REVIEWS

The problem of choice: current biologic

agents and future prospects in RA
Ernest H. Choy, Arthur F. Kavanaugh and Simon A. Jones
Abstract | The introduction of biologic agents to clinical practice has had a major bearing on the treatment of
patients with chronic inflammatory diseases such as rheumatoid arthritis. These drugs have the potential
to improve the outcome of disease and the quality of life for patients. However, clinical criteria alone are
inadequate for determining which therapy is most appropriate for an individual patient. Furthermore, why
a particular drug is effective in a particular patient, or indeed in any patient, but is ineffective for other
individuals, is often unknown. In this Review, we provide an overview of biologic therapies currently available
for patients with rheumatoid arthritis, and discuss why certain immunological regulators represent potential
targets for intervention. Current agents can be clustered into three major types: cytokine blockers, lymphocytetargeting agents, and small-molecule inhibitors of signal transduction pathways. We differentiate among the
modes of action of each of these types of therapy and consider the challenges associated with their use in
clinical practice.
Choy, E.H. etal. Nat. Rev. Rheumatol. advance online publication 19 February 2013; doi:10.1038/nrrheum.2013.8

Introduction
Targeting breach of tolerance in RA
An effective immune response ensures competent host
defence. When distorted, however, it can aid the pro
gression of chronic diseases including several auto
immune rheumatic conditions. The natural course of
inflammationincluding resolutionis lost, creating an
imbalance in proinflammatory and anti-inflammatory
cytokine responses, which promotes autoimmunity,
chronic inflammation, and associated tissue injury.
In rheumatoid arthritis (RA), this breach of tolerance
culminates in severe joint damage, which, if uncon
trolled, leads to irreversible destruction of the synovial
membrane, cartilage, and bone.
Early diagnosis is an important factor in the treatment
of patients with RA, and the sooner treatment begins, the
more effective the therapeutic response is likely to be.
Current therapies for RA are broadly aimed at restrict
ing inflammation. Traditionally, these approaches were
based on agents that reduce the symptoms of disease.
However, advances in the past 20years have led to a new
generation of therapies that block the actions of specific
Competing interests
E.H. Choy declares an association with the following
companies: Abbott, Allergan, AstraZeneca, Boehringer
Ingelheim, Chelsea Therapeutics, Chugai Pharma, Eli Lilly,
GlaxoSmithKline, Jazz Pharmaceuticals, Merrimack
Pharmaceutical, Merck Sharp & Dohme, Pfizer, Pierre Fabre
Medicament, Roche, Schering Plough, Synovate, UCB, and
Wyeth. A.F. Kavanagh declares an association with the following
companies: Abbott, Amgen, Bristol-Myers Squibb, Janssen,
Pfizer, Roche, and UCB. S.A. Jones declares an association with
the following companies: Chugai Pharma Europe, F-Hoffmann-La
Roche, Genentech and NovImmune SA. See the article online for
full details of the relationships.

cytokines or immune regulators. These therapies, termed

biologic agents, are unique in their designs and modes
of action and have been developed in part because of a
better understanding of how inflammation contributes
to disease initiation and perpetuation.

Biologic agents
Biologic agents are now recognized as major therapies in
RA, but are prescribed only when conventional therapy
has failed.1,2 This novel class of DMARD includes TNFblocking agentsthe neutralizing anti-TNF monoclonal
antibodies infliximab, adalimumab, and golimumab;
the polyethylene glycollinked mAb fragment certoli
zumab pegol; and the soluble TNF receptor2IgG-Fc
fusion protein etanercept. Other FDA-approved biologic
DMARDs are the interleukin (IL)6 receptor (IL-6R)blocking monoclonal antibody tocilizumab, the antiCD20 Bcell-depleting monoclonal antibody rituximab,
the Tcell-activation inhibitor abatacept, which is a
fusion of recombinant cytotoxic T lymphocyte antigen4
(CTLA4) and IgG1, and the IL1 receptor antagonist
anakinra. Furthermore, second-generation agents are
now emerging in early-stage clinical development,
including anti-IL17 monoclonal antibodies secuki
numab and ixekizumab, the IL17 receptor-blocking
monoclonal antibody brodalumab, and alternative IL6
blocking strategies. In addition, selective small-molecule
inhibitors of intracellular signal transduction events,
such as the Janus kinase (JAK) pathway (tofacitinib and
ruxolitinib) and spleen tyrosine kinase (fostamatinib),
are also being developed. Indeed, tofacitinib has been
approved in the USA for the treatment of RA since
late2012.

