Smolen 2016

Seminar
Rheumatoid arthritis
Josef S Smolen, Daniel Aletaha, Iain B McInnes
Rheumatoid arthritis is a chronic inammatory joint disease, which can cause cartilage and bone damage as well as Lancet 2016; 388: 202338
disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk Published Online
factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment May 3, 2016
http://dx.doi.org/10.1016/
algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use
S0140-6736(16)30173-8
of conventional, biological, and newz non-biological disease-modifying antirheumatic drugs. After the treatment
This online publication has
target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. been corrected. The corrected
Although the prospects for most patients are now favourable, many still do not respond to current therapies. version first appeared at
Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and thelancet.com on June 10, 2016
aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with Division of Rheumatology,
unmet needs of patients with rheumatoid arthritis. Department of Medicine 3,
Medical University of Vienna,
Vienna, Austria
Introduction rheumatoid arthritis, but lower (20%) for seronegative (Prof J S Smolen MD,
Rheumatoid arthritis is one of the most prevalent chronic disease.13,14 D Aletaha MD);
inammatory diseases. It primarily involves the joints, Modern genetic technologies combined with large, 2nd Department of Medicine,
Hietzing Hospital Vienna,
but should be considered a syndrome that includes extra- well-characterised clinical cohorts have advanced our Vienna, Austria
articular manifestations, such as rheumatoid nodules, understanding of the genetics of the disease. Genome- (Prof J S Smolen); and Institute
pulmonary involvement or vasculitis, and systemic wide association studies using single nucleotide poly- of Infection, Immunity and
comorbidities. A therapeutic revolution in the treatment morphisms have characterised more than a hundred loci Inflammation, University of
Glasgow, Glasgow, UK
of rheumatoid arthritis in the past decadewith the associated with rheumatoid arthritis risk, most of which (Prof I B McInnes MD)
advent of novel therapeutics, introduction of early implicate immune mechanisms (gure 1), some of Correspondence to:
therapy, development of new classication criteria, and which are shared with other chronic inammatory Prof Josef S Smolen, Division of
application of new eective treatment strategieshas diseases.15 The HLA system (particularly HLA-DRB1) Rheumatology, Department of
transformed articular and systemic outcomes.16 In this remains the dominant inuence, strongly implicating Medicine 3, Medical University of
Vienna, A-1090 Vienna, Austria
Seminar, we highlight recent insights into most aspects peptide (and self-peptide) binding in pathogenesis.16 josef.smolen@wienkav.at
of rheumatoid arthritis, from diagnosis to treatment Disease-associated alleles share common aminoacid
strategies, and from aetiology to novel therapies. There is sequences in the peptide-binding groove (the so-called
still a considerable unmet need in rheumatoid arthritis; shared epitope).17 Moreover, some HLA genotypes
full or stringent remission is not typical, nor is it usually particularly associate with more aggressive erosive
sustained without continuing treatment, and as such it disease and with higher mortality, pointing to a crucial
should now be the priority of research eorts. role of peptide binding.18
Other genetic loci probably contribute smaller
Epidemiology, genetics, and aetiology functional eects that are presumably singly or
Rheumatoid arthritis is a chronic disease that carries a cumulatively mediated,19 for example, via altered co-
substantial burden for both the individual and society.7 stimulatory pathways (eg, CD28, CD40), cytokine
The individual burden results from musculoskeletal signalling, lymphocyte receptor activation threshold (eg,
decits, with attendant decline in physical function, PTPN22), and innate immune activation (gure 1). The
quality of life, and cumulative comorbid risk.8 The increased risk for rheumatoid arthritis in patients with
socioeconomic burden, aside from major direct medical the shared epitope is linked with seropositivity for
costs, is a consequence of functional disability, reduced autoantibodies against citrullinated peptides (ACPAs)
work capacity, and decreased societal participation.9 and autoantibodies against IgG (rheumatoid factor [RF]).
Eorts to establish the diagnosis early, initiate treatment These characteristic autoantibodies for rheumatoid
promptly, and design novel treatment strategies to
control inammation and reduce or prevent consequent
damage are paramount. Search strategy and selection criteria
Rheumatoid arthritis has an incidence of 05% to 1%, We searched MEDLINE using the terms rheumatoid arthritis
with an apparent reduction from north to south (in the in conjunction with diagnosis, classication,
northern hemisphere) and from urban to rural areas.10,11 epidemiology, and pathogenesis. For treatment, we used
Some Native American populations have a very high recent systematic literature searches, and updated the
prevalence.10 A positive family history increases the risk of respective searches in October, 2015, including terms on novel
rheumatoid arthritis roughly three to ve times; con- therapies and treatment strategy. Selection of articles was
cordance rates in twins are increased, implicating genetic based on our personal judgment of relevance within the scope
factors in pathogenesis.10,12 The heritability of rheumatoid of this Seminar.
arthritis is currently estimated as 4065% for seropositive
www.thelancet.com Vol 388 October 22, 2016 2023

