1. health and fitness
2. disease

Autoimmunity Reviews 10 (2011) 707–713
Contents lists available at ScienceDirect
Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev
Review
Rheumatoid arthritis: What is refractory disease and how to manage it?
Joaquim Polido-Pereira, Elsa Vieira-Sousa, João Eurico Fonseca ⁎
Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
Rheumatology Department, Centro Hospitalar de Lisboa Norte, EPE, Hospital de Santa Maria, Lisbon, Portugal
a r t i c l e
i n f o
Available online 5 May 2011
Keywords:
Refractory disease
Remission
Treatment strategies
Rheumatoid arthritis
a b s t r a c t
Despite the enthusiastic progresses in the field of rheumatoid arthritis pharmacotherapy the presence of
prognostic factors associated with an unfavorable outcome and the inappropriate and/or delayed initiation of
DMARDs can diminish the likelihood of achieving remission and increase the probability of refractoriness to
treatment.
During the last decade we have experience exciting developments regarding the approval of new treatment
options but few patients are reaching sustained remission and refractory patients continue to be a problem.
Thus, it is critical to understand how clinicians can decrease the risk of refractoriness by close monitoring
disease activity, using well defined and accepted composite measures, and by early and optimized use of
DMARDs, including biologics.
The goal of this review paper is to offer an evidence based roadmap to prevent and to deal with refractory RA.
Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . .
2.
The ever changing concept of early disease . . . . . . . . . .
3.
New rheumatoid arthritis classification criteria . . . . . . . .
4.
What is refractory rheumatoid arthritis? . . . . . . . . . . .
5.
Response criteria . . . . . . . . . . . . . . . . . . . . . .
6.
Treating a moving target . . . . . . . . . . . . . . . . . . .
7.
Mitigating refractoriness: early and optimal use of DMARDs . .
8.
Refractoriness to synthetic DMARDs. What to do next? . . . .
9.
Refractoriness to TNF inhibitors. What to do next? . . . . . .
10.
Could biologics used as a first line therapy reduce refractoriness
11.
Refractoriness to approved therapies. What to do next? . . . .
12.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . .
Take-home messages . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
Rheumatoid arthritis (RA) is still an incurable disease, but if
patients are early diagnosed and adequately treated an increasing
number of affected individuals are able to achieve a state where only
⁎ Corresponding author at: Rheumatology Research Unit, Instituto de Medicina
Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
Tel.: + 351 969049532; fax: + 351 217999412.
E-mail address: jefonseca@netcabo.pt (J.E. Fonseca).
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mild or no symptoms persist, which, depending on the defined criteria
might be classified as remission [1]. However, the presence of some
disease characteristics associated with a worse prognosis and/or
inappropriate and/or delayed treatment of this disease, leads to
refractoriness to treatment and to progressive joint destruction,
functional impairment and increased mortality. To decrease the risk of
refractoriness it is crucial to early diagnose RA patients, monitor
tightly with appropriate tools disease activity, identify those who
have the worse prognosis and select the adequate treatment strategy.
The goal of this review paper is to offer an evidence based roadmap to
prevent and to deal with refractory RA.
1568-9972/$ – see front matter. Crown Copyright © 2011 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2011.04.023
708
J. Polido-Pereira et al. / Autoimmunity Reviews 10 (2011) 707–713
2. The ever changing concept of early disease
Back in the 1980s, the concept of early RA included disease duration
of up to 5 years and the management strategy was based on the
pyramid concept. Only patients with severe disease and joint
destruction received effective disease modifying antirheumatic drugs
(DMARDs) and this was due to the fact that RA was mostly viewed as a
mild chronic disease, with joint damage and disability occurring very
slowly and late in the disease course. With the increasing evidence of
the efficacy of early RA treatment and the advent of the “window of
opportunity” concept, this paradigm changed, and in the 1990s the
early RA definition evolved into maximum disease duration of 12 to
24 months [2]. In fact, if left improperly treated, most of these patients
develop significant joint damage during this period of time [3]. More
recently, this critical early period has been progressively reduced to
few weeks, as there is increasing evidence that very early patients
(within the first 6–12 weeks) may have a distinct immunopathogenic
process and that they will benefit from earlier intervention [4–8].
