus erythematous remains to be seen.
Stem-cell transplantation
Stem-cell transplantation, mainly autologous, has been
used in various autoimmune conditions to obtain disease
control in patients who are refractory to conventional
treatment. The notion underlying its usefulness is the
depletion of autoreactive lymphocytes that have evaded
conventional treatment followed by reconstitution of the
immune system with healthy immune cells from haemo-
poietic stem cells resulting in so-called immune resetting.
Results from the European Group for Blood and Marrow
Transplantation and EULAR (2001–08) showed the 5 year
outcomes of 28 patients with systemic lupus erythema-
tosus given autologous bone marrow transplantation.87
Investigators reported an overall survival of 81% with 56%
of patients relapsing (mild) at 5 years. An 18% mortality
was recorded at 2 years, slightly higher than previous
reports. Patients who had manipulation of re-infused cells
before transplantation (CD34 selection) seemed to have a
better outcome with a lower relapse index than patients
with CD34 selection. Despite the high morbidity and
mortality, the ability to achieve a sustained disease-free or
low disease activity state in a cohort of patients with
especially poor prognosis supports the application of
autologous stem-cell transplantation in patients with
refractory systemic lupus erythematosus. In systemic
sclerosis, data from case series88
and the phase 2 ASSIST
trial77
suggest rapid and sustained improvement in skin
thickening and functional status, with a suggestion of
benefit for pulmonary disease.88,89
More recently, data
from the ASTIS (ISRCTN54371254) phase 3 study have
supported these findings and confirmed long-term
survival of stem-cell transplantation in systemic sclerosis.90
The role of stem-cell transplantation in other autoimmune
rheumatic diseases is less clear. Case studies91
have
reported an improvement in muscle strength and muscle
enzymes in the short to medium term in patients with
inflammatory myopathies such as dermatomyositis;
however, further work is needed to clarify the role of stem-
cell transplantation in these disorders.
Controversies about the use of biological agents
for autoimmune rheumatic diseases
By contrast with the highly successful introduction of
biological drugs for the treatment of rheumatoid arthritis,
the use of these drugs in systemic lupus erythema-
tosus, Sjögren’s syndrome, myositis, and vasculitis has
remained more problematic. Some notable successes of
clinical trials have been belimumab in systemic lupus
erythematosus and rituximab in antineutrophil cyto-
plasmic antibody-positive vasculitis; however, several
frustrating failures have also been reported including
the use of abatacept and rituximab in systemic lupus
erythematosus. Several reviews have considered why
rituximab did not meet its endpoints in the EXPLORER
and LUNAR trials. In view of the drug’s success in
double-blind controlled trials in treating rheumatoid
arthritis (the National Institute for Health and Clinical
Excellence [NICE] approved rituximab for use in rheuma-
toid arthritis in 2007) and antineutrophil cytoplasmic
antibody-positive vasculitis, together with data supporting
its efficacy in systemic lupus erythematosus, which were
published in more than 20 different open-label studies
and registry reports, rituximab is most probably effective
for many patients with systemic lupus erythematosus.
Why the major trials in systemic lupus erythematosus
did not meet their endpoints has been the subject of
much debate. The possibilities include inadequate
training of the participating physicians and the potential
inclusion of unsuitable patients. However, the con-
comitant use of large doses of glucocorticoids and
immunosuppressives is probably the most likely
explanation. Additionally, as pointed out by Wofsy and
colleagues in 2012,92
the precise definitions of response
establish whether a study of lupus nephritis is judged

8. Series
816 www.thelancet.com Vol 382 August 31, 2013
4 Barrat FJ, Meeker T, Gregorio J, et al. Nucleic acids of mammalian
origin can act as endogenous ligands for Toll-like receptors and may
promote systemic lupus erythematosus. J Exp Med 2005;
202: 1131–39.
5 Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P,
Khamashta MA. Clinical efficacy and side effects of antimalarials
in systemic lupus erythematosus: a systematic review.
Ann Rheum Dis 2010; 69: 20–28.
6 Houssiau FA, D’Cruz D, Sangle S, et al, and the MAINTAIN
Nephritis Trial Group. Azathioprine versus mycophenolate
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results from the MAINTAIN Nephritis Trial. Ann Rheum Dis 2010;
69: 2083–89.