Seminar
HLA DR4
As is the case with many autoimmune diseases, there
PADI4
p CTLA4 is now considerable interest in the eect of the
DC CD28 microbiome on disease risk and progression (gure 2).30,35
Treg
cell Data from animal models of arthritis suggest an essential
m Th1 (Th17)
DC cell role for the gut microbiome in the development of
IL2 IL21 disease.35 Initial studies in humans have implicated
IL2RB
Neutrophil
gastrointestinal dysbiosis in rheumatoid arthritis,
CD40 B cell particularly in early disease.30 One study36 detected
PTPN22 Macrophage alterations in common microbial populations in oral,
TYK2 STAT4
TNFAIP3 IL6R Mast cell
salivary, and gastrointestinal sites, which were associated
TRAF1 IRAK1 with C-reactive protein and ACPA status, and further
Germinal
centre Fibroblast-like synoviocyte altered by therapy with disease-modifying antirheumatic
formation C5
drugs. The mechanisms underpinning such observations
Plasma cell
and their importance remain to be elucidated.
CCL21 Chondrocyte
Osteoclast
Pathophysiology of rheumatoid arthritis
Figure 1: Important loci associated with risk and progression of Autoimmune response
rheumatoid arthritis Rheumatoid arthritis is pathologically heterogeneous. The
Key immune cells implicated in the pathogenesis of rheumatoid arthritis. presence of autoantibodies (seropositivity) is associated
Th1=T-helper-1. Th17=T-helper-17. Treg=regulatory T. mDC=myeloid dendritic
cell. pDC=plasmacytoid dendritic cell.
with more severe symptoms and joint damage, and
increased mortality.3539 This is most likely due to formation
arthritis are present in 5070% of patients at diagnosis, of immune complexes by ACPAs with citrulline-
with remarkable stability throughout the disease containing antigens and subsequent binding of RF, which
course.20,21 The shared epitope has only poor association can lead to abundant complement activation.4042 The
with ACPA-negative and RF-negative rheumatoid detection of autoimmune responses to citrullinated self-
arthritis.18 proteins is a major advance.43,44 ACPAs can bind
Epigenetics contribute to pathogenesis, probably by citrullinated residues on many self-proteins including
integrating environmental and genetic eects.22 A recent vimentin, -enolase, bronectin, brinogen, histones,
epigenome-wide association study identied ten and type II collagen. The tissue in which these immune
dierentially methylated positions that could promote responses are activated is uncertain, but the lung is an
genetic risk in rheumatoid arthritis.23 Altered histone attractive candidate, which is consistent with a role for
acetylation and DNA methylation can regulate the smoking in rheumatoid arthritis and the presence of
biology of synovial broblasts and leucocytes.22 shared citrullinated peptides in lung and synovial tissue
MicroRNAs represent an additional epigenetic aspect by biopsies (gure 2).45 Circulating ACPAs can be detected
targeting mRNA for degradation, thereby ne-tuning up to 10 years before diagnosisso-called pre-rheumatoid
cellular responses.24,25 Many microRNAs have been arthritis.46 Over time, the concentration and epitope
identied as key regulators of lymphocytes, macrophages, diversity of ACPAs increases, as do serum cytokine
and synovial broblasts (eg, miR146a or miR155).25 concentrations, especially before onset of articular
Whether microRNAs will oer therapeutic utility in involvement. ACPAs can be of IgG, IgA, or IgM isotype,
rheumatoid arthritis is as yet unclear.22 are indicative of T-cell help, and have an altered
Development of rheumatoid arthritis is associated with glycosylation status that confers enhanced Fc-receptor and
environmental factors. Consistently reported risk factors citrullinated antigen binding.47,48 ACPA-producing B cells
include smoking26,27 and low socioeconomic status or are present in the synovium and in the circulation.47,49
educational attainment.28,29 Rheumatoid arthritis is ACPAs themselves can be pathogenic, either by activating
associated with periodontal disease, although the macrophages (eg, by ligating to toll-like receptors via the
causality and nature of this relationship remains ill bound antigen, or by Fc-receptor engagement, or both), or
dened.30 One hypothesis proposes that Porphyromonas by activating osteoclasts via immune complex formation
gingivalis (a bacterium frequently found in periodontitis) and Fc-receptor engagement or, possibly, by binding
promotes aberrant citrullination and provokes local membrane citrullinated vimentin,50 thus promoting bone
breach of tolerance to citrullinated peptides via loss. With eective therapy, both RF and ACPA
endogenous expression of its PADI4, which converts concentrations decrease, but patients rarely become
arginine to citrulline.31 Indeed, other infectious agents ACPA negative, whereas RF decreases more profoundly
(eg, Proteus mirablis, Escherichia coli, and Epstein-Barr and more frequently and patients may serocovert to RF
virus) have been suggested to trigger rheumatoid negativity.51 Anti-carbamylated and acetylated peptide
arthritis,32 generally via molecular mimicry; however autoantibodies have also been identied in patients with
these proposed mechanisms have not yet been rheumatoid arthritis;52 additional autoantibodies, directed
substantiated. against other post-translational protein modications,
2024 www.thelancet.com Vol 388 October 22, 2016

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Pre-arthritis
Susceptibility Environmental factors Epigenetic modications Post-translational

genes Recurrent exposure to exogenous, modications
endogenous, or commensal viral, Acetylation
bacterial, or other agents; smoking; Carbamylation
silica Citrullination
+ Oral
microbiome Peridontitis
+ + Methylation
Phosphorylation
Sumoylation
MHC-shared epitope Ubiquitination
PADI Smoking
PTPN22 Bronchial
microbiome
Gut
microbiome
Loss of Asymptomatic synovitis Symptomatic arthritis

tolerance (cellular inltrate) (swelling, pain, stiness, damage)
Autoantibodies Lymph node
ACPA
RF
Secondary
lymphoid tissue Transition
to
Dendritic cells
manifest
T cells arthritis
B cells
Figure 2: Pathways to rheumatoid arthritis

In a genetically predisposed host with susceptibility genes, environmental insults, epigenetic modications, and post-translational modications can lead to loss of
tolerance with subsequent asymptomatic synovitis, ultimately leading to clinically overt arthritis. ACPA=autoantibodies against citrullinated peptides. RF=rheumatoid
factor. Adapted from Smolen and colleagues33 by permission of Elsevier, and McInnes and Schett34 by permission of the Massachusetts Medical Society.
might emerge. RF is more directly involved in mechanisms enhanced chondrocyte catabolism and synovial
of macrophage activation and induction of cytokine osteoclastogenesispromotes articular destruction.33,34
activation than ACPAs.42,53 ACPAs might form immune Findings from ultrasound-guided biopsies of small joints
complexes that interact with RF, thus potentiating the and detailed molecular (particularly transcriptomic)
eect on the inammatory and destructive response.37,53 analyses suggest that myeloid-dominant, lymphocytic-
Less is known of the T-cell response that supports these dominant, and broid-dominant synovial subtypes might
processes.54 Using HLA-DRB1*0401 tetramers, elevated exist, which could be of therapeutic signicance.59
numbers of citrulline-specic T-helper-1 cells have been The inammatory milieu in the synovial compartment
found in the circulation of patients with rheumatoid is regulated by a complex cytokine and chemokine
arthritis, particularly in those with early disease,55 although network; clinical interventions clearly demonstrate that
their contribution to autoimmune mechanisms remains of these components, tumour necrosis factor (TNF),
uncertain. Lymph node biopsies in early rheumatoid interleukin 6, and probably granulocyte-monocyte colony
arthritis suggest T-cell activation distant from the stimulating factor are essential to the process, whereas
synovium.56 others (such as interleukin 1 and various lymphokines)
may be less important.60 Cytokines and chemokines lead
Inammation to the induction or aggravation of the inammatory
Joint swelling in rheumatoid arthritis reects synovial response by activating endothelial cells and attracting
membrane inammation consequent to immune immune cells to accumulate within the synovial
activation, and is characterised by leucocyte inltration compartment. Activated broblasts, together with the
into the normally sparsely populated synovial com- accumulated activated T cells and B cells, and monocytes
partment (gure 3). The cellular composition of synovitis and macrophages, ultimately trigger osteoclast generation
in rheumatoid arthritis includes innate immune cells via receptor activator of nuclear factor B ligand (RANKL)
(eg, monocytes, dendritic cells, mast cells, and innate expressed on T cells, B cells, and broblasts, with its
lymphoid cells) and adaptive immune cells (eg, T-helper-1 receptor RANK on macrophages, dendritic cells, and pre-
and T-helper-17 cells, B cells, plasmablasts, and plasma osteoclasts.61,62 Bony erosions ensue, arising from the so-
cells). A robust tissue responsewhereby synovial called bare area at the junction between cartilage,
broblasts assume an aggressive inammatory, matrix periosteal synovial membrane insertion, and bone.
regulatory, and invasive phenotype, together with Cartilage undergoes damage by catabolic eects in

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chrondrocytes after their stimulation by cytokines.