NATURE REVIEWS | RHEUMATOLOGY

Institute of Infection
and Immunity, Cardiff
University School of
Medicine, Cardiff
University, Tenovus
Building, Heath Park,
Cardiff CF14 4XN, UK
(E.H. Choy, S.A. Jones).
Division of
Rheumatology, Allergy
and Immunology,
Department of
Medicine, University of
California San Diego,
La Jolla, San Diego, CA
920930943, USA
(A.F.Kavanaugh).
Correspondence to:
E.H. Choy
choyeh@cardiff.ac.uk

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Key points
Current interventions in rheumatoid arthritis (RA) can be classified into three
major types: cytokine blockers, lymphocyte-targeting agents, and small-molecule
inhibitors of signal transduction pathways
In the absence of reliable biomarkers, mode of action could be a useful tool in
guiding choice of biologic therapy
Adverse effects of biologic agents are either class specific or compound
specific; class-specific effects reflect the biological role of the target
Early-phase clinical trials in RA in the past few years have mostly focused on
cytokine blockers and small-molecule inhibitors of signal transduction pathways

Variable response and safety considerations

Although biologic agents show considerable efficacy
in RA, not all patients respond to an individual drug
or a class of drug.3 Efforts in biomarker discovery and
histopathology are currently aimed at improving patient
stratification at the earliest possible stage of disease.
Resultant advances are already providing information on
the course of disease progression and are geared toward
identifying the most appropriate therapy for a particu
lar patient group. Although these approaches relate pri
marily to the pathology observed within the inflamed
joint, the impact of cytokine-network modulation on
systemic homeostatic processessuch as mood, fatigue,
depression, infection and cardiovascular riskand
haematologic processes, is also an important aspect of
biologic intervention (Figure1). In other words, biologic
therapies must, above all, be safe. Thus, pharmaceutical
companies invest heavily in differentiating modes of
action of particular drugs in efforts to define efficacy as
well as safety profiles. At present, no effective treatment
for RA exists that does not occasionally cause unwanted
effects. Minor adverse events are not uncommon,
whereas serious events are, thankfully, rare. However,
with the increasing number of biologic agents enter
ing the clinical arena, it is often difficult for practising
rheumatologists to keep pace with drug developments
as they emerge.
In this Review, we discuss current interventions in RA,
which can be clustered into three major types: cytokine
blockers, lymphocyte-targeting agents, and small-
molecule inhibitors of signal transduction pathways. We
outline existing clinical guidelines for the use of biologic
agents, and discuss challenges in comparative assess
ments of their efficacy. We provide an overview of how
understanding the molecular mechanisms that underlie
the efficacyand lack thereofof these therapeutics is
increasing with clinical experience and informing clini
cal development. Why certain immunological regulators
are potential targets for intervention, and data relating to
their application in RA, are also discussed.

Biologic agents in clinical practice

From targeted therapy to targeted strategy
Increasing momentum drives current efforts to move
from prescribing therapies that simply reduce inflam
mation, to instead implement more targeted regimens
that are geared toward the remission of disease and the
prevention of irreversible joint damage.1,2 The clinical

introduction of biologic drugs such as TNF blockers

has helped to shape this approach. Although anti-TNF
therapies have had a major impact on the outcome of
RA, a considerable proportion (approximately 4044%)
of patients show negligible improvement.3 Indeed, clini
cal trials of individual biologic agents using standard
American College of Rheumatology (ACR) response cri
teria show that the proportions of patients attaining 20%,
50% and 70% improvement (that is, ACR20, ACR50, and
ACR70 response rates) are comparable between drugs.
All approved biologic agents can, of course, attenuate the
signs and symptoms of disease. These effects extend to
some reduction in radiographic joint damage in patients
with RA who were previously naive to biologic agents.
The key, however, is to identify the most appropriate
therapy for an individual patient sufficiently early in the
course of the disease.
In randomized, controlled trials (RCTs), patients for
whom at least one TNF inhibitor has failed can display
marked improvements when switched either to another
TNF inhibitor 4 or to agents with a distinct mechanism of
action (rituximab, abatacept, and tocilizumab).57 Never
theless, ACR response rates in RCTs of these non-TNF
biologic agents are similar to those in RCTs of first-line
biologic therapiesa considerable proportion of patients
continue to have an inadequate response. Thus, two
major challenges exist: to predict the course of inflamma
tory arthritis in patients whose disease is undifferentiated
at presentation; and to define the major contributing
pathways that drive chronic disease progression in indivi
dual patients. Although the identification of biomarkers
that stratify patients according to their disease might
help to address these points, equally important is the
consideration of how individual drugs can be differen
tiated according to their modes of action. Collectively,
this knowledge will lead to a better appreciation of who
might benefit from a particular therapy.

