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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 rst 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 briey review the treatment of these disorders, focusing mainly on systemic lupus erythematosus, 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 ecacy for
mycophenolate as an induction agent for lupus nephritis7,10
and the equivalent ecacy 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 leunomide, are used as steroid-sparing agents to
treat systemic lupus erythematosus and the other autoimmune 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 multifaceted 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
www.thelancet.com Vol 382 August 31, 2013

the immune system, highlighting the diculties associated 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-inammatories, glucocorticoids, 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.

Lancet 2013; 382: 809818

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,
London WC1E 6JF, UK
d.isenberg@ucl.ac.uk

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 antigenpresenting cells.11
CD20 is a B-lymphocyte specic 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
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 identied by this strategy
and selected those that were relevant.

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Series

Mode of action

Typical usage

Other

Glucocorticoids

Changes gene expression, decreases

pro-inammatory cytokines and adhesion
molecules, and induces anti-inammatory
cytokines

Rapid onset of action, dose dependent on degree of organ

involvement (typically 560 mg daily)

Substantial long-term side-eects 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

Eective for control of articular, cutaneous, and constitutional
immunomodulative action through changing symptoms (eg, fatigue), usual dose 200400 mg per day
activation of toll-like receptor 7 and toll-like
receptor 94

Findings from a recent systematic review5

showed improved disease activity, reduced
mortality, and a modest eect on thrombotic risk
and damage accrual, potential benecial eect on
lipid prole and cardiovascular disease,5 safe for
use in pregnancy

Azathioprine

Purine analogue, inhibits synthesis of

xanthylic and adenylic acids

Data from trial6 suggest similar ecacy to

mycophenolate as maintenance treatment for
lupus nephritis after induction with low-dose
cyclophosphamide

Mycophenolate

Inhibits monophosphate dehydrogenase and Used for induction and maintenance treatment of lupus nephritis,
blocks synthesis of guanosine nucleotides and also useful agent for other systemic features of systemic lupus
erythematosus, usual dose 053 g per day
proliferation of T cells and B cells

Cyclophosphamide

Forms active alkylating metabolites in liver

and other tissues and prevents cell division by
crosslinking DNA and suppressing DNA
synthesis

Used for active systemic disease including maintenance treatment

of lupus nephritis, selective use as induction treatment for lupus
nephritis, usual dose 13 mg/kg per day

Used as induction treatment of lupus nephritis (orally or

intravenously); Euro-lupus project showed equivalent ecacy of
low-dose intravenous cyclophosphamide (six fortnightly pulses of
500 mg) to the National Institutes of Health protocol (750 mg/m
monthly intravenous cyclophosphamide for 6 months followed by
quarterly infusions for 2 years)9

Findings from ALMS (370 patients) study7

showed no signicant dierence between
cyclophosphamide and mycophenolate as
induction agents for lupus nephritis;7 more
benecial than cyclophosphamide in
AfricanAmerican and Hispanic populations;8
more benecial than azathioprine as
maintenance treatment in ALMS
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

typically lasts between 6 and 12 months. This eect 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 shortlived 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 o-label for
diseases including antineutrophil cytoplasmic antibodyassociated vasculitis, cryoglobulinaemia, dermatomyositis,
and Sjgrens syndrome. Many descriptions also exist of
the use of rituximab in patients with systemic lupus
erythematosus who have refractory disease.1319
Up to now, two large double-blind trials20,21 have
assessed the ecacy 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
810

Assessment Group (BILAG) index at week 24 and to

avoid moderate or severe are up to week 52. No overall
dierence was recorded in primary and secondary
endpoints, but benecial eects were noted in African
American and Hispanic patients.20 Additionally, ndings
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 anticardiolipin antibody and increased complement component
C3.22 Thus, although clear evidence existed of biological
benet of rituximab in patients with systemic lupus
erythematosus, this benet had not translated into
clinical advantage.22
The LUNAR trial,21 a randomised, double-blind, placebocontrolled 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 o-label ecacy of rituximab in the
treatment of active systemic lupus erythematosus are
available.2327 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 (14770) and a decrease of 59% in the
mean Systemic Lupus Erythematosus Disease Activity
Index (SLEDAI) score (14854). Specically, in the
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Rontalizumab
Sifalimumab

Interferon

Immune stimulation
Rituximab
Ocrelizumab
Veltuzumab
Ofatumumab

Belimumab
Atacicept
pDC
Iniximab
Anti-interleukin 10

Peptide

Immune
complexes
containing
nucleic acids

Ruplizumab
Toralizumab

Interleukin 10
Apoptotic
material

BLy S

CD20

TNF

APC

T cell

B cell

Interleukin-6
receptor
Abatacept

Tocilizumab

Antibodies

CD22
Epratuzumab

Abetimus

Figure: Targeted biological agents available and in present or previous clinical trials of systemic lupus erythematosus
pDC=plasmacytoid dendritic cell. BLys=B-lymphocyte stimulator. TNF=tumour necrosis factor . APC=antigen-presenting cell.