Within the joint
Normal Rheumatoid Cartilage matrix is degraded by matrix metalloproteinases
Bone
joint arthritis and other enzymes.63 Cytokines bind cognate receptors to
joint
Osteoclast trigger various intracellular signal transduction events,
Capsule Fibroblast the intermediaries between extracellular events and
Macrophage
Synovium
Dendritic cell
activation of an array of genes that lead to or aggravate
inammation and damage (gure 3).
Pathobiology
Neutrophil T cell
B cell
Plasma cell Learning from success and failure of therapies
Cartilage Extensive Many of these cells and molecules have been tested as
angiogenesis therapeutic targets with notable success in rheumatoid
Synoviocytes Mast cell arthritis and subsequently other inammatory diseases,
Hyperplastic whereas targeting of other molecules rendered low or no
synovial lining
Bone therapeutic success. Thus, whereas the pathogenetic
events initiating and mediating chronicity of synovitis
are not yet fully understood, remarkable insights have
arisen from genetic, epidemiological, translational
Within the synovial Blood biological, and therapeutic studies.
tissue T cell Monocyte Taken together, this evidence suggests that rheumatoid
arthritis probably arises from multiple hits, whereby an
Adhesion Endothelial cells initial combination of environmental, lifestyle, and
molecules IL12, IL23
APC T cell
stochastic insults occurring in a genetically predisposed,
TLR IL1, TNF, IFN1
Angiogenesis
Synovium tissue
epigenetically modied individual leads to breach of
immunological tolerance. An additional trigger, perhaps
IL2
IFN IL21 infectious (facilitated particularly by pathways associated
IFN
B cell with HLA class II), drives expansion of T-cell-mediated
CR
IL17
T cells help
autoimmunity, and thereafter articular localisation via
currently obscure mechanisms (eg, neurological, vascular,
Cell biology
IL12
FcR IL23 co-stimulation
Macrophage Th1/Th17 biomechanical). This crucial transition to chronic (non-
Treg
IL15
IL18, IL32 resolving) synovitis is characterised by leucocyte and
stromal cell dysregulation and wider comorbidity aecting
TNF, IL6, IL1 Autoantibody (RF, ACPA, anti-RA33) CD25
CD80
various organs, such as the heart and the bone. Importantly,
IC
CD28 this transition must occur quite early, because treatment of
TCR
Synovial Plasma cell TLR very early, clinically incipient but overt rheumatoid arthritis
broblast MHCII
Matrix metalloproteinases CD40 usually does not reverse arthritis, and because synovial
CD40L
RANKL
CD4
inltration by inammatory cells can occur before clinical
Chondrocyte TACI signs and symptoms.64,65 Therefore, diagnosis of preclinical
Blys
Cartilage RANK rheumatoid arthritis has become a focus of research
RANK RANKL
Auto (?) activity,66,67 with the goal of using preventive therapy; the
antigen
Bone CD20
term window of opportunity increasingly refers to
Osteoclast
Antibody preventive aspects rather than interventions in early but
clinically already manifest disease.
Within a cell SYK
(and BTK)
signalling PI3K
NFKB
Diagnostic approach and dierential diagnosis
MAPK cascade signalling JAK
signalling cascade signalling
signalling
No diagnostic criteria exist for rheumatoid arthritis. The
cascade cascade
Lipid
cascade typical patient presents with tender and swollen joints of
Molecular biology
messengers recent onset, morning joint stiness, and abnormal

SyK PI3K
PI3K PI3K laboratory tests such as elevated concentrations of
PI3K JAK
BTKK
Second JAK C-reactive protein or erythrocyte sedimentation rate.
Kinases Messengers
STAT Unfortunately, this presentation is not specic to
IKK STAT
ERK Kinases
JNK STAT
p38 NFKB STAT
Figure 3: Pathogenetic pathways in rheumatoid arthritis
API
Green text shows molecules or cells which are successfully targeted by respective
Cytoplasm therapies. Red text relates to molecules or cells for which targeting was not
Nucleus eective. Adapted from Smolen and colleagues33 by permission of Elsevier,
Gene transcription Mavers and colleagues57 by permission of Springer, and Smolen and Steiner58 by
permission of Nature Publishing Group.