Clinical guidelines for biologic agents in RA

With the advent of biologic agents and the use of com
bination DMARD therapies, disease activity in patients
with RA can be more effectively suppressed than was
possible in the twentieth century. Sustained suppression
of disease activity is, however, important in preventing
joint destruction.8 Therefore, the ACR and the European
League Against Rheumatism (EULAR) 2 now recom
mend treat-to-target approaches using goals of remission
or low disease activity as the standard of care.
Both the ACR and EULAR recommend the initia
tion of DMARD treatment as soon as RA is diagnosed.
Methotrexate monotherapy is the recommended initial
therapy.1,2 For patients with moderate-to-high disease
activity or poor prognostic factors, glucocorticoids or
other DMARDs may be added to the initial regimen. If
disease activity is not controlled after 36months, TNF
inhibitors in combination with methotrexate are recom
mended, unless contraindicated. For patients with early
RA (disease duration <6months) displaying high disease
activity and poor prognosis, the ACR recommends use
of a TNF inhibitor (as monotherapy or in combination

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REVIEWS
Macrophages
Bone:
osteoporosis

Inflammation
Systemic
circulation

IL-1
IL-6

Adhesion

T cells
Bone marrow:
anaemia,
thrombocytosis

IL-6
IL-6
TNF
IL-1

TNF

TNF

Cathepsins
MMPs

Cartilage
Osteoclasts

B cells

Matrix
degradation

Fever,
fatigue,
depression

Synovial inflammation

Plasma cells
Dendritic cells
Acute-phase
response,
systemic
inflammation

Blood vessels
Bone

Figure 1 | Pathogenesis of RA: synovial and systemic inflammation. Inflammation in RA is caused by activation of Tcells,
Bcells and macrophages, which releases cytokines such as IL-1, IL-6 and TNF. These cytokines cause local joint damage
through increased production of metalloproteinases and activation of osteoclasts. IL-1, IL-6 and TNF also leak out to the
blood stream resulting in systemic inflammation: anaemia, thrombocytosis, fatigue, osteoporosis and the acute-phase
response. Abbreviations: IL, interleukin; RA, rheumatoid arthritis.

with methotrexate) as an immediate, first-line course

of therapy.1,2 EULAR, but not the ACR, also endorses
combining non-methotrexate DMARDs with a TNF
inhibitor. If, after 3months of anti-TNF therapy, the
patient continues to experience no substantive improve
ment in disease activity or develops an adverse response
to treatment, both organizations recommend that he or
she should be switched to an alternative TNF inhibitor
or a non-TNF biologic agent. Similarly, patients with
moderate-to-high disease activity after 6months of
therapy with a non-TNF biologic drug should be switched
to another non-TNF biologic therapy or a TNF inhibitor.
In some patients, such as those with a history of malig
nancies, although TNF inhibitors are not absolutely
contraindicated, some clinicians and patients might prefer
to use a non-TNF inhibitor as the first biologic therapy.1,2
TNF inhibitors in combination with methotrexate
display a synergistic mode of action. This combined
therapeutic strategy should be used in routine clinical
practice, but a monotherapy regimen may be considered
if a patient cannot tolerate methotrexate or has a contra
indication to it.1,2 Data on combining non-methotrexate
DMARDs with TNF inhibitors have shown superiority of
adding a TNF inhibitor over continuing without one,9 but
no study has yet shown such combinations to be superior
to TNF inhibitor monotherapy.

Outcomes and biomarkers

Systemic inflammationa hallmark of RAis associ
ated with fatigue, anaemia, osteoporosis, and increased

risk of cardiovascular disease (Figure1). In addition to

reducing articular inflammation in patients with RA,
biologic agents can reduce systemic inflammation and
improve health-related quality of life by effecting control
of the acute-phase response and fatigue. All these out
comes can be measured, andto some extentpredicted
using clinical parameters such as swollen-joint counts
and patient questionnaires. In the absence of reliable
biomarkers, however, clinical criteria alone are often
inadequate for identifying the probable course of disease
and response to specific agents in an individual patient,
especially given the imperative to act as early as possible
in the disease course.
The presence of rheumatoid factor (RF) and/or anti-
citrullinated protein autoantibodies (ACPA), elevated
levels of Creactive protein, and genetic markers such
as alleles of HLA and PTPN22 are associated with the
development of RA;10 nevertheless, they provide no infor
mation on the specific inflammatory pathways that drive
disease in an individual patient. Identification of novel
biomarkers that reflect disease activity during early arthri
tis would provide valuable insight into patients inflam
matory status, and help to stratify their disease according
to the underlying pathology and most likely subsequent
course. Thus, biomarkers have the potential to aid indivi
dual treatment decisions, and to predict response to
therapy. Reliable biomarkers for predicting response
to biologic agents have not yet been established; how
ever, a systematic review of four RCTs (2,177 patients in
total: rituximab, n=1,416; placebo, n=761) suggests that

