Series
Targeted treatments for rheumatoid arthritis 2
Lancet 2017; 389: 2338–48
See Editorial page 2263
This is the second in a Series of
two papers about targeted
treatments for rheumatoid
arthritis
Department of Rheumatology
and Clinical Immunology,
Charité–University Medicine
Berlin, Berlin, Germany
(Prof G R Burmester MD); and
Division of Rheumatology,
St Joseph’s Hospital, Western
University, London, ON,
Canada (Prof J E Pope MD)
Correspondence to:
Prof Gerd R Burmester,
Department of Rheumatology
and Clinical Immunology,
Charité-University Medicine
Berlin, 10117 Berlin, Germany
gerd.burmester@charite.de
2338
Novel treatment strategies in rheumatoid arthritis
Gerd R Burmester, Janet E Pope
New treatment strategies have substantially changed the course of rheumatoid arthritis. Many patients can achieve
remission if the disease is recognised early and is treated promptly and continuously; however, some individuals do
not respond adequately to treatment. Rapid diagnosis and a treat-to-target approach with tight monitoring and control,
can increase the likelihood of remission in patients with rheumatoid arthritis. In this Series paper, we describe new
insights into the management of rheumatoid arthritis with targeted therapy approaches using classic and novel
medications, and outline the potential effects of precision medicine in this challenging disease. Articles are included
that investigate the treat-to-target approach, which includes adding or de-escalating treatment. Rheumatoid arthritis
treatment is impeded by delayed diagnosis, problematic access to specialists, and difficulties adhering to treat-to-target
principles. Clinical management goals in rheumatoid arthritis include enabling rapid access to optimum diagnosis
and care and the well informed use of multiple treatments approved for this disease.
Introduction resources if conservative treatments, such as drug
Until the 1990s, the diagnosis of rheumatoid arthritis therapy, physical therapy, and non-surgical interventions,
had devastating consequences, which usually led to have failed, but are beyond the scope of this Series.
progressive joint destruction, reduced life expectancy,
early unemployment, and considerable disability.1 Early recognition: the window of opportunity
Treatment included the pyramid approach, which started The onset of rheumatoid arthritis is usually insidious
with bed rest, non-steroidal anti-inflammatory drugs, with patients presenting with only one or a small number
and the addition of effective disease-modifying anti- of swollen joints, morning stiffness, and non-specific
rheumatic drug (DMARD) therapy following disease constitutional symptoms, including fatigue and a flu-like
progression.2 The first paper in this Series,3 outlined the feeling. Joint involvement in early rheumatoid arthritis
pathophysiology of rheumatoid arthritis learned from might be asymmetric and not polyarticular. Only in later
use of biologics and small molecule inhibitors in stages of the disease does the typical symmetric
rheumatoid arthritis, and this paper will focus on novel polyarthritis evolve.4 Thus, the immediate recognition of
treatment concepts that substantially alter the disease rheumatoid arthritis represents a challenge for
course of the condition, including treatment of early physicians, and early referral, ideally to specialised early
disease with classic DMARD medication often in arthritis clinics, is critical to attaining more rapid
combination, and recently introduced drugs. assessment of patients with early-onset signs and
Today, the aim of treatment in any disease state is to symptoms of inflammatory arthritis.5 Early arthritis
achieve remission, or low disease activity if remission is clinics screen patients with recent onset of joint pain
not possible because of long-standing disease or clinically, using laboratory and imaging techniques. The
comorbidities. Treatment should aim to avoid joint 2010 American College of Rheumatology (ACR)/European
damage and disability, as well as systemic manifestations, League Against Rheumatism (EULAR) classification
such as cardiovascular damage, which is best achieved by criteria6 for rheumatoid arthritis were not intended to be
a treat-to-target approach that includes tight disease diagnostic, but nevertheless can help to identify early
control. Non-pharmacological treatments, such as rheumatoid arthritis and have been instrumental for the
physical and occupational therapy, patient counselling inclusion of patients in clinical trials of early disease.6
with regard to lifestyle changes (eg, smoking cessation, Panel 1 outlines important features used to identify
attaining ideal bodyweight, exercise, and drug adherence) patients early. An optimum window of opportunity of
and surgical approaches, are important treatment 3 months (or up to 6 months in some studies) might
exist from the onset of joint swelling, in which, following
treatment, less damage might occur and remission is
Search strategy and selection criteria more likely. Early rheumatoid arthritis trials suggest a
We searched MEDLINE and PubMed for articles published in strong correlation between disease duration and
English from Jan 1, 2000, to May 29, 2017, using the terms achieving remission.7,8 However, this window of
(early) “rheumatoid arthritis” in conjunction with (early) opportunity has not been found in all studies.9
“diagnosis”, “treatment”, “strategies”. Articles were selected In 2016, the EULAR recommendations for management
on the basis of our personal judgment of their relevance of early arthritis10 have been updated to aid the
within the scope of this Series paper. management of undefined but suspected synovitis even
before the diagnosis of definite rheumatoid arthritis or
www.thelancet.com Vol 389 June 10, 2017