Seminar
rheumatoid arthritis. Other causes of arthritis need to be recommended for daily practice.77 The ACR improvement
considered, such as reactive arthritis, osteoarthritis, criteria78 distinguish a change from baseline of several
psoriatic arthritis, infectious arthritis (viral or bacterial, dened variables by at least 20% (ACR20, minimal
and particularly Lyme disease depending on geographic response), 50% (ACR50, moderate response), or 70%
region), or some rarer autoimmune conditions such as (ACR70, major response). They were developed to
connective tissue diseases if additional suggestive signs dierentiate active therapy from placebo in clinical trials
or symptoms are present (eg, rash, mouth ulcers, (in particular, ACR20), but cannot be used in practice
alopecia, Raynauds phenomenon, Sicca syndrome, because they are not based on a continuous scale;
antinuclear antibodies, elevated muscle enzymes). In improvement is related to baseline values of the respective
fact, in many patients no specic diagnosis can be made variable, which dier between individual patients or
at rst presentation, and the diagnosis of exclusion is within patients at dierent treatment starts. By contrast
undierentiated arthritis. Providing such preliminary with the DAS28, a disease activity score using 28 joint
diagnosis, while leaving the future evolution to a distinct counts along with other components in a complex
diagnosis open, is important, because disease-modifying calculation (table 1),80 the simplied disease activity index
treatment is indicated and necessary for any type of (SDAI) and clinical disease activity index (CDAI)81,82
chronic inammatory arthritis. provide continuous numerical scales reecting disease
New classication criteria for rheumatoid arthritis were activity (higher is worse; table 1).80,83 These measures can
presented in 20101 to eliminate shortcomings of the former also classify disease activity states (high, moderate, low,
American College of Rheumatology (ACR) criteria, and remission). There is an almost linear relationship
particularly inclusion of features of chronicity and poor between these disease activities and impairment of
prognosis.68 Briey, the new criteria, developed using physical function77,82,84 or damage progression.82,8587 Other
cohorts and case scenarios of patients with early arthritis, disease activity measures that do not include joint counts88
require at least a single clinically swollen joint as entry
criterion in the absence of other diseases explaining the
Components Cutpoints
clinical symptoms. Thereafter, the classication criteria
Remission Low disease Moderate High disease
allow for sensitive assessment of extent of joint
activity disease activity activity
involvement (tender joints or joints positive by ultrasound
DAS28-ESR* Tender joint count (of 28), <26 26 to 32 >32 to 51 >51
or MRI can be classied as active joints, just as well as
swollen joint count (of 28),
clinically swollen joints). Additional features are serological erythrocyte sedimentation
markers (RF and ACPA), long symptom duration, and rate (in mm), global health
laboratory markers of systemic inammation. The criteria DAS28-CRP Tender joint count (of 28), <26 26 to 32 >32 to 51 >51
have been validated in many settings and oer 21% higher swollen joint count (of 28),
C-reactive protein (in mg/dL),
sensitivity than the former criteria, at the cost of 16% lower
global health
specicity.69 However, classication is not synonymous
SDAI Tender joint count (of 28), 33 >33 to 11 >11 to 26 >26
with diagnosis. Whereas diagnosis has the ultimate goal of swollen joint count (of 28),
being correct at the level of the individual patient, patient global assessment,
classication aims to maximise homogeneous populations evaluator (physician) global
assessment both in cm,
for study purposes, but can be used to support diagnosis. C-reactive protein (in mg/dL)
CDAI Tender joint count (of 28), 28 >28 to 10 >10 to 22 >22
Extra-articular manifestations and comorbidities swollen joint count (of 28),
Patients with insuciently treated rheumatoid arthritis patient global assessment,
evaluator (physician) global
can have various extra-articular manifestations, including
assessment both in cm
vasculitis or interstitial lung disease.69 Moreover, the
ACR-EULAR Index: SDAI, CDAI; SDAI 33,
chronic inammatory state of rheumatoid arthritis has remission79 Boolean: swollen joint count CDAI 28,
been associated with secondary amyloidosis, lymphoma,70 (of 28), tender joint count Boolean all
and cardiovascular disease8 and increased mortality.71 All (of 28), patient global 1
assessment, C-reactive protein
these risks appear to be strikingly reduced with modern (in mg/dL)
therapeutic strategies.72,73 Of note, methotrexate can induce
nodulosis, which is indistinguishable from rheumatoid Patient global assessment reects global health in DAS28; mm in DAS28; cm in CDAI, SDAI, Boolean. ACR=American
College of Rheumatology. EULAR=European League against Rheumatism. DAS28=disease activity score using 28 joint
nodules,74 and TNF inhibitors can elicit psoriasis-like counts. SDAI=simplied disease activity index. CDAI=clinical disease activity index. TJC28=tender joint count (of 28).
lesions75 that only subside after cessation of the drugs. SJC28=swollen joint count (of 28). ESR=erythrocyte sedimentation rate (in mm). GH=global health.
CRP=C-reactive protein (in mg/dL). *DAS28-ESR calculated according to the following equation:
056 (TJC28) + 028 (SJC28) + 070 loge(ESR) +0014 GH. DAS28-CRP calculated according to the following
Disease assessment and denition of treatment equation: 056 (TJC28) + 028 (SJC28) + 036 loge(CRP + 1) + 0014 GH + 096. SDAI calculated according to
targets the following equation: TJC28 + SJC28 + PtGA + EGA + CRP. CDAI calculated according to the following equation:
Assessment of disease activity is crucial in the follow-up TJC28 + SJC28 + PtGA + EGA.
of patients with rheumatoid arthritis.76,77 Composite
Table 1: Composite measures of disease activity including joint counts, and ACR-EULAR remission criteria
measures that include joint counts have been

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and the European League Against Rheumatism (EULAR)

A
Disease activity
recently developed new remission criteria, based on a
(CDAI) Boolean approach or on an index approach using the
50
criteria of the SDAI or CDAI (table 1).79 Other denitions of
45
High disease remission (eg, remission according to DAS28-ESR criteria;
40 activity table 1) might not correspond to true remission, because
HDA
35
Insucient
they are associated with progression of joint damage,91
30 response High or moderate presence of comorbidities,92 and signicant residual
activity in many patients,93,94 even if the established cutpoint
CDAI
25 disease activity
Continue therapy
20 of 26 is lowered.79,95 Although this issue is controversial,
Insucient our analyses96,97 suggest that classication of remission
15 MDA ~80% improvement Low-moderate response Low-moderate
to low disease to low disease according to DAS28-ESR or DAS28-CRP criteria (table 1)
10 activity apt activity
LDA
Ad results in high frequency of false-positive responses,
5 Continue therapy Low disease particularly when drugs aecting the acute-phase
REM activity or
0 response are used. Indeed, sometimes major dierences
0 1 2 3 4 5 remission
Month 6
between DAS28-ESR and DAS28-CRP activity states are
Continue therapy observed.98,99 Importantly, with the development of the new
remission criteria, remissioneither index-based or
B Boolean-basedis now closely related to the absence of
Early diagnosis
residual inammatory disease activity,100 leaving other
Follow up denitions consistent with a state of low disease activity.96,101
patients using
Immediate treatment initiative a composite Finally, it is important to evaluate structural progression
measure of of the disease. Treatment of rheumatoid arthritis should
Methotrexate disease
plus low-dose activity that
prevent or halt structural changes and thereby minimise
glucocorticoid comprises or reverse physical disability. In routine practice,
joint counts. radiographs are usually done annually and evaluated
Aim at clinical
remission semi-quantitatively. Formal scoring of radiographs for
Upon failure, stratify
C (ACR-EULAR progression of erosions and joint space narrowing, as
With criteria) or at
With
risk factors absent least low
done in trials, is more accurate and sensitive.102 Other
risk factors present
add any biological
switch to (or add) another disease imaging modalities are being increasingly used, especially
csDMARD plus gluco- activity within
agent
corticoids for diagnostic purposes. MRI scans detect bone marrow
6 months
Upon failure, switch (this requires oedema as a potential area of (early or future) erosions,103
about 80% but erosions also correlate well with clinical joint swelling.
improvement
D of disease Ultrasound can quantify the degree and extent of synovial
Upon failure: switch to
any other biologic agent activity within inammation by using greyscale and power Doppler
3 months of
(even within same class)
starting
measurements.95,104,105 However, in follow-up, targeting
plus methotrexate or
to a tsDMARD treatment) sonographic remission does not provide any benet over
(+/ methotrexate) targeting clinical remission or even low disease activity,
but is associated with substantial overtreatment.106,107
After any of the treatment regimens has led to the treatment target and its maintenance, consider reducing Notably, many healthy people have detectable ultrasound
dose or increasing interval (suggested sequence: glucocorticoids, bDMARDs, csDMARDs) and MRI signals of synovitis and vascularity.108 Physical
function is typically assessed using the Health
Figure 4: Therapeutic approaches to rheumatoid arthritis Assessment Questionnaire Disability Index,109 usually at
(A) General strategy. (B) Early treatment phase. (C) Treatment approach if methotrexate (plus glucocorticoid)
does not achieve the treatment target. (D) Treatment approach after a rst biologic has failed. The every clinical visit.
recommendation to potentially use a TNF inhibitor after another TNF inhibitor has failed is based on the available
evidence for biological DMARDs, but in some countries switching to another mode of action is recommended or Treatment strategies
mandated (against this evidence). Treatment algorithm based on EULAR recommendations.89,100 DMARD=disease- Because inammation is at the apex of clinical events
modifying antirheumatic drug. tsDMARD=targeted synthetic DMARD. csDMARD=conventional synthetic
DMARD. bDMARD=biological DMARD. ACR=American College of Rheumatology. EULAR=European League (driving clinical symptoms, joint damage, disability, and
Against Rheumatism. CDAI=clinical disease activity index. HDA=high disease activity. MDA=moderate disease comorbidity),33 its reversal is the major therapeutic target;
activity. LDA=low disease activity. REM=remission. TNF=tumour necrosis factor. if inammation subsides rapidly, damage or its progression
are prevented, and physical function can be maximally
have also been developed but are not widely recommended improved without further sequelae. Treatment of
because of insucient evidence for reliability across all rheumatoid arthritis thus requires a strategic approach
patient populations and reection of all outcomes. whereby regular assessment of disease activity drives
Remission (primarily for early rheumatoid arthritis) or therapeutic adaptations or changes of drugs in accordance
low disease activity (especially in long-standing disease) with such activity (treat to target).100 Composite measures
have been established as treatment targets.89,90 The ACR of disease activity that include joint counts are preferred