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REVIEWS
patients who are seronegative for RF and ACPA are less
likely than seropositive patients to respond to rituximab.11
The local pathology associated with autoimmunity
is diverse, and the natural progression of disease is
often varied and clinically difficult to track. This inter-
individual heterogeneity has led to the introduction of
innovative approaches, albeit common practice in onco
logy, that have become extremely informative in the
diagnosis of RA.1214 Evaluation of patients with early
inflammatory arthritis through ultrasound-directed
biopsy sampling of tender joints has allowed the disease
to be stratified according to histopathology. The dis
ease process can thus be classified according to whether
synovial tissues are rich in fibroblasts, myeloid tissue or
lymphocytes, which in some individuals form ectopic
lymphoid aggregates that resemble organized secon
dary lymphoid organs. The characterization of histo
pathology in this way suggests that the natural course of
arthritis progression is distinct for these patient groups.
Although the mechanisms that drive these patholo
gies remain to be fully established, this individualized
approach has the potential to help tailor the most appro
priate therapy for a given histopathology and aid future
biomarker discovery. Genome-wide association study
analyses of data from various patient cohorts have iden
tified specific genetic associations that statistically predict
the risk of acquiring certain autoimmune conditions.15,16
Many of these risk alleles are located within, or close to,
genes of known immune function; for example, cyto
kines, cytokine receptors or proteins involved in signal
transduction events activated by cytokines.5,6 In 2012,
meta-analysis of a genome-wide association study in a
European patient cohort identified seven new RA risk
loci together with several validated risk alleles for auto
immunity.17,18 Importantly, many of the gene products are
linked to cytokine signalling (IL6ST [encoding IL6R,
also known as gp130], SPRED2, CCR6), whilst a further
suggestive risk allele was noted in IL6R.18 Although these
findings highlight the power of such screening methods,
future studies now need to take a more integrated view to
validate the functional impact of these risk loci. Ideally,
this investigation should not only include their potential
impact on chronic disease progression, but also secon
dary outcomes associated with biologic interventions
such as plasma lipid profiles, infection incidence, mood,
fatigue and malignancy.

Adverse events
Biologic therapies act by suppressing the immune res
ponse; consequently, all such agents are associated
with an increased risk of infection. Each class of agent,
howe ver, has class-specific and compound-specific
risks. Class-specific adverse effects are those that can
be expected from the biology of the target, such as a
decrease in immunoglobulin associated with Bcell
depletion, intracellular opportunistic infection associ
ated with TNF inhibitors, and anaemia associated with
JAK2 inhibition. Compound-specific adverse effects
are those specific to one compound within a class,
such as infusion reactions and infliximab. In general,

c ompound-specific adverse effects are less common with

biologic agents than with oral synthetic compounds, as
the larger, biologic agents are not metabolized by the
body. The safety of biologic agents in RA was thoroughly
reviewed in this journal in 2011.19 To date, it seems that
all biologic agents are associated with a slightly increased
risk of serious infection (approximately 20%), although
certain infections, such as reactivation of tuberculo
sis, are more common with TNF inhibitors than with
non-TNF biologic agents.1,2

Rational development of biologic agents

In the complex signalling networks of the immune
system, biologic agents remain fairly blunt tools with
which to tackle RA. Nevertheless, as experience of them
increases, they are providing data not only on how to
refine their use, but also on new targets that might enable
more specific disruption of disease processes.

Actions of anticytokine therapies

Inflammatory cytokines contribute to the pathogenesis
of RA, orchestrating symptoms of joint pathology.20,21
In addition, certain cytokines act like hormones, exert
ing systemic control of accelerated vascular disease, lipid
metabolism, insulin resistance, fatigue, mood, and depres
sion.22,23 Indeed, whereas cytokines such as IL12, IL15,
IL17, IL18, and IL23p19 modulate local inflamma
tory activities,21 others such as IL1, TNF, and IL6 are
capable of regulating homeostatic processes in addition
to classical inflammatory responses.17 The recognition
of these cytokines as primary targets for therapy led to
the development of anakinra (targeting IL1),24 the TNF
blockers (beginning with etanercept and infliximab),20
and the IL6R inhibitory antibody tocilizumab.25
Anakinra has been of limited application in the
management of RA, but has considerable efficacy in
conditions in which activation of the inflammasome is a
central feature of the pathology (such as gout and various
inflammatory syndromes).26 By contrast, biologic agents
that target TNF or IL6 have had a major impact on the
management of RA.27,28 The clinical successes of antiTNF agents have defined a high threshold against which
new therapies with other mechanisms of action are now
judged. It was hypothesized that some targets, such as
IL6, might be redundant in patients for whom TNF
inhibitor therapy failed, because TNF was considered
to act upstream of IL6 in an inflammatory cascade.29
However, the identification of an alternatively regulated
mode of IL6 signallingtermed IL6 trans-signalling
that acts through its soluble receptor has substan
tially altered this traditional view of cytokine hierarchy
(Figure2).17 Thus, TNF and IL6 might elicit unique
activities in RA, as well as in other autoimmune condi
tions, and a switch from TNF to IL6 inhibition might be
appropriate. For example, good responses to tocilizumab
were observed in a trial in 56 patients with systemic juve
nile idiopathic arthritis refractory to previous treatment,
including TNF inhibition.30 Indeed, whereas various
invitro and invivo studies have linked both TNF and
IL6 to the control of central disease processes, including