another joint disorder. These recommendations suggest
that patients presenting with arthritis (any joint swelling,
associated with pain or stiffness) should be seen by a
rheumatologist within 6 weeks of symptom onset. Risk
factors for persistent or erosive disease should be
assessed, including number of swollen joints, acute
phase reactants, rheumatoid factor, and anti-citrullinated
protein antibody concentration to aid management
decisions. Ultrasound is routinely used in many clinics
to establish whether joints are active (ie, positive power
Doppler signal), but in an early rheumatoid arthritis
trial,11 a treat-to-target strategy using ultrasound guidance
was found to have no added advantage compared with an
approach based on clinical findings alone, whereas in
another study,12 ultrasound provided added benefit.
Patients at risk of persistent arthritis should begin
treatment with DMARDs as soon as possible. Smoking
cessation, dental care, weight control, assessment of
vaccination status, and management of comorbidities
should be a part of overall patient care.
Treatment recommendations
Treating to a target can vary depending on the treatment
goals of the patient and physician and according to which
individualised outcomes can be achieved. The outcome
targets might vary (ie, remission, low disease activity)
and might also include prevention of joint damage,
disability, reduction of mortality, and cardio­ vascular
events.13 In active rheumatoid arthritis, rapid achievement
of tight control of disease activity is required with
frequent assessments of the patient and modification of
treatment until the target is achieved and sustained
(figure 1).
The number of therapeutic resources available for the
treatment of rheumatoid arthritis has grown
tremendously in the past 30 years.14 Currently available
drugs include non-steroidal anti-inflammatory drugs,
glucocorticoids, and DMARDs of synthetic origin
(conventional DMARDs, such as methotrexate or
targeted DMARDs, such as janus kinase [JAK]-inhibitors)
or of biological origin (biological DMARDs, such as
tumour necrosis factor [TNF]-inhibitors, costimulation
modifiers, interleukin-6-inhibitors, and B-cell depleting
drugs).15 To establish treatment algorithms, both the ACR
and EULAR have updated their rheumatoid arthritis
management guidelines and recommendations.16,17
Important similarities exist between these guidelines16
and recommendations,17 including the treat-to-target
approach, the initial use of methotrexate as the anchor
drug in monotherapy with DMARDs rather than
in combination DMARD therapy, and the inclusion
of glucocorticoids as adjunct therapy. The ACR
discriminates between early rheumatoid arthritis and
DMARD-naive established rheumatoid arthritis, whereas
the EULAR has a unified approach that accommodates
both situations. The overarching principles of the EULAR
recommendations17 stress that treatment should aim at
www.thelancet.com Vol 389 June 10, 2017
Series
Panel 1: Early identification of suspected rheumatoid arthritis
• Symptoms persisting more than 2 weeks
• Features that suggest rheumatoid arthritis in recent-onset inflammatory arthritis
• Swollen joints especially in hands (wrists, metacarpalphalangeal joints, proximal
interphalangeals)
• Tenderness across the metatarsophalangeal joints
• Positive rheumatoid factor
• Positive anti-citrullinated protein antibodies
• Elevated inflammatory markers (erythrocyte sedimentation rate, C-reactive protein)
• Number of swollen joints
• Symmetrical pattern (can start asymmetrically)
• Absence of an alternative diagnosis such as erosive osteoarthritis, crystal arthritis
the best care and must be based on a shared decision
between the patient and the rheumatologist, and that
treatment decisions should be made according to disease
activity and patient factors, such as progression of
structural damage, comorbidities, and safety issues.
Furthermore, the individual management recom­
mendations17 state that therapy with DMARDs should be
started as soon as the diagnosis is made, with a target of
sustained remission or low disease activity. Methotrexate
should be part of the first treatment strategy, unless
contraindications (or early intolerance) are observed, in
which case leflunomide or sulfasalazine are alternative
therapies. Short-term glucocorticoids should be
considered when initiating or changing conventional
DMARDs, but should be tapered as rapidly as clinically
feasible. In addition to these recom­mendations, consider­
ation of intra-articular joint injections is also an
adjunctive strategy.17 Rapid treatment, reassessment, and
adjustment of medications to a target of remission is the
goal wherever possible, as patients who achieve
remission early are more likely to have sustained
remission.13,18
If the treatment target is not achieved with the first
conventional DMARD strategy within 3–6 months, in the
absence of poor prognostic factors, other conventional
DMARDs should be considered.17 When poor prognostic
factors are present, addition of a biological DMARD or a
targeted DMARD should be considered. These
un­favourable prognostic factors include the presence of
anti-citrullinated protein antibodies or rheumatoid
factors, high disease activity despite treatment with
methotrexate, early erosions, and an inadequate response
to two previous conventional DMARDs. Generally,
biological DMARDs and targeted DMARDs (eg, JAK
inhibitors) should be combined with a conventional
DMARD (usually methotrexate).17 In patients who cannot
tolerate or have contraindications to methotrexate,
interleukin-6 pathway inhibitors and targeted DMARDs
might have some advantages compared with other
biological DMARDs.19–22 However, a trial21 that compared
baricitinib and methotrexate with baricitinib alone was
done in a population who were methotrexate-naive, not in
2339
 Series