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Timepoint Methotrexate plus glucocorticoid Methotrexate plus other csDMARDs plus glucocorticoid, or
methotrexate plus bDMARD
Dose LDA (% of Dose LDA (% of
patients) patients)
CareRA113 4 months 15 mg methotrexate plus 30 mg 87% 15 mg methotrexate plus 2 g sulfasalazine 85%
prednisone (tapered) plus 60 mg prednisone (tapered)
tREACH114 6 months 25 mg methotrexate plus 15 mg 68% 25 mg methotrexate plus 2 g sulfasalazine 71%
prednisone (tapered) plus 400 mg hydroxychloroquine plus
15 mg prednisone (tapered)
IDEA115 6 months 20 mg methotrexate plus single 67% 20 mg methotrexate plus iniximab 65%
intravenous dose of 250 mg
methylprednisolone
BeSt116 6 months 75 mg methotrexate (increased to 67% 25 mg methotrexate plus iniximab 64%
30 mg if needed) plus 2 g sulfasalazine
plus 60 mg prednisone
LDA=low disease activity. DMARD=disease-modifying antirheumatic drug. csDMARD=conventional synthetic DMARD. bDMARD=biological DMARD.
Table 2: Achievement of low disease activity using methotrexate monotherapy (with glucocorticoids) or combination therapy
tools in treat-to-target approaches. In practice, if a state of the optimal approach. First, clinical trials comparing
low disease activity or approximately 80% improvement in methotrexate plus glucocorticoids with combinations of
SDAI or CDAI has been attained by 3 months, the methotrexate plus a biological agent have shown no
likelihood of reaching the target at 6 months from therapy signicant dierence in outcomes (table 2).115,116 Clearly,
initiation is very high.110 If improvement is small at the dose of all conventional synthetic DMARDs should be
3 months (gure 4), treatment should be adapted. Likewise, optimised, escalating methotrexate to 2530 mg per week
if the state of low disease activity (or remission) is not (about 03 mg/kg)either orally or subcutaneouslyor
attained at 6 months, treatment should be re-evaluated. sulfasalazine up to 3 g per day. Second, comparing
However, escalation of therapy needs to be balanced methotrexate plus glucocorticoids with combinations of
against patient factors and treatment-related risks.100 conventional synthetic DMARDs plus glucocorticoids
revealed similar ecacy with less toxicity (table 2).113,114
Therapies Glucocorticoids are given at low to intermediate oral doses
Therapeutic approaches or parenterally as single intravenous or intramuscular
Disease-modifying antirheumatic drugs (DMARDs) target applications. Low doses of glucocorticoids (<75 mg daily)
inammation and by denition must reduce structural combined with methotrexate confer additive structural
damage progression. Non-steroidal anti-inammatory protection when compared with methotrexate alone.117
drugs (NSAIDs), while reducing pain and stiness and Oral glucocorticoids should be tapered and then stopped
improving physical function, do not interfere with joint within 6 months, when conventional synthetic DMARDs
damage and are thus not disease modifying. Gluco- should have induced signicant improvement.89 With
corticoids oer rapid symptomatic and disease-modifying respect to the choice of a conventional synthetic DMARD,
eects,111 but are associated with serious long-term methotrexate is considered the anchor drug that also
side-eects. optimises ecacy of biological DMARDs.89,90 However, it
There are two major classes of DMARDs: synthetic and has not yet been conclusively shown that methotrexate is
biological. Synthetic DMARDs are further dened as superior to other conventional synthetic DMARDs
conventional synthetic or targeted synthetic.112 The use of clinically or structurally; rather, comparisons with
conventional synthetic DMARDs has evolved empirically sulfasalazine or leunomide revealed similar outcomes,
and their modes of action are still largely unknown. but the doses of methotrexate in these studies were low
By contrast, targeted synthetic DMARDs have been compared with those in current use.118 Other conventional
developed to modulate a particular target implicated in synthetic DMARDs include sulfasalazine, leunomide,
the generation of inammation. Key examples include and (for very mild disease) hydroxychloroquine or
janus kinase (JAK) inhibitors, such as tofacitinib or chloroquine, although these antimalarials have few
baricitinib (Eli Lilly, Indianapolis, IN, USA). structural eects.119 In some countries parenteral gold is
still used,120 but it can have serious side-eects.121
Conventional synthetic DMARDs and glucocorticoids Table 2 summarises the most recent data on
According to EULAR recommendations,89 treatment conventional synthetic DMARD monotherapy and com-
should be initiated with a conventional synthetic DMARD, bination therapy. These data suggest some uncertainty as
ideally methotrexate, plus low-dose glucocorticoids to general use of conventional synthetic DMARD
(gure 4). There is compelling evidence that this is combinations. By comparison with methotrexate