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-eects 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
120 points compared with 132 for the patients given
conventional treatment (non-signicant). However, the
mean cumulative prednisolone doses at 6 months were
12873 mg for the patients with B-cell depletion lupus
versus 28346 mg in the control group.30 Although
rituximab is generally well tolerated and has an acceptable
safety prole, 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, denition of
response, and use of concomitant immunosuppressives
(especially cyclophosphamide, which might be especially
eective 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 dierence 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 cyclophosphamide. Guidelines from both the American College of
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Rheumatology (ACR)32 and European League against

Rheumatism (EULAR)33 support the use of rituximab in
the treatment of refractory lupus nephritis. Furthermore,
ndings from a recent study by Condon and coworkers34
showed that B-cell depletion is of benet 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 rheumatic diseases is benecial. The RAVE trial,35 a doubleblind, randomised trial in patients with antineutrophil
cytoplasmic antibody-associated vasculitis, compared
remission induction in 197 patients given oral cyclophosphamide 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
o-label successes with rituximab in patients with
refractory myositis have been reported, a large doubleblind, 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 ecacy 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 08 week phase. No signicant
dierence 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
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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-specic response) were suggested by the
investigators as potential reasons for the absence of an
apparent benet for rituximab; further trials are awaited.
Some evidence suggests that rituximab is eective for
the treatment of some aspects of Sjgrens syndrome.
Dass and colleagues37 reported the results of the rst
randomised controlled trial of rituximab in 2008, nding
marked improvements in fatigue and quality of life in
patients given the drug. More recently, Meijer and
colleagues38 reported ecacy of rituximab in comparison
with placebo in 30 patients with primary Sjgrens
syndrome. Stimulated salivary ow, fatigue, and laboratory parameters (rheumatoid factor and B-cell concentrations) were substantially improved. Findings from
observational studies including data from the AutoImmune and Rituximab registry support a benet on
disease activity, including peripheral neuropathy.39
The detection of a human antichimeric antibody
response, which might have a negative eect on therapeutic ecacy, in patients given rituximab has led to
the development of fully humanised monoclonal antibodies that target CD20. These antibodies have less
complement-dependent cytotoxicity and increased
antibody-dependent cellular cytotoxicity. Although
several such agents are availableeg, ocrelizumab,
ofatumumab, and veltuzumablarge phase 3 studies in
the specic 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 cyclophophamide, prednisolone, and azathioprine or mycophenolate, was terminated early because of concerns
about high rates of serious or opportunistic infections.
Ofatumumab was eective in the treatment of patients
with rheumatoid arthritis who inadequately responded
to methotrexate; the drug resulted in signicantly
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 receptorseg,
CD22 and Fc receptor IIB. CD22 is a B lymphocytespecic transmembrane sialoglycoprotein and links
-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 signalling by reducing calcium eux in B cells. Epratuzumab, 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
812

and activation of B cells. Findings from an initial openlabel 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 nonrenal systemic lupus erythematosus is in progress
(NCT01262365).

Inhibition of B-cell survival

To support proliferation, activation, and maturation, B cells rely on several dierent 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 dierent regions and included patients
with skin or joint disease. Many patients were taking
glucocorticoids (6771% of patients took prednisone
>75 mg in BLISS-52 and 4448% in BLISS-76) and some
also took other immunosuppressants. A steroid-sparing
eect 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 eect of atacicept is also mediated
through modulation of B-cell function. Atacicept is a socalled decoy receptor consisting of TACI-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 dierentiation (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 conjunction 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 ecacy of atacicept was
not assessed.49 Atacicept could be an encouraging therapeutic agent in the treatment of systemic lupus erythematosus, 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 specic to anti-doublestranded DNA. Despite the serological eect on antidouble-stranded DNA antibodies, ndings from two
large trials50,51 in patients with lupus nephritis failed to
show a signicant therapeutic eect.
An alternative approach to B-cell treatment is to target
plasma cells. Findings from murine studies have shown
that the proteasome inhibitor bortezomib is eective 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 eect. 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 signicant reduction
in disease activity and antibody concentrations with
increased complement concentrations was reported;
however, three of 13 patients had reversible polyneuropathy.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-specic
antibody MDX 1342 is in early phase trials in patients with
rheumatoid arthritis;54 no specic trial in patients with
other autoimmune rheumatic diseases has been done.
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Inhibition of T-cell function