patients with an inadequate response to methotrexate.

A Tofacitinib monotherapy might be less effective than with
Diagnostic procedures Diagnosis established Immediate treatment
methotrexate after methotrexate failure: in the ORAL
Clinical signs Strategy trial,23 tofacitinib monotherapy did not meet
equivalency assumptions compared with the combination
Safety screening
arm of tofacitinib plus methotrexate. Following an
Liver, kidney, blood counts, inadequate response to treatment with a biological
hepatitis B and C serology, evidence DMARD or targeted DMARD, another biological
of lung disease, liver disease, alcohol
use, pregnancy DMARD or a targeted DMARD should be considered; if
Joint swelling one TNF inhibitor therapy has failed, patients might
Laboratory Methotrexate receive another TNF inhibitor or treatment targeting
Acute phase another pathway. Randomised trials24–26 in early
reactants
• Erythrocyte sedimentation rate rheumatoid arthritis have shown that monotherapy with
Rheumatoid
• C-reactive protein
arthritis methotrexate only achieves the target outcome in one of
Autoantibodies
• Rheumatoid
three patients, whereas initial treatment with combination
factors Window of Prednisone DMARDs (eg, triple therapy with methotrexate,
• Anti-citrullinated protein opportunity
• Patient education of about
sulfasalazine, and hydroxychloroquine) increases that to
antibodies
Imaging (if available) • Shared decision 4 months two of three patients reaching target outcomes. Therefore,
• Search for Remission*?
Yes/No the initiation of combination therapy at the start of
comorbidities
treatment is advocated by some clinicians,24 despite
recom­ mendations for initial monotherapy with
methotrexate. This recommendation for initial
Alternative treatments for patients
who are intolerant to methotrexate: conventional DMARD combination therapy is debated
ie, ultrasound, (grey scale, leflunomide, sulfasalazine because the addition of gluco­ corticoids might be the
power doppler)
reason for the greater efficacy observed; a 2015 study
B (CareRA)27 showed no superior efficacy of combination
Treatment strategies: treat-to-target therapy at the start of treatment compared with initial
Monitor comorbidities (ie, cardiovascular, Treatment goals
methotrexate mono­therapy plus glucocorticoids.
osteoporosis) • No inflammation For patients who are in persistent remission after
• No tender or swollen joints treatment with tapered glucocorticoids, tapering
• No radiological progression
• Normal quality of life biological DMARDs might be considered, especially if
• Normal function treatment is combined with a conventional DMARD
• Normal participation in social and occupational activities
• None or lower level of comorbidities (usually methotrexate), and finally if a patient is in
• Normal life expectancy persistent remission, tapering the conventional DMARD
could be considered.17 Generally, in early rheumatoid
Remission*? Continue Add biological DMARD arthritis, predictors that indicate the appropriateness of
Yes or targeted DMARD
tapering biological DMARDs include deep and sustained
remission, male sex, early disease, and negative anti-
Change
conventional
No citrullinated protein antibodies status.28 The goal of
No DMARD lowering medication burden is to maintain remission
strategy
Unfavourable factors • Combination
Remission*? Continue using the lowest dose of medications possible after
Yes
No
(ie, high disease activity, • Switch sustained remission (usually for at least 6 months) has
rheumatoid factors,
anti-citrullinated protein been achieved. Non-steroidal anti-inflammatory drugs
antibodies, early joint Add ** biological Remission*? Continue are often tapered or used only as needed because of their
damage) DMARD or
targeted
Yes potential toxicity.29 Discontinuation of glucocorticoids
Yes
DMARD No should always be attempted because of their side-effect
• Combination profile, and biological DMARDs are reduced in dose or
• Switch
frequency, usually as a result of their high cost. Generally,
Glucocorticoids to treat flares Change biologic or targeted medication-free remission is not sustained: two out of
Oral, parenteral (intramuscular), or intra-articular DMARD strategy three patients who stop all treatment, including
methotrexate, experience flares within a year.30
*Alternative goal (ie, in case of **In patients who are intolerant to methotrexate consider monotherapy Additionally, tapering of biological medications is
comorbidity): low disease activity with interleukin-6 inhibiting treatment or targeted DMARDs considered off-label therapy.