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REVIEWS
extracellular matrix degradation, osteoclastogenesis and
bone erosion, leukocyte activation, and the control of
hepatic acute-phase responses, the intracellular signal
ling mechanisms activated by the cytokines are dis
tinct.31 TNF primarily acts through the nuclear factorB
(NFB) and extracellular signal-regulated kinase (ERK)
signalling pathways (Figure3).31 By contrast, IL6 signals
through the transcription factors signal transducer and
activator of transcription (STAT)3 and, to a lesser extent,
STAT1 (Figure3).32 Elevated STAT3 activity has been
reported in the synovial tissue of patients with RA,33
and studies invitro and invivo have linked STAT3 to
chronic disease progression through the regulation of
synovial hyperplasia and proinflammatory mediators.34
Activation of these pathways is not, however, unique
to IL6 and TNFvarious other cytokines and pattern
recognition molecules signal through NFB (including
IL1, IL17 and Toll-like receptors)35 or STAT3 (for
example, IL10, IL21, IL23) (Figure3).36

Future of cytokine targeting agents

At present, tocilizumab is the only IL6 inhibitor available
for routine management of RA, but its success has led to
the development of a number of alternative drugs that
target different structural domains of IL6 or its recep
tor.37 Although most of these agents (such as sirukumab,38
olokizumab,39 BMS94542940 and sarilumab41) inhibit
both classical IL6R signalling and IL6 trans-signalling,
several biologic agents in preclinical development selec
tively target IL6 trans-signalling.33,42,43 Clinical trials of
these compoundswhich include soluble gp130are
being planned and will further elucidate and refine the
best therapeutic strategy to inhibit IL6.
Given the success of anti-TNF and anti-IL-6R therapy
in a proportion of patients with RA, it is unsurpris
ing that several newer biologic agents target cytokines
that signal through similar signal transduction
mechanismsIL17 (which is targeted by secukinumab
and ixekizumab,44 and its receptor by brodalumab 45),
and the p40 subunit common to both IL12 and IL23
(targeted by ustekinumab).46 These factors are centrally
involved in the programming of early innate and adap
tive immune responses,47 including, the differentiation
and commitment of naive CD4 + Tcells into effector
Tcell populations. Tcell subsets that secrete IFN
(type 1 Thelper [TH1] cells), IL4, IL5 and IL13 (type 2
Thelper [TH2] cells), or IL17A, IL17F and IL22 (type
17 Thelper [TH17] cells) have received particular atten
tion.48 The phenotypes of these cell populations are not,
however, fixed; increasing evidence in mice indicates
their plasticity,4951 and in people, effector CD4+ Tcells
that secrete IFN in combination with either IL4
(known as type1+2 Thelper [TH1+2] cells) or IL17.52,53
Thus, it seems that CD4+ Tcells are a dynamic popu
lation that adapts to the cytokine environment to shape
the immune response. Biologic agents that target hetero
dimeric cytokines such as IL12 and IL23 could be of par
ticular therapeutic interest. IL12 is involved in TH1-cell
development and IL23 in the maintenance of TH17cells.47
In the antigen-induced arthritis animal model of RA,

Early synovial histopathology

Fibroblast

Myeloid

Lymphoid

IL-11, IL-10, IL-12,

IL-27, IL-32, OSM,
GM-CSF, M-CSF, IFN-,
PDGF, RANKL, TGF-

OSM, IL-11, IL-17,

IL-18, IFN-, IL-19,
IL-20, IL-22, TGF-

Macrophage,
dendritic cell

Synoviocyte

Cytokine
interplay

Bone and
cartilage

T cell,
B cell

IL-2, IL-4, IL-7, IL-9,

IL-10, IL-12, IL-13,
IL-15, IL-21, IL-23,
IL-27, IFN-,TGF-

Figure 2 | Cytokine network in RA: overlap and interplay between cytokines drives
synovial inflammation. Fibroblast, myeloid and lymphoid patterns of
immunohistology can be seen in patients with RA. These features reflect complex
interactions between Tcells and Bcells, macrophages, dendritic cell and
synoviocytes, such that different cytokines and immune cells are more or less
important to disease pathology in the individual patient. Abbreviations: GMCSF,
granulocyte macrophage colony-stimulating factor; MCSF, macrophage colonystimulating factor; OSM, oncostatin M; PDGF, platelet-derived growth factor; RA,
rheumatoid arthritis; RANKL, receptor activator of nuclear factor B ligand; TGF,
transforming growth factor .

inflammatory arthritis was attenuated in IL17 recep

torAgene knockout mice and IL23p19-deficient mice, in
comparison with wild-type mice.54 Agents such as briaki
numab and ustekinumab, which target the common p40
subunit of IL12 and IL 23, may therefore have a broader
impact on Tcell effector function than monoclonal anti
bodies targeting a single cytokine. Consequently, as agents
such as ustekinumab enter the clinic, it will be important
to compare their efficacies and biologic effects with those
of the currently available biologic therapies and newer
modalities including JAK inhibitors.