Seminar
Molecule type Usual dose* Loading dose Comments

Conventional synthetic DMARDs
Methotrexate Small chemical 25 mg once weekly* No Starting dose 10 mgescalation to 25 mg within
48 weeks; folate use important (suggest
10 mg/week or 1 mg/day)
Sulfasalazine Small chemical 3 g/day* No Starting dose 1 g, escalation to 3 g/day within
48 weeks
Leunomide Small chemical 20 mg/day Optional Loading dose associated with more gastrointestinal
side-eects
Hydroxychloroquine Small chemical 400 mg/day No For mild arthritis or as combination therapy
Biological DMARDs
TNF inhibitors
Adalimumab Human monoclonal antibody 40 mg every 2 weeks No Biosimilars expected
subcutaneously
Certolizumab F(ab) fragment of a 200 mg every 2 weeks Yes
pegol humanised monoclonal subcutaneously
antibody
Etanercept IgGFc-receptor construct 50 mg/week subcutaneously No Biosimilar approved
(fusion protein)
Golimumab Human monoclonal antibody 50 mg/month subcutaneously No
Iniximab Chimeric monoclonal antibody 310 mg/kg intravenously Yes Biosimilars approved
every 48 weeks
Anti-B-cell
Rituximab Chimeric monoclonal antibody 1000 mg intravenously every No Biosimilars expected
6 months
Anti-T-cell
co-stimulation
Abatacept IgGFc-receptor construct 125 mg/week subcutaneously No Intravenous dosing available
(fusion protein)
Anti-IL 6R
Tocilizumab Humanised monoclonal 1626 mg/week Intravenous dosing available; sarilumab (anti-IL6R
antibody subcutaneously [Regeneron, Tarrytown, NY, USA]) and anti-IL6
cytokine antibodies (sirukumab [Janssen,
Springhouse, PA, USA]) in development
Targeted synthetic DMARDs
Janus kinase inhibitors
Tofacitinib Small chemical 5 mg twice daily No JAK1/2/3 inhibitor; once daily medication in
development; baricitinib (Eli Lilly, Indianapolis, IN,
USA), a JAK1/2 inhibitor, has completed phase 3
trials
IL6R=interleukin 6 receptor. IL6=interleukin 6. DMARD=disease-modifying antirheumatic drug. TNF=tumour necrosis factor. *Contraindicated or dose reductions needed
with renal or hepatic impairment; for adverse events see package inserts.
Table 3: DMARDs and recommended doses
monotherapy, there might be no added ecacy of combinations compared with methotrexate monotherapy,
conventional synthetic DMARD combinations at the but more toxicity and discontinuations.113,114
potential cost of more toxicity. By comparison with Notably, the new ACR guidelines no longer advocate an
biological agents used after methotrexate, conventional early use of combination conventional synthetic DMARD
synthetic DMARD combination confers profound therapy.90 Many studies of such combination therapies
responses (eg, ACR70) at only low frequencies.122 This is a were investigator initiated and these trials could have
controversial issue,118,123 and triple therapy (methotrexate limitations, as discussed by Landew and colleagues.125
plus sulfasalazine plus hydroxychloroquine) was thought However, in patients with low risk of progressive disease,
to be more ecacious than monotherapy. Several reviews adding a conventional synthetic DMARD when
that addressed higher glucocorticoid doses in the triple methotrexate has not suciently improved disease activity
therapy arm arrive at dierent conclusions.4,124 Indeed, if is a possible therapeutic option, although switching the
the same dose of glucocorticoids is applied across both conventional synthetic DMARD is just as good an option.116
study groups, the most recent randomised controlled When the rst treatment cycle fails, EULAR
trials show no signicant clinical, functional, or recommends stratication for predictors of severe
structural advantage of conventional synthetic DMARD disease as suggested by high disease activity despite the

Seminar
previous therapy, autoantibodies (ACPA or RF, especially

A B
at high titres), and early joint damage on radiography 50 Methotrexate monotherapy
(gure 4).89 Patients with these risk factors should receive Abatacept (~10 mg/kg) + methotrexate
45
a biological DMARD, whereas those without should Golimumab (50 mg) + methotrexate
40
receive another conventional synthetic DMARD again in
ACR70 responders (%)

35
combination with glucocorticoids. 32%
30
24%
Biological DMARDs 25
20% 20% 20%
Currently approved biological therapeutics for rheumatoid 20
16%
arthritis have four dierent modes of action:3 TNF 15 12%
inhibition, interleukin 6 receptor inhibition, T-cell co- 10%
10
stimulation blockade, and B-cell depletion (table 3, 5
gures 3, 4, 5). A small proportion of patients respond to 0
inhibition of interleukin 1 pathways.3 Among the TNF MTX-naive MTX-naive MTX-IR Anti-TNF-IR MTX-naive MTX-naive MTX-IR Anti-TNF-IR
inhibitors, ve compounds are currently approved, one AGREE AIM ATTAIN GO- GO- GO-
for intravenous use (iniximab) and four for subcutaneous BEFORE FORWARD AFTER
application (adalimumab, certolizumab pegol, etanercept, C D

and golimumab). Etanercept is a TNF-receptor construct, 50 Methotrexate monotherapy 47%
whereas the others are monoclonal antibodies or 45
Tocilizumab (8 mg/kg) + methotrexate
Rituximab (1000 mg) + methotrexate
fragments of monoclonal antibodies (certolizumab). 40 39%
Etanercept appears to have a lower (but not absent) risk of
35
reactivating tuberculosis than monoclonal antibodies.127
30
Patients with a positive tuberculosis test should receive 25% 25%
25
appropriate prophylactic therapy. Biosimilar iniximab is 22%
20%
already available and a biosimilar etanercept has been 20
approved in Europe and other countries (table 3). 15 12% 12%

Interleukin 6 inhibition is currently achieved by treatment 10
with tocilizumab, a humanised monoclonal antibody 5
directed at the interleukin 6 receptor; sarilumab 0
(Bridgewater, NJ, USA), a human interleukin 6 receptor MTX-naive MTX-naive MTX-IR Anti-TNF-IR MTX-naive MTX-naive MTX-IR Anti-TNF-IR
inhibitor, has completed phase 3 trials. Interleukin 6 itself FUNCTION OPTION RADIATE IMAGE DANCER REFLEX
is targeted by several monoclonal antibodies, including E F
sirukumab (Janssen, Springhouse, PA, USA), which has 50 Methotrexate monotherapy
completed phase 3 trials (eg, NCT01606761). Abatacept is Tofacitinib (5 mg/kg twice a day)
45 42%
Baricitinib (4 mg/day)
presently the only T-cell co-stimulation inhibitor approved 40
for rheumatoid arthritis; intriguingly its ecacy might
35
result not only from T-cell targeting but also from 29%
30
inhibition of myeloid cell function.128,129 Rituximab is the 24%
25
only B-cell-directed monoclonal antibody approved for the 20% 21%
20
treatment of rheumatoid arthritis, targeting CD20; 15%
17%
15 14%
biosimilars are expected in the near future.
These mechanistically discrete therapies seem to 10
convey similar ecacy.3 Patients who have not previously 5
received methotrexate have the highest ACR70 response 0
MTX-naive MTX-naive MTX-IR Anti-TNF-IR MTX-naive MTX-naive MTX-IR Anti-TNF-IR
rates (a surrogate for achieving low disease activity) with
these therapies. Overall, ACR70 response rates to Oral-START Oral- Oral-STEP RA-BEGIN RA-BUILD RA-BEACON
STANDARD
biological DMARDs in combination with methotrexate
in these patients are around 3040% (gure 5). However, Figure 5: Response to dierent DMARD therapies
embedded within this group of responders are those who (A) Abatacept (inhibition of T-cell co-stimulation). (B) Golimumab (TNF inhibitor). (C) Tocilizumab
(anti-interleukin 6 receptor antibody). (D) Rituximab (anti-CD20 mediated B-cell depletion). (E) Tofacitinib
would experience ecacy with methotrexate alone (pan-JAK inhibitor). (F) Baricitinib (JAK1/2 inhibitor; Eli Lilly, Indianapolis, IN, USA). ACR70 improvement rates as a
(2025%). These data informed the decision of EULAR surrogate for profound treatment responses. Baricitinib is not yet approved by regulatory authorities but has
and, more recently, ACR to recommend starting completed phase 3 trials. For the full list of references, see appendix. DMARD=disease-modifying antirheumatic
treatment with methotrexate.89,90 Importantly, despite drug. MTX=methotrexate. Adapted from Smolen and Aletaha2 by permission of Nature Publishing Group.
dierences in targets, all four major modes of action of
targeted biologics (in combination with methotrexate) that all these drugs might mediate their ecacy by See Online for appendix
have similar response rates, decreasing with increasing interfering with a common nal pathwaynamely,
previous drug experience (gures 4, 5).3,130,131 This suggests proinammatory cytokine production.132