Figure 1: Diagnosis and treatment of rheumatoid arthritis Treatment strategies in early disease
Summary of diagnostic procedures (A) and treatment strategies (B) for rheumatoid arthritis. Several randomised controlled trials31–44 have assessed the
DMARD=disease-modifying anti-rheumatic drug.
efficacy of treatment with biologics in patients with early

2340 www.thelancet.com Vol 389 June 10, 2017

 Series

Combination Biological DMARD or targeted DMARD alone Methotrexate alone

ACR 20
Infliximab37 ASPIRE 54 weeks ACR 50
ACR 70
ACR 20
Tumour necrosis factor-inhibition

Adalimumab38 PREMIER 1 year ACR 50

ACR 70
ACR 20
Etanercept39 COMET 2 years ACR 50
ACR 70
ACR 20
Certolizumab40 C-EARLY 1 year ACR 50
ACR 70
ACR 20
Golimumab41 GO-BEFORE 24 weeks ACR 50
ACR 70
ACR 20
Abatacept42 AGREE 25 weeks ACR 50
Costimulation
modulation

ACR 70
ACR 20
Abatacept43 AVERT* 1 year ACR 50
ACR 70
ACR 20
Tocilizumab35 FUNCTION 24 weeks ACR 50
Interleukin-6-
inhibition

ACR 70
ACR 20
Tocilizumab36 U-ACT 24 weeks ACR 50
ACR 70
ACR 20
depletion
B-cell

Rituximab44 IMAGE 52 weeks ACR 50

ACR 70
ACR 20
Tofacitinib33 ORAL START 1 year ACR 50
Janus kinase-
inhibition

ACR 70
ACR 20
Baricitinib34 RA-BEGIN 24 weeks ACR 50
ACR 70
0 10 20 30 40 50 60 70 80 90 100
Patients (%)

Figure 2: Results of randomised trials of biologics and small molecule JAK inhibitors compared with methotrexate in patients with rheumatoid arthritis who are methotrexate-naive
ACR 20=improvement in disease activity of 20% or more, according to the American College of Rheumatology criteria.45 ACR 50=improvement in disease activity of 50% or more, according to the
American College of Rheumatology criteria. ACR 70=improvement in disease activity of 70% or more, according to the American College of Rheumatology criteria. DMARD=disease-modifying
anti-rheumatic drug. *Major clinical response.43

rheumatoid arthritis who are methotrexate-naive either as
monotherapy or combination therapy with metho­trexate
compared with methotrexate alone (figure 2). These
studies have shown the significant clinical and structural
superior efficacy of the combination therapy versus
monotherapy, with a similar outcome observed when
using the biologic or methotrexate alone, with the
exception of interleukin-6 inhibition or JAK kinase
inhibitors, which have shown superior efficacy in early
rheumatoid arthritis compared with methotrexate
monotherapy.19,20,33–35 Methotrexate alone is known to be
effective in early rheumatoid arthritis,27 and its activity can
be enhanced to reach similar levels as that of combination
therapy with biologics if combined with moderate doses
of glucocorticoids. For example, the OPTIMA trial46
compared initial adalimumab and methotrexate
combination with the addition of adalimumab after 26
weeks of methotrexate monotherapy in patients who did
not achieve low disease activity. Nearly double the number
of patients treated with the initial combination achieved
low disease activity at 26 weeks compared with patients
treated with methotrexate monotherapy, but at week 78
(the primary outcome), the difference in the number of
patients who had achieved low disease activity was not
statistically significant between the two treatment groups.
Thus, this approach does not lead to significantly more
damage if the use of biologics is delayed for only a short
period of time. A meta-analysis47 comparing methotrexate