Lymphocyte-targeting agents
Activated Tcells and Bcells are pivotal to the development
of autoimmunity and drive disease progression through
mechanisms including autoreactive antibody generation
and the expansion of memory cells into effector cell popu
lations with defined proinflammatory cytokine signatures.
Two cell-directed therapeutic strategies are currently in
clinical practice: rituximab and abatacept.
B-cell targeting agents
Bcells have several roles in autoimmunity, including
antigen presentation, secretion of inflammatory and
immunoregulatory mediators including cytokines,

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REVIEWS
Infliximab
Adalimumab
Anakinra
Golimumab
Ixekizumab
Secukinumab Certolizumab

Interleukin

TNF family

Olokizumab
Sirukumab
Situximab
Ustekinumab

TLR agonist

Interleukin

Bevacizumab

Interferon

Growth factor

Tocilizumab
Sarilumab
ALX-0061

Etanercept
Brodalumab
Extracellular

Intracellular

JAK

NFB

MAP kinase

JAK

STAT

Tofacitinib
Ruxolitinib
VX-509
R-348
INCB-28050
AC-430
CEP-33779

Classic cytokine-regulated responses

Proliferation, differentiation, gene expression, survival, death

Figure 3 | Cytokines and their signalling pathways: different cytokines use different
intracellular signalling pathways. Different cytokines utilize distinct cell-surface
molecules and signal transduction pathways to cause cellular responses. NFB is
important to the TNF family of cytokines whereas STAT is important to IL6. This
diagram illustrates the targets of different biologic treatments in RA.
Abbreviations: JAK, Janus-activated kinase; MAP, mitogen-activated protein; NFB,
nuclear factor B; RA, rheumatoid arthritis; STAT, signal transducer and activator of
transcription; TLR, Toll-like receptor.

production of autoantibodies (including RF and ACPA),

and modulation of lymphoid organization within
inflammatory sites. The most successful Bcell target
ing antibody therapy, rituximab, depletes Bcell num
bers through binding to CD20, a cell-surface molecule
expressed by all Bcells including preBcells and mature
Bcells. CD20 is not, however, expressed by antibodysecreting plasma cells. 55 The mechanism by which
rituximab depletes Bcell numbers is the subject of some
debate. Various models have been proposed, includ
ing complement-dependent cytotoxicity, induction of
apoptotic cell death, and antigen-dependent cellular
cytotoxicity.56 Which of these mechanisms is relevant to
the clinical efficacy of the drug in patients with RA has
not yet been defined. Of note, the therapeutic efficacy
of rituximab is not strictly dependent on the extent of
Bcell depletion; virtually all treated patients experience
profound depletion of circulating peripheral Bcells,
but only 60% of these patients respond clinically. 57,58.
However, the degree of Bcell depletion, as assessed by
highly sensitive flow cytometry, correlates with response
to the drug.59 Furthermore, re-emergence of circulating
Bcells is associated with recurrence of disease.59 As we
have mentioned, rituximab is more effective in patients
who are either RF or ACPA positive (or both). 11 The
onset of response to rituximab is not immediate and RF
and ACPA titres reduce gradually, suggesting that one of
the mechanisms of action might relate to indirect effects
on short-lived autoreactive plasma cells.60

Future of Bcell targeting

The success of rituximab has spawned the development
of several alternative antiCD20-depleting antibodies,
including ocrelizumab, 61 veltuzumab, 62 and ofatu
mumab,63 that are in phaseII and early phaseIII clinical
trials. Other targets for Bcell depletion include CD22,
which is targeted by epratuzumab (currently in develop
ment for systemic lupus erythematosus).64 Whether these
newer agents will have an advantage over rituximab
remains to be defined.
Several strategies aside from Bcell depletion inhibit
Bcell growth and development, such as targeting Bcell
activating factor (BAFF, also known as BLyS and as TNF
ligand superfamily, member 13b) and the related cytokine
APRIL (TNF ligand superfamily, member 13). TNF
receptor superfamily member 13B (also known as TACI)
is a cell surface receptor for BAFF and APRIL. Belimumab
(directed against soluble forms of BAFF) and ataci
cept (TACIFc fusion protein) have been examined in
phaseII clinical trials in RA.65,66 At present, neither agent
is moving forward in further clinical trials. Two phaseII
clinical trials of atacicept recruited over 500 patients with
RA in total and failed to demonstrate any significant effi
ciacy.67,68 Results of a phaseII trial of belimumab have not
been published.
T-cell targeting agents
T-cell activation requires both antigen recognition (signal
one) and a co-stimulatory event (signal two), triggering
cytokine production, clonal expansion, prevention of
anergy, and resistance to apoptosis.69 Whereas signal one
relies on the MHC-associated presentation of antigen to
the Tcell receptor, signal two requires engagement of costimulatory molecules, in particular Tcell specific surface
glycoprotein CD28 with Tlymphocyte activation antigens
CD80 and CD86 (also known as B71 and B72) expressed
by antigen-presenting cells.70 To counterbalance this acti
vation state, CTLA4 (which is structurally homologous to
CD28) acts as a suppressor of Tcell activation and is con
sidered a master regulator of peripheral Tcell tolerance
invivo.70 The mode of action of abatacept (CTLA4IgG1)
is designed to block the interaction of CD28 with CD80 or
CD86 and to thus antagonize Tcell coactivation.71 Binding
of abatacept to antigen-presenting cells might also contrib
ute to its inhibitory action.72 Abatacept is the only licensed
Tcelldirected therapy for inflammatory arthritis.
Although extensive data from phaseIII and phaseIV trials
on the efficacy of abatacept in patients with RA who were
either biologic agent-naive or for whom anti-TNF therapy
had failed are available and have been confirmed in sys
tematic reviews,73 few data on its invivo biologic effects
exist; therefore, its precise mode of action in RA remains
unclear. An exvivo study using samples from patients
with RA and healthy controls has shown that abatacept
inhibits Tcell interactions with synovial fibroblasts, which
mediates inactivation of telomeric repeat-binding factor
2interacting protein1 (also known as RAP1 homolog)
and subsequent production of reactive oxygen species.74
Synovial biopsy samples taken before and 16weeks after
treatment with abatacept from 15 patients with RA for