Seminar
All biological DMARDs exhibit enhanced ecacy adalimumab plus methotrexate;146 moreover, the roughly
when combined with methotrexate and presumably 15% ACR70 response rate in patients whose disease had
any other conventional synthetic DMARD, especially previously not responded to or not tolerated a TNF
leunomide.133,134 No biological DMARD used as mono- inhibitor was similar to the response rate in patients
therapy has shown consistent statistically signicant who had not responded to multiple biologics.147
clinical or functional superiority compared with
methotrexate.126,135,136 Progression of structural damage is Tapering therapy
inhibited more strongly with biological monotherapy After the desired treatment target (low disease activity
than with methotrexate monotherapy, albeit to a lesser or remission) has been reached, it should be sustained
extent than with the combination therapies. Also, over time. Maintenance of a good outcome will
combination of biologics with methotrexate has shown normalise or at least maximise physical function,
clinical and functional superiority to biological quality of life, and ability to work. When remission (or a
monotherapy.135138 Moreover, methotrexate (plus gluco- targeted low disease activity) is sustained on biological
corticoids) conveys similar clinical, functional, and DMARDs for some time (usually about 6 months), the
structural ecacy as methotrexate plus biological agent treating clinician should consider tapering therapeutics.
(table 2).115,116 However, if a monotherapy of a biological Glucocorticoid should be reduced and discontinued
DMARD must be given because of intolerance of all within about 6 months, and this should be done rst.
conventional synthetic DMARDs, then tocilizumab For biological therapies, the risk of a are in disease
would be the biologic of choice, since it has better activity after halving dose or doubling the interval
ecacy than TNF inhibitor monotherapy139 and also between doses is low, whereas complete withdrawal
somewhat better ecacy than methotrexate.126,140 often leads most patients to experience a are in disease
Clinical and structural ecacy is similar across all activity; however, the rate of ares decreases with
types of biological DMARDs. This has been shown in increasingly lower disease activity and longer duration
meta-analyses, as well as in head-to-head studies.3,130,141 of sustained response.148150 Importantly, when a are
When a patient does not achieve the treatment target on occurs, patients usually respond very well to re-
a biological DMARD (plus methotrexate), then any other introduction of the same agent. However, more than
biological DMARD or a targeted synthetic DMARD can 10% of the patients do not regain their original good
be used.89 Indeed, even sequential use of TNF-inhibitors outcome and, therefore, subjecting patients to abrupt
after initial lack of response appears to provide similar stopping of biologics and thus risking potentially
outcomes as biologics targeting other molecules, at least permanent deterioration of their status may be regarded
in clinical trials.130,131,142 Of note, in most recommendations as ethically unsound. Therefore, gradual dose
or guidelines, rituximab should be used after other reduction, rather than sudden stopping of biologics,
biologics have failed; however, it is highly eective in should be the norm.
early rheumatoid arthritis143 and is often used as a rst
biologic when others are contraindicated. Adverse event proles
The biological agents and the targeted synthetic
Targeted synthetic DMARDs DMARDs induce more adverse events than do
The rst approved targeted synthetic DMARD is conventional synthetic DMARDs. In particular, the
tofacitinib, a pan-JAK inhibitor; JAK inhibition interferes incidence of serious infections is increased, although it
with signal transduction and thus cell activation elicited decreases over time.5,151 A special risk relates to
by interleukin 6, granulocyte-monocyte colony stimu- reactivation of tuberculosis,127 although this has not been
lating factor, interferons (type I and type II), and reported with rituximab. Rituximab is also the drug of
common -chain cytokines (such as interleukin 2 or choice in patients with concomitant multiple sclerosis,
interleukin 15).144 Tofacitinib has been approved in the because it has shown ecacy in this disease,152 whereas
USA and many other countries, but is not yet approved TNF inhibitors can elicit ares of multiple sclerosis.153
for use within the European Union. The ecacy of Patients with hepatitis B or hepatitis C, whose disease is
tofacitinib plus methotrexate at the approved dose of well controlled with antiviral therapy, can be treated with
5 mg twice a day appears to be similar to that of biologics biologics, but hepatologists should be consulted to
(gure 5). Intriguingly, tofacitinib monotherapy is introduce and monitor antiviral therapy.154 However, the
clinically superior to methotrexate,145 by contrast with introduction of curative treatment for hepatitis C is likely
most biological DMARDs. In phase 3 clinical trials the to eliminate the potential risk for these patients.
JAK 1/2 inhibitor baricitinib, which is not yet approved Biological agents (except rituximab) should be avoided
in any jurisdiction, appears to convey a similar range of within 5 years after malignant disease has been cured,
ecacy as the biological DMARDs and tofacitinib although registry data do not suggest increased risks.155
(gure 5). Interestingly, however, baricitinib plus However, in patients with a history of lymphoma,
methotrexate elicited a superior clinical and functional rituximab or possibly tocilizumab would be drugs
(although not structural) outcome compared with of choice.