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Panel 2: Advantages and disadvantages of initial methotrexate treatment versus
initial combination therapy in early rheumatoid arthritis
Advantages
• More patients will achieve rapid remission (2:1)
• Faster remission might result in long-term benefits (ie, less joint damage, higher
chance of reducing therapy in future)
Disadvantages
• More expensive (especially with biological disease-modifying anti-rheumatic drugs)
• Not all patients need combination therapy (possibility of overtreatment, side-effects)
• Little time is lost if frequent reassessments occur and the treat-to-target approach is
used
• More patient acceptance of monotherapy
• More time in the clinic
strategies, which included the addition of etanercept in
early rheumatoid arthritis, showed that in patients who
were methotrexate-naive, triple therapy and methotrexate
with etanercept outcome was not different, but in patients
who did not achieve low disease activity with methotrexate,
adding etanercept had better efficacy than adding
sulfasalazine and hydroxychloroquine for an ACR 70
(defined as an improvement in ACR criteria45 of at least
70% from baseline) response. The HIT HARD trial48 used
an induction strategy that compared methotrexate plus
adalimumab with methotrexate alone for 6 months
followed by discontinuation of adalimumab with
methotrexate monotherapy for a further 6 months.
Although a significantly better treatment response was
observed after 6 months in the combination arm, after
1 year this improved response was no longer evident, but
the radiological outcome was superior in the (initial)
combination arm. A meta-analysis49 suggested that early
treatment of rheumatoid arthritis with methotrexate and
a TNF inhibitor followed by the discontinuation of the
TNF inhibitor, using a so-called induction maintenance
approach, has clinical benefits for patients both during
the combined treatment period and when the TNF
inhibitor was discontinued. Thus, treating early
rheumatoid arthritis with methotrexate and a TNF
inhibitor followed by maintenance with methotrexate
alone might be a reasonable strategy.49 The U-ACT-Early36
trial of early rheumatoid arthritis showed that 84–86% of
patients had a sustained remission with tocilizumab
(anti-interleukin-6 biological DMARD) with or without
methotrexate, compared with 44% in the methotrexate
monotherapy group. Combining TNF inhibitor treatment
with methotrexate as initial therapy resulted in less
radiographic damage after 3 years even if the TNF
inhibitor was discontinued when patients were in a low
disease state.50 Decreasing or stopping treatment with
some rheumatoid arthritis biologics when a patient is in
sustained remission is twice as likely in early rheumatoid
arthritis compared with established rheumatoid arthritis
(one in three patients vs one in six patients).30
2342
With consideration of the high costs of initial treatment
with biologics, and often similar outcomes of using
glucocorticoids or combination targeted DMARDs
instead of biologics, and the good response to
methotrexate alone observed in one of three patients,
how initial treatment with biologics in early rheumatoid
arthritis will evolve is unclear. Ultimately, tight control of
disease activity is paramount. Biomarkers are urgently
needed to rapidly identify patients who might benefit
most from the early use of biologics or a comprehensive
strategy of repeated assessment and treat-to-target
approach. Panel 2 contrasts the advantages and
disadvantages of initial combination therapy in early
rheumatoid arthritis.
Treatment after TNF inhibitor use in early or established
rheumatoid arthritis
Despite the possibility of directly switching from one
TNF inhibitor to another with some efficacy with the
second drug,51 a shift has been observed in patients in
whom conventional DMARDs have not been effective,
from using another TNF inhibitor as a third-line therapy
to drugs that target different pathways. This shift
includes the use of interleukin-6 inhibitors, oral JAK
inhibitors, and abatacept as subsequent treatment
following conventional synthetic DMARD therapy, partly
because of their superior efficacy in head-to-head trials in
monotherapy (JAK inhibitors and interleukin-6
inhibitors) or improved safety profiles (abatacept vs
infliximab and adalimumab).52–54 Patients might prefer a
therapeutic that is administered orally, is effective, and is
well tolerated, which might be the case with JAK kinase
inhibitors.55 Indeed, following TNF inhibitor treatment,
switching from one drug class to another with a different
mechanism of action (eg, B-cell depletion, JAK inhibition,
interleukin-6 inhibition, costimulatory molecule
inhibition) is common. Generally, after TNF inhibitor
treatment, patients will have a blunted response to their
next treatment irrespective of drug class, but the response
or durability might be better if the mechanism of action
is changed.56 After continued inadequate responses to
multiple treatment strategies, few patients have high
responses to new treatment strategies, and a low disease
state might be the target instead of remission.
For patients with established rheumatoid arthritis,
treat-to-target concepts also apply, but after inadequate
response to multiple treatment strategies, or intolerances
or joint damage, remission might not be common;
however, goals for the best possible control should be
individualised.
Recent treatment advances in rheumatoid
arthritis
JAK inhibitors
Many rheumatoid arthritis trials with novel oral small
molecules have been ineffective. The mitogen-activated
protein kinase pathway seemed important in rheumatoid
www.thelancet.com Vol 389 June 10, 2017