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REVIEWS
whom TNF-blocker therapy had failed showed signifi
cant reduction in IFN expression with abatacept treat
ment (P<0.05), which correlated with improvements in
joint pathology as visualized using MRI, suggesting that
the therapy reduced Tcell activation.71 Changes in the
number of circulating subsets of CD4+ and CD8+ Tcells
after abatacept therapy have also been reported in a small
case series.75 In animal models of autoimmune diseases,
co-stimulatory blockade induces Tcell anergy and toler
ance, suggesting that treatment-free remission might be
feasible.76 To date, this outcome has not been studied or
reported in clinical studies of abatacept.

transamines. These adverse effects have also been asso

ciated with tofacitinib and baricitinib. Whereas IL6 inhi
bition by tocilizumab is associated with improvement of
anaemia in chronic diseases such as RA, tofacitinib and
baricitinib are, by contrast, associated with decreases in
haemoglobin, probably mediated through inhibition of
JAK2, which regulates the response to erythropoietin.86
Head-to-head RCTs comparing tofacitinib with other
current biologic agents will be helpful to compare their
clinical effectiveness. Ideally, biomarkers will be devel
oped to help to identify patient subpopulations that will
derive most benefit from particular treatments.

Future of Tcell targeting

Alternative approaches to inhibiting aberrant Tcell acti
vation in RA, such as anti-CD4 antibodies 4162W9477 and
keliximab,78 which were developed through analogy to the
mode of action of the fungus-derived, cyclic immuno
suppressant peptide cyclosporine, and anti-CD52 anti
body (alemtuzumab) have been less impressive than
abatacept. A study with an aglycosyl, nonmitogenic antiCD3 monoclonal antibody, which can modulate antigenspecific Tcell responses, in RA has been proposed.79
Alongside these developmental approaches, the avail
ability of subcutaneous abatacept might expand usage
of this agent in clinical practice, providing opportunities
to examine its biologic effects in inflammatory arthritis
indetail.

Combining biologic therapies

Small-molecule inhibitors
A novel class of DMARD is emerging as an oral treat
ment for inflammatory disorders such as RA, psoriasis,
inflammatory bowel disease, and the prevention of organ
transplant rejection. 80 Among these small-molecule
developmental drug programs, the most advanced is that
of tofacitiniba selective Janus kinase (JAK) inhibitor
that inhibits the JAK-STAT signalling pathway. JAK family
kinases (JAK1, JAK2, Tyk2, and JAK3) are ubiquitous
intracellular regulators with important roles in immune
response and homeostasis.81,82
Tofacitinib primarily targets JAK1 and JAK3 and, to
a lesser extent, JAK2, whereas another developmen
tal agent, baricitinib, blocks both JAK1 and JAK2.83
Members of the chain cytokine family (IL2, IL4, IL7,
IL9, IL15, IL21) typically control lymphocyte activa
tion, proliferation, and survival through the activation of
JAK3, whereas JAK1 governs the activities of interferons
and JAK2 regulates colony-stimulating factors, erythro
poietin, and cytokines belonging to the IL6/IL12, IL10,
and IL3/IL5 families.84
In a phaseIII RCT, 399 patients with RA for whom
TNF inhibitors failed were randomized to receive
tofacitinib 5mg, 10mg or placebo twice daily. At the
end of month 3, ACR20 response rates were signifi
cantly superior for tofacitinib 5mg (41.7%; P=0.0024)
and 10mg (48.1%; P <0.0001) versus placebo (24.4%).85
Subsequently, tofacitinib has been approved by the FDA
for the treatment of moderate and severe RA.
Adverse effects associated with tocilizumab include
increases in levels of lipids, neutropenia and liver

Although the advent of biologic therapies has substantially

improved the management and outcome of inflamma
tory arthritis, the percentage of patients achieving disease
remission remains low. A literature review published in
2005 reported a remission rate of 50% in clinical trials of
biologic agents,87 whereas a systematic review of prog
nostic studies concluded in 2010 that <30% of patients
treated with biologic agents in clinical practice achieve
remission.88 Treatment strategies that achieve higher rates
of sustained disease remission are, therefore, needed. One
option is to combine biologic agents. Combination thera
pies, however, present not only potential benefits, but also
intrinsic risks and challenges.