7 Appel GB, Contreras G, Dooley MA, et al, and the Aspreva Lupus
Management Study Group. Mycophenolate mofetil versus
cyclophosphamide for induction treatment of lupus nephritis.
J Am Soc Nephrol 2009; 20: 1103–12.
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69: 61–64.
11 Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus.
J Clin Pathol 2003; 56: 481–90.
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Long-lived autoreactive plasma cells drive persistent autoimmune
inflammation. Nat Rev Rheumatol 2011; 7: 170–78.
13 Chen H, Zheng W, Su J, et al. Low-dose rituximab therapy for
refractory thrombocytopenia in patients with systemic lupus
erythematosus—a prospective pilot study. Rheumatology (Oxford)
2011; 50: 1640–44.
14 Efthimiou P, Kukar M, Hersh A. Rituximab and lupus interstitial
lung disease: friend or foe? Int J Rheum Dis 2011; 14: e3–4.
15 Al-Musawi ZS, Nabar UJ. Successful treatment of recurrent
pancreatitis secondary to systemic lupus erythematosus with B-cell
depletion therapy. Arch Iran Med 2011; 14: 66–70.
16 Tayal V, Chiu YH, George E, Mane S. Colitis associated with active
systemic lupus erythematosus successfully treated with rituximab.
J Clin Rheumatol 2011; 17: 79–82.
17 Pottier V, Pierrot M, Subra JF, et al. Successful rituximab therapy in
a lupus patient with diffuse alveolar haemorrhage. Lupus 2011;
20: 656–59.
18 Alsanafi S, Kovarik C, Mermelstein AL, Werth VP. Rituximab in the
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Group. Efficacy and safety of rituximab in patients with active
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22 Tew GW, Rabbee N, Wolslegel K, et al. Baseline autoantibody
profiles predict normalization of complement and anti-dsDNA
autoantibody levels following rituximab treatment in systemic lupus
erythematosus. Lupus 2010; 19: 146–57.
23 Melander C, Sallée M, Trolliet P, et al. Rituximab in severe lupus
nephritis: early B-cell depletion affects long-term renal outcome.
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successful or not. If the bar is set too high, no clinical
trial of this complex disease will ever meet its primary
endpoints. In particular, Wofsy and coworkers argue that
the data for the trial of abatacept in lupus nephritis, when
re-interpreted with criteria from other studies of lupus
nephritis, strongly suggest that a study regarded as a
failure was actually successful and that further trials with
abatacept are strongly encouraged. Therefore, we are in
an unusual situation in that a drug, belimumab, which
met its endpoints in two clinical trials and is approved by
the FDA and EMA, cannot easily be prescribed in the
UK, whereas another drug, rituximab, which failed to
meet its clinical trial endpoints, and is not approved
(apart from for rheumatoid arthritis) by the FDA and
EMA, is widely used in the treatment of autoimmune
rheumatic diseases. For example, we have treated more
than 100 patients with systemic lupus erythematosus and
20 patients with myositis.
Another controversial issue is cost. NICE, a UK institute
that issues guidelines for the management of medical
disorders on the basis of evidence and health economics,
seems to favour drugs that are priced less than £30000 per
quality-adjusted life-year. In the USA, FDA-approved
Benlysta is expensive (well in excess of £30000), but not
prohibitively so. However, in the UK, the cost has clearly
been an issue when the sellers GlaxoSmithKline
(Middlesex, UK) have sought NICE approval. It will be
interesting to see what happens when rituximab (two
infusions, which in 1 year costs £4000–5000 in the UK)
comes off licence and biosimilar drugs become available.
Conclusions
We are at a challenging crossroads with regards to the
treatment of autoimmune rheumatic diseases. The limit
of what conventional drugs can achieve has probably
been reached. Improved understanding of the aetio-
pathogenesis of these diseases with the introduction of
more targeted biological treatment is beginning to show
some encouraging signs of improvement in the outlook
for these patients. However, this improvement is still
lagging behind what has been achieved in the past decade
for rheumatoid arthritis.
Conflicts of interest
We declare that we have no conflicts of interest.
Contributors
GM wrote the manuscript and did the literature search, LL contributed
to the literature search and editing of the manuscript, and DI
contributed to the writing and editing of the manuscript.
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