arthritis but trials of agents targeting this pathway were
negative.57,58 By contrast, medications that inhibit the JAK
pathways have led to a considerable breakthrough in
rheumatoid arthritis treatment. Although efficacy could
be anticipated because of the numerous cytokines that
use JAK pathways for intracellular signalling, potential
safety concerns arose because knock-out of either JAK1
or JAK2 in rodent models is lethal and a human severe
combined immunodeficiency disease exists in which the
gene for JAK3 is defective.59 Randomised controlled trials
in rheumatoid arthritis have demonstrated both efficacy
and acceptable safety for JAK inhibitors.60
In many countries, such as the USA, Russia, Canada,
and Switzerland, tofacitinib (JAK1/2/3) was the first JAK
inhibitor to be approved. This compound was reassessed
by the European Medicines Agency (EMA) in between
2016 and 2017, resulting in approval of tofacitinib with
methotrexate for patients with moderate to severe active
rheumatoid arthritis who have responded inadequately to,
or who are intolerant to one or more DMARDs and can be
given as monotherapy if metho­trexate is inappropriate or
not tolerated.61 The EMA has approved baricitinib (JAK1/2)
for treatment in patients with moderate to severe active
rheumatoid arthritis with an inadequate response or
intolerance to one or more DMARDs as monotherapy or
in combination with methotrexate.62
Both tofacitinib and baricitinib have been investigated
in extensive clinical trial programmes, in patients
ranging from those with early rheumatoid arthritis who
are methotrexate-naive33,34 to patients with an inadequate
response to conventional DMARDs,34,63 and patients who
do not respond to biological drugs,64,65 most notably TNF
inhibitors. One trial21 was powered to compare baricitinib
and the TNF inhibitor adalimumab in a head-to-head
design, which showed a modest, nevertheless
significantly better efficacy of baricitinib. The ORAL
Strategy trial23 showed that tofacitinib plus methotrexate
was not inferior to adalimumab plus methotrexate.
Monotherapy with the JAK inhibitors (tofacitinib or
baricitinib) was clinically more effective than metho­
trexate in early rheumatoid arthritis, including the
analysis of radiological progression.33,34
Although the 2016 EULAR recommendations17 place
these targeted DMARDs somewhat behind the biologics,
preferred treatment strategies might change with more
clinical experience. The safety signals of the JAK
inhibitors do not differ considerably from biologics with
the exception of increased incidence of herpes zoster
infection, especially with tofacitinib; most notably in
Japanese and Korean patients.66–69 However, patient
preference for oral drugs instead of injectable compounds
and the possibility to use them in monotherapy might
lead to a shift in practice in the future.
Biosimilars
A biosimilar is a biopharmaceutical product that is highly
similar to an approved biological drug with no clinically
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Series
meaningful differences in safety and efficacy compared
with the reference product.70 Multiple biosimilars for the
treatment of rheumatoid arthritis are in clinical
development or have already been approved, including
infliximab and etanercept.71–73 Guidelines for switching
from the innovator product to its biosimilar are being
developed and whether prescriptions could be
interchangeable is being investigated.74,75 The NOR-
SWITCH study76 examined switching from infliximab to
the biosimilar CT-P13 regarding efficacy, safety, and
immunogenicity in patients with Crohn’s disease,
ulcerative colitis, spondyloarthritis, rheumatoid arthritis,
psoriatic arthritis, and chronic plaque psoriasis. The
study showed that switching from infliximab to the
biosimilar was not inferior to continued treatment with
infliximab. The uptake of biosimilars will be determined
by how they are listed in each jurisdiction, where
preferential listing as a result of cost saving might lead to
higher use compared with equal listing with the reference
biological drug.
Prescriptions for biosimilars vary substantially between
countries77 and it seems that the uptake is only high when
a mandatory preferential access to biosimilars exists for
both incident and prevalent users.77 This mandatory
preferential access would include Scandinavian
countries, whereas in the USA and Canada, the uptake of
biosimilars has been poor because generally, switching
does not seem to be advocated. The Canadian
Rheumatology Association has released an updated
position statement78 that does not endorse inter­
changeability between the innovator drug and the
biosimilar unless prescribed by the physician, but use of
a biosimilar might be considered if an individual is naive
to the specific molecule. Unique identification of each
biosimilar is important in order to identify any potential
issues.78 A number of factors will be central to the uptake
of biosimilar biological DMARDs. These factors include
competitive prices, lower costs of production, incentives
for switching, and strong management support,
particularly during the early phase of biosimilar adoption
when physician resistance might be an important factor.
Safety of rheumatoid arthritis treatment
Traditional DMARDs have well known side-effects,
including cytopenia, transaminase elevation, poor
tolerability (fatigue, nausea, and central nervous system
side-effects), rash, and, rarely, interstitial lung disease or
liver damage. The side-effects of glucocorticoids and
non-steroidal anti-inflammatory drugs have been
described previously.79–81 Biologics might lead to more
infections (common and atypical), elevations of
cholesterol, and rarely cytopenia, transaminase elevation,
multiple sclerosis type conditions, psoriasis, other
autoimmune conditions, bowel perforation, and
worsening congestive heart failure.82 In patients with
early rheumatoid arthritis, infection was not different in