Redundancy versus synergy

A trial in 244 patients with RA unsuccessfully treated
with methotrexate and previously naive to anticytokine
therapy compared etanercept alone with two combined
regimens of etanercept plus anakinrathat is, combining
inhibition of TNF and IL1 in a trial for the first time.89
The combination therapies failed to enhance efficacy
compared with etanercept alone, and were also associated
with more adverse events, especially infection.89 Given,
however, that the biologic effects of IL1 and TNF overlap
considerably, the negative result was not unexpected.
Compared with anakinra, less redundancy in the action
of abatacept (CTLA4IgG1) and etanercept might have
been expected. Unfortunately, a study assessing the com
bination of TNF inhibition and co-stimulatory blockade
in 121 patients with active RA showed minimal clinical
benefit and raised some safety concerns.90 Nevertheless,
as access to biologic agents that target different inflamma
tory pathways continues to increasefacilitating a clearer
understanding of how these signalling pathways inter
actpotential synergistic combinations may be identi
fied and tested. Major limitations of standard clinical trial
design for comparative assessment of the efficacy and risk
of biologic agent combinations, however, have hitherto
restricted the number of clinical trials conducted.
Trial design challenges
Given the potency and potential for immunosuppres
sion of combination biologic therapies, clinical trials
need to assess their safety and efficacy in stepwise,
escalating-dose combinations. Conventional parallel
group clinical trial design is inefficient for this purpose;

NATURE REVIEWS | RHEUMATOLOGY

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REVIEWS
if, for example, 3 doses of two biologic agents are to be
assessed, 9 possible dose combinations exist, and the
necessary sample size to use a conventional trial design
becomes prohibitive. Advances in clinical trial method
ology are, however, rapidly occurring. Adaptive designs
and multi-arm, multi-stage approaches are particularly
attractive, as unpromising and toxic combination treat
ments are dropped early, and the proportions of patients
in control arms are restricted. Moreover, these designs
allow for gradual dose titration of individual agents until
the optimal dosages are identified.

Potential benefits of combination therapies

Besides achieving reductions in disease activity for
patients for whom biologic monotherapy regimens have
failed, combination therapies have other anticipated
advantages. Although a combination might seem to be
expensive, if the drugs act synergistically and enable
substantial reductions in doses of the individual agents,
the combination therapy will be economically viable.
Furthermore, combining biologic agents might induce
immunological tolerance; in the collagen-induced arthri
tis mouse model of RA, for example, a short course of
combined anti-CD3 and anti-TNF therapy was shown
in 2012 to synergistically deplete pathogenic Tcell
subsets.91 If drug-free remission can be induced by a
short course of biologic combination therapy, it will be an
attractive therapeutic option. Indeed, a number of studies
examining whether biologic treatment can be tapered or
stopped in patients whose disease is in remission are
in progress. Although this is an important question,
the overall impact is likely to be low as the percentage
of patients who achieved sustained disease remission
with biologic therapy remains low.88 For some patients
1.

2.

3.

4.

5.

6.

Singh, J.A. etal. 2012 update of the 2008

American College of Rheumatology
recommendations for the use of diseasemodifying antirheumatic drugs and biologic
agents in the treatment of rheumatoid arthritis.
Arthritis Care Res. 64, 625639 (2012).
Smolen, J.S. etal. EULAR recommendations for
the management of rheumatoid arthritis with
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7.

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9.

10.
11.

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13.

who have failed multiple biologic agents because of sub

optimal responses, combination biologic therapy might
be a treatment option.

Conclusions
Biologic agents have brought major therapeutic advances
to the treatment of patients with RA. These advances
can be categorized as three major types: cytokine bloc
kers, lymphocyte-targeting agents, and small-molecule
inhibitors of signal transduction pathways. Their modes
of action and class-specific adverse events are different.
Most of the recent biologic developments have focused
on cytokine and small-molecule inhibitors. However,
opportunities exist to expand the range of treatments
that target lymphocytes. Furthermore, novel trial design
might allow biologic combinations to be evaluated
scientifically and systematically. These novel treatments
and therapeutic strategies are needed to make disease
remission a possibility for most patients with RA.
Review criteria
The references included in this Review were chosen by
the authors according to their opinion of their relevance
to the subject, by consultation of personal libraries
and databases, and searches of the PubMed database
using the following key words: rheumatoid arthritis,
treatment, clinical trials, lymphocytes, cytokine,
small molecule, and signal pathway, alone and in
combination. No limit as to date of publication was
applied, but only full-text papers in English were included.
Reference lists of selected papers were also used to
identify further key papers. The initial searches were
completed by May 2012, although references published
later were included during revisions to this manuscript.

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Acknowledgements
Professors Ernest Choy and Simon Jones thank
Arthritis Research UK for funding support provided
through the CREATE Centre (20016) and research
grants (19796, 19381, 18286).
Author contributions
All authors made substantial contributions to
researching data for the article and writing the article.
E.H. Choy handled review and editing of the article
before submission.

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