Seminar
During pregnancy, the drugs of choice are sulfasalazine

or possibly azathioprine, which is approved for rheumatoid Panel: Potential future therapeutics for rheumatoid arthritis
arthritis although it seems to have little ecacy.4 Biologics
Methotrexate and leunomide are contraindicated.156 The Cytokine inhibitors (human, or humanised; eg, targeting
use of biological therapies in pregnancy is controversial.157,158 interleukin 6, interleukin 21, interferons, granulocyte-
Recent data suggest that use of TNF inhibitors is not monocyte colony stimulating factor or its receptor)
associated with eects on conception or teratogenic risk. CytokineIgG fusion proteins (eg, interleukin 4IgG)
Similar data have been reported for abatacept and Bi-specic antibodies
tocilizumab.159,160 miRNA targeting
Cell-targeting agents (eg, B-cell depletion, co-stimulatory
Open questions, unmet needs, and future blockade)
therapeutics
Despite advances made over the past two decades, many Intracellular signal inhibitors
open issues remain. First, we do not understand how Janus kinase inhibitors (eg, baricitinib [Eli Lilly,
therapies targeting dierent molecules achieve such Indianapolis, IN, USA], lgotinib)
similar ecacies, and we do not even know if profound Brutons tyrosine kinase inhibitors
responses are elicited by these agents in the same, PI3 kinase inhibitors
totally dierent, or overlapping patient populations. Cellular therapies
Second, we cannot predict optimal responses or toxic Tolerogenic dendritic cell transfer
risk for a given treatment; molecular analyses have Stem cell transfer
failed to answer this question,161163 although we rmly T-regulatory-cell activation
believe that predictors to permit precision medicine
approaches in rheumatology will emerge. Third, Miscellaneous approaches
although stringent remission (or at least low disease Toll-like receptor inhibitors
activity) is todays therapeutic goal for rheumatoid PADI4 inhibitors
arthritis, many patients do not reach this target or Epigenetic modiers (eg, histone deacetylase inhibitors)
achieve it but remain dependent on medication, GnRH antagonists
implying that new therapies are still needed. Fourth, Vagus nerve stimulation
many patients lose responsiveness over time, the
reasons for which are not known but might include clinically signicant.164 The lower the disease activity
immunogenicity, or non-adherence. Finally, therapeutics achieved at 6 months, the better the long-term outcome;
are not delivered via a pathogenetically coherent reaching stringent clinical remission within 36 months
protocol that takes account of early dominant halts damage progression independent of the type of
autoimmunity and later damage-related eector therapy used.85,91 Setting a treatment target of low disease
pathways. In this context, early treatment might be activity or remission, following up patients regularly
highly eective at preventing manifestation of using composite disease activity measures (especially
rheumatoid arthritis, but how to detect pre-rheumatoid joint counts) to determine the disease activity status,
arthritis or patients at increased risk is unknown. Future and modulating DMARD therapy rapidly if the targeted
diagnostic approaches and therapeutics must address state has not been achieved within a period of few
these issues. We contend that there is value in studying months lead to better outcomes than routine care.165,166
the mechanisms of therapeutic failurefor example, Adding low-dose glucocorticoids to conventional
interleukin 1, interleukin 12, interleukin 17, inter- synthetic DMARDs maximises clinical, functional, and
leukin 20, interleukin 21, interleukin 23, anti-CD4, anti- structural benet.117,167 In higher-risk patients, using
BAFF, and inhibitors of p38-MAPK and SYK. The panel methotrexate as a rst DMARD and adding a biologic,
shows new therapeutics that are currently being for those who do not attain at least low disease activity
developed on the basis of pathogenic insights and are within 6 months and have high progression risk,
being tested in early trials. The ultimate goal is to optimises benet.168 And nally, if a state of low disease
develop cause-directed, curative therapies, but this will activity or an 80% reduction of disease activity is
not be possible without better understanding of the achieved within 3 months from start of treatment,
causeor causesof rheumatoid arthritis. attainment of the target of low disease activity or
remission at 6 months is highly likely. Rigorous
Conclusions attention to this regimen, coupled with the development
The therapeutic insights presented in this Seminar of further therapeutic options for patients who remain
constitute the basis for recommendations for the unresponsive, should ensure within the next 10 years
management of rheumatoid arthritis (gure 4).89 Early that most patients will achieve cessation of disease
diagnosis and initiation of DMARD therapy are pivotal progression and disability, and retention of high levels
to prevent damage from occurring or becoming of quality of life.

Seminar
Contributors 16 Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis

JSS wrote the rst versions of the introduction, the sections on treatment contributes to biology and drug discovery. Nature 2014; 506: 37681.
strategies, therapies, tapering, adverse events, failed therapies and open 17 Gregersen PK, Silver J, Winchester RJ. The shared epitope
questions, and contributed to all other parts of the manuscript. DA hypothesis: an approach to understanding the molecular genetics of
performed the search and wrote the rst versions of the sections on susceptibility to rheumatoid arthritis. Arthritis Rheum 1987;
epidemiology, dierential diagnosis and assessment, and contributed to all 30: 120513.
other parts of the manuscript. IBM wrote the rst versions of the sections 18 Viatte S, Plant D, Han B, et al. Association of HLA-DRB1 haplotypes
on genetics and pathophysiology, contributed to all other parts of the with rheumatoid arthritis severity, mortality, and treatment
manuscript, and amended language aspects. All authors performed several response. JAMA 2015; 313: 164556.
rounds of amendments and also had a face-to-face meeting to nalise the 19 Lenz TL, Deutsch AJ, Han B, et al. Widespread non-additive and
interaction eects within HLA loci modulate the risk of
manuscript. All authors have seen and approved of the nal text.
autoimmune diseases. Nat Genet 2015; 47: 108590.
Declaration of interests 20 Barra L, Pope J, Bessette L, Haraoui B, Bykerk V. Lack of
JSS has received grants and/or personal fees from Abbvie, Lilly, MSD, seroconversion of rheumatoid factor and anti-cyclic citrullinated
Pzer, Roche, personal fees from Amgen, AstraZeneca, Astro, Celgene, peptide in patients with early inammatory arthritis: a systematic
Chugai, GSK, ILTOO, Janssen, Novartis, Samsung, Sano, UCB, all literature review. Rheumatology (Oxford) 2011; 50: 31116.
outside the submitted work. DA has received personal fees from AbbVie, 21 Nell-Duxneuner V, Machold K, Stamm T, et al.
BMS, and MSD and personal fees from UCB, Janssen, AstraZeneca, Autoantibody proling in patients with very early rheumatoid
Pzer, Medac, Roche, Eli Lilly & Co, all outside the submitted work. arthritis: a follow-up study. Ann Rheum Dis 2010; 69: 16974.
IBM has received grants and/or personal fees from AbbVie, 22 Klein K, Gay S. Epigenetics in rheumatoid arthritis.
AstraZeneca, BMS, Celgene, Crescendo Bioscience, Janssen, MSD, Curr Opin Rheumatol 2015; 27: 7682.
Novartis, Lilly, UCB, Amgen, and Pzer, all outside the submitted work. 23 Liu Y, Aryee MJ, Padyukov L, et al. Epigenome-wide association data
implicate DNA methylation as an intermediary of genetic risk in
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Susceptibility Environmental factors Epigenetic modications Post-translational

Loss of Asymptomatic synovitis Symptomatic arthritis

Figure 2: Pathways to rheumatoid arthritis

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chrondrocytes after their stimulation by cytokines.

messengers recent onset, morning joint stiness, and abnormal

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and the European League Against Rheumatism (EULAR)

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Molecule type Usual dose* Loading dose Comments

Table 3: DMARDs and recommended doses

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previous therapy, autoantibodies (ACPA or RF, especially

ACR70 responders (%)

application (adalimumab, certolizumab pegol, etanercept, C D

approved in Europe and other countries (table 3). 15 12% 12%

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During pregnancy, the drugs of choice are sulfasalazine

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Contributors 16 Okada Y, Wu D, Trynka G, et al. Genetics of rheumatoid arthritis

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