patients who were naive to methotraxate randomised to
2343
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methotrexate or TNF inhibitor.58 Although a single meta-
analysis83 reported a higher incidence of malignancies in
patients with rheumatoid arthritis treated with
adalimumab or infliximab in randomised controlled
trials, registries that include more than 1000 patients
showed no evidence of a higher incidence of
malignancies, but the incidence of infection was about
two times higher in biologic users than in patients
treated with conventional DMARDs.84,85 JAK inhibitors
might cause gastrointestinal side-effects, cytopenia
(lymphopenia or neutropenia), elevated cholesterol, and
more infections (especially viral infections such as
herpes zoster67,68).
Combination treatment of methotrexate with biologics
in patients with an inadequate response to
methotrexate
Patients who use biologics with methotrexate might have
better responses and durability of treatment than patients
who use biologics alone, but approximately one-third of
patients in biologic registries are not receiving
methotrexate with their biologic.86 Generally, when using
TNF inhibitors in patients with rheumatoid arthritis after
inadequate response to methotrexate alone, combination
therapy with methotrexate is superior to TNF inhibitor
monotherapy, but in some patients who are in a low
disease state, monotherapy might be a reasonable
option.87 Whether tocilizumab is sufficient as
monotherapy remains debated. A 2016 meta-analysis
showed a slight advantage of tocilizumab in combination
with methotrexate compared with tocilizumab
monotherapy in patients who did not respond to
methotrexate monotherapy.88 In patients with early
rheumatoid arthritis who were methotrexate-naive,
clinical outcomes did not differ between those treated
with baricitinib alone and baricitinib and methotrexate,
and patients treated with combination therapy had only a
small advantage with regard to radiographic changes.34
Currently, no biomarkers are available that indicate
which patients would benefit from continuation of
concomitant methrotrexate treatment, which patients
would benefit from cessation, or which patients would
not relapse following cessation of treatment with
conventional DMARDs. The order of treatment following
methotrexate monotherapy varies: some clinicians
recommend the addition of more DMARDs, whereas
others would prescribe a TNF inhibitor, oral JAK
inhibitors, or even rituximab, which is not approved as a
first biologic therapy but might be more cost-effective
than TNF inhibitor treatment.89
Prevention of rheumatoid arthritis
The concept of pre-rheumatoid arthritis has evolved.90
This concept can be applied to patients who do not meet
criteria for rheumatoid arthritis but have features, such as
some swollen joints, or others who are anti-citrullinated
protein antibodies positive and have arthralgia. Patients
2344
with undifferentiated inflammatory arthritis who do not
meet criteria for rheumatoid arthritis6 have been studied
in trials comparing treatment with no treatment to
prevent the onset of rheumatoid arthritis, using an
arbitrary definition of rheumatoid arthritis. Some
medications such as methotrexate, intra-articular
steroids, sulfasalazine, infliximab, etanercept, abata­cept,
and rituximab might delay or even prevent rheumatoid
arthritis onset,91–97 whereas intramuscular corticosteroids
do not prevent rheumatoid arthritis and when treatment
is stopped, the advantage seems to wane.98–100 At present,
no obvious treatment is available to prevent rheumatoid
arthritis in high-risk individuals. Patients who are positive
for anti-citrullinated protein antibodies who do not have
clinical synovitis are more likely to develop rheumatoid
arthritis if they have abnormal power doppler on
ultrasound of joints.101 People who are positive for anti-
citrullinated protein antibodies with an elevated body-
mass index are more likely to develop rheumatoid
arthritis.102 Whether altering lifestyle factors (eg, smoking)
and attaining a healthy body-mass index might prevent
rheumatoid arthritis in individuals who are anti-
citrullinated protein antibody positive remains unclear.
This field of research is evolving rapidly and a 2016
review103 discusses risk factor modification and potential
prevention of rheumatoid arthritis.
Comorbidities and mortality
Patients with rheumatoid arthritis (both established and
early) have a higher burden of cardiovascular disease and
cardiovascular risk factors such as hypertension,
diabetes, obesity, hyperlipidaemia, and smoking.104,105 The
incidence of infections and lymphoproliferative cancers
are increased in patients with rheumatoid arthritis
compared with the general population.106 Patients with
the disease also have a higher incidence of lung disease
(obstructive and restrictive) and are more likely to have a
depressed mood.104,105 Other autoimmune diseases are
more common in patients with rheumatoid arthritis
such as hypo­thyroidism and hyperthyroidism.106 Recom­­­
mendations for identification and treatment of
comorbidities have been published.107 The presence of
comorbidities might change the approach to treatment
because rapid tight control of rheumatoid arthritis might
be more important; however, in other circumstances,
safety concerns might arise when treating patients with
multiple comorbidities. Some comorbidities such as
smoking and obesity decrease the chance of remission.108
When DMARDs or biologics are avoided, often
glucocorticoids are used, which have increased infection
and cardiovascular risks compared with other treatment
options.108–110 Control of inflammation in rheumatoid
arthritis might decrease cardiovascular events.111 The
cardiovascular safety profiles of etanercept and
tocilizumab were not significantly different in patients
with active rheumatoid arthritis with cardiovascular risk
factors who did not respond to conventional DMARDs.112
www.thelancet.com Vol 389 June 10, 2017