Although pathogenic autoantibodies in systemic lupus
erythematosus are derived from B cells, evidence suggests
that T-cell dysfunction exists in systemic lupus erythematosus. T-cell inltration 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 rst 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
CD80/86 on antigen-presenting cells are two costimulatory
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 modied
Fc portion of human immunoglobulin.57 CTLA-4 competes
with CD28 for binding to CD80/86; thus, abatacept downregulates 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 ares after
steroid tapering. The study did not meet the primary
endpoint, but treatment dierences were recorded in
individuals with arthritis. Additional post-hoc analyses
showed a reduced rate of physician-assessed ares and
improved functional outcomes (Short Form 36 [SF-36]
health survey, sleep, and fatigue) in patients given
abatacept. 194% of the patients were negative for
antinuclear antibody and double-stranded DNA antibodies, 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
ecacy of the combination approach with abatacept and
cyclophosphamide in animal models of lupus nephritis,
whether this eect 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 375 months after
treatment initiation. Studies of abatacept in patients with
myositis are also scarce. Potential ecacy is suggested by a
positive eect 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
CD40Lruplizumab and toralizumabhave shown
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moderate clinical ecacy 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 rst
complementarity-determining region of a supposedly
pathogenic human monoclonal anti-DNA antibody. Edratide was eective 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 (TNF)
and transforming growth factor , and thereby reduce
T-cell apoptosis.64,65 Although ndings from a doubleblind controlled trial66 of edratide in patients with systemic
lupus erythematosus showed no signicant 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-helper2-driven disease with increases in the serum concentration 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 aect both pro-inammatory
and anti-inammatory pathways, dependent on several
dierent factors including the receptor with which they
interact. Therefore, the ultimate biological eect of their
inhibition can be dicult 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; ndings from the rst
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
814

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 inammatory
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 preliminary 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 of TNF
The potential role of TNF in the pathogenesis of
systemic lupus erythematosus is controversial. Although
serum concentrations are increased and TNF has been
reported histologically in biopsy samples of individuals
with lupus nephritis,75,76 TNF inhibitors (used in
rheumatoid arthritis) can induce antinuclear antibody
and, rarely, drug-induced lupus.77 Findings from several
small studies78,79 have shown ecacy of TNF inhibitors,
in particular iniximab, in patients with systemic lupus
erythematosus. In one study,78 six patients with lupus
nephritis and arthritis or both were given iniximab and
azathioprine or methotrexate with a resultant marked
improvement in proteinuria and arthritis. A less meaningful 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
TNF inhibition has also been used in the treatment of
other autoimmune rheumatic diseases. In the inammatory myopathies, the results have been variable. Data
from a 2011 double-blind trial80 suggested some benet
in the facilitation of glucocorticoid tapering. In this
study, 16 patients with dermatomyositis were randomly
assigned to receive etanercept (11 patients) or placebo
(ve patients) and followed a standardised steroid
tapering as tolerated over 24 weeks. The average daily
prednisone dose at the time of completion was 12 mg
per day in the etanercept group and 292 mg per day in
the placebo group. Moreover, all patients in the placebo
group were so-called treatment failures by contrast with
ve of the 11 in the group given etanercept who were
successfully weaned o glucocorticoids. The use of
etanercept in vasculitis (eg, polyangiitis with granulomatosis) remains contentious; a particular concern is
safety.81 Iniximab might be a more relevant alternative.
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Series

Type 1 interferon
In systemic lupus erythematosus, serum concentrations
of interferon 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 .84 Sifalimumab and rontalizumab
are monoclonal antibodies that target interferon 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 eect on normalisation of the aberrant interferon
signature, in addition to changing interferon expression
in skin biopsy samples. In view of encouraging ndings from phase 1 mechanistic studies, a multicentre
phase 2 trial86 of rontalizumab in patients with moderate
to severe active systemic lupus erythematosus is underway. Other targets under investigation in systemic lupus
erythematosus include interferon (NCT00818948) and
an immunisation strategy with interferon- kinoid with
the aim of inducing a polyclonal anti-interferon antibody
response (NCT01058343).

Complement inhibition
Deciency 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 complement cascade have been proposed in systemic lupus
erythematosus. One example is eculizumab, a monoclonal anti-C5 antibody, approved for the treatment of
paroxysmal nocturnal haemoglobinuria. Whether such
agents will be of benet 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 haemopoietic stem cells resulting in so-called immune resetting.
Results from the European Group for Blood and Marrow
Transplantation and EULAR (200108) showed the 5 year
outcomes of 28 patients with systemic lupus erythematosus 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
www.thelancet.com Vol 382 August 31, 2013

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
benet for pulmonary disease.88,89 More recently, data
from the ASTIS (ISRCTN54371254) phase 3 study have
supported these ndings and conrmed 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
inammatory myopathies such as dermatomyositis;
however, further work is needed to clarify the role of stemcell 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 erythematosus, Sjgrens 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 cytoplasmic 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 drugs success in
double-blind controlled trials in treating rheumatoid
arthritis (the National Institute for Health and Clinical
Excellence [NICE] approved rituximab for use in rheumatoid arthritis in 2007) and antineutrophil cytoplasmic
antibody-positive vasculitis, together with data supporting
its ecacy in systemic lupus erythematosus, which were
published in more than 20 dierent open-label studies
and registry reports, rituximab is most probably eective
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 concomitant 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 denitions of response
establish whether a study of lupus nephritis is judged
815

Series

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 30 000 per
quality-adjusted life-year. In the USA, FDA-approved
Benlysta is expensive (well in excess of 30 000), 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 40005000 in the UK)
comes o licence and biosimilar drugs become available.

10

11
12

13

14
15

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 aetiopathogenesis 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.
Conicts of interest
We declare that we have no conicts 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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