Mortality in rheumatoid arthritis seems to be
decreasing over time, especially in patients with
controlled inflam­ mation; however, patients with
rheumatoid arthritis with persistent disease activity seem
to have increased mortality compared with age-matched
and sex-matched controls in the general population.113,114
Conclusion and perspectives
Several strategies and accompanying recommendations
can facilitate optimal care for patients with rheumatoid
arthritis with a better prognosis than that observed
historically. The most important aspects of rheumatoid
arthritis management are the early diagnosis of patients,
prompt initiation of DMARD therapy, and regularly
assessing patients to achieve a target of remission or low
disease state. This management strategy will result in
favourable outcomes for most patients.
Contributors
Both authors wrote the manuscript and performed the literature
research. The authors had an initial face-to-face meeting and amended
the manuscript several times. Both authors approved the final text.
Declaration of interests
GRB reports grants and personal fees from AbbVie, Bristol-Myers
Squibb, Pfizer, Roche, and UCB; and personal fees from MSD and
AstraZeneca. JEP has received consulting fees for AbbVie, Actelion,
Amgen, Bayer, Bristol-Myers Squibb, Celgene, Genzyme,
GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche,
Regeneron, Sanofi, UCB; and reports research grants from AbbVie,
Actelion, Amgen, Bayer, Bristol-Myers Squibb, Genentech, Merck,
Pfizer, Roche, Regeneron, and UCB.
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