3. New rheumatoid arthritis classification criteria
According to the 1987 American College of Rheumatology (ACR)
RA classification criteria, revised by Arnett et al., there has to be at
least 4 out of 7 criteria to establish the diagnosis of RA [9]. Two of
these seven criteria are related with damage and, in early disease,
rheumatoid factor (RF) is frequently negative. Thus, it is not surprising
that these criteria do not perform well in early disease. A systematic
review of the literature showed that sensitivity and specificity of the
1987 ACR criteria in early RA were 77% (68% to 84%) and 77% (68% to
84%) respectively [10,11]. Taking into account the relevance of early
diagnosis, new classification criteria for RA had to be developed. This
was clearly an unmet medical need as many arthritis patients that
were not fulfilling the 1987 criteria were in fact early RA cases and this
misclassification could be hindering effective therapy and was surely
affecting the way epidemiological studies and clinical trials were
being designed and interpreted [12,13]. A major collaborative effort
between the ACR and the European League Against Rheumatism
(EULAR) was settled and this seminal paper was recently published,
emphasizing a major issue in early arthritis management which is to
probabilistically decide whether or not we are facing a persistent
form of arthritis that will likely benefit from immediate methotrexate
(MTX) treatment. These new diagnostic criteria are a score based
algorithm that take into account joint involvement (2–10 large joints
score 1; 1–3 small joints score 2; 4–10 small joint score 3; more than
10 joints, including at least 1 small joint, score 5), serology (RF or anticitrullinated peptide antibodies (ACPA) in low titer score 2; RF or
ACPA in high titer score 3), acute phase reactants (abnormal
erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
score 1) and symptom duration (more than 6 weeks score 1). The
scoring system allows a relatively objective way of classifying a
patient as having RA (≥6 points), with potential relevant impact on
clinical practice and research [14].
4. What is refractory rheumatoid arthritis?
Refractory RA is an elusive and moving concept. The definition of
refractory disease is dependent on the ability to delineate predetermined quantitative targets in well defined variables. In the case of RA it
is relatively easy to identify the clinical and laboratorial manifestations
of inflammation (disease activity) as our primary target. Closely monitoring of disease activity and changing treatment according to
predefined targets leads to better disease control, less damage and
disability, as is demonstrated in both the TICORA and BeSt trials [15,16].
Assessment of disease activity is critical to set predetermined targets.
Evaluation of RA clinical activity by an experienced clinician is quite
intuitive. However, in order to adequately monitor patients, quantita-
tive joint evaluation is fundamental. Performing 66 swelling and 68
tenderness joint counts can be difficult to implement in routine clinical
practice. The 28 joint count performs well in most patients and clearly it
works adequately at a group level, even though, by excluding feet, it
might be inappropriate to some individual patients [17]. A good
practical compromise can be to persistently verify the 28 joints and
carefully register other positive joint findings not included in this count.
On top of this, markers of inflammatory activity and the symptoms
reported by the patients are also relevant aspects for the global
assessment of disease activity. In fact, this has been tried to be captured
by composite measures of RA disease activity. Two composite measures
are extensively studied and validated: the EULAR Disease Activity Score
(DAS) and the ACR Core Data Set. The use of composite measures usually
partially overcomes the problem of the heterogeneity of RA clinical and
laboratorial manifestations. In fact, there are patients that have normal
ESR and still maintain painful and swollen joints and develop erosions;
others have essentially high ESR and/or CRP and scarce clinical
manifestations but have a radiologic progression that is equally severe.
Composite measures have been shown to have a closer relationship
with radiographic progression than single measures. Besides, composite
measures diminish the sample size needed in clinical trials to detect
significant differences between groups [18].
The ACR Core Data Set includes three visual analogue scales (VAS)
for the physician and patient global assessment of disease activity and
for patient perception of pain, two joint counts (number of tender and
swollen joint counts), one laboratory measure (CRP or ESR), a measure
of function (usually the Health Assessment Questionnaire, HAQ), as
well as a yearly measure of radiological damage [19]. Nevertheless, the
ACR Core Data Set fails to numerically quantify disease activity. The
DAS score was developed to meet this requirement. It is based on a
mathematical formula that computes four variables: the Ritchie
articular index, the 44 swollen joint count, ESR and VAS for patient
global assessment of wellbeing, which can be used interchangeably
with VAS for disease activity. In the absence of the VAS a three item
DAS (DAS3 variables) can be calculated [18]. Later on a DAS28 was
developed using the 28 joint count for both tenderness and swelling,
simplifying the joint count [17]. Levels of DAS28 are somewhat higher
than DAS values and this is reflected in the way results have to be
clinically interpreted, as is the case of the definition of low disease
activity and remission. Only the DAS28 CRP has been compared with
the DAS28 using ESR. Some studies show equivalence between these
two scores whereas others do not [20–22]. Other simplified scores
were developed, such as the simplified disease activity index (SDAI)
and the clinical disease activity index (CDAI). Despite being less used,
the SDAI offers a very simplified approach (defined as the simple sum
of the tender joint count (using 28 joints), swollen joint count (using
28 joints), patient global assessment (0–10 scale), physician global
assessment (0–10 scale), and C-reactive protein level (mg/dl)) and
was included in the new remission criteria recently published [23,24].
5. Response criteria
Both EULAR and ACR developed response criteria. The ACR response
criteria are based on the previously reviewed core set. ACR 20, 50 or 70
stands for the percentage of improvement in this core set. A response (at
least 20, 50 or 70% improvement) must be observed on both joint
counts, and at least in three out of the remaining five variables. The
EULAR response criteria are based on the DAS or DAS28 and take into
account both the variation and the absolute value. This response can be
classified as “no response”, “moderate response” or “good response”
[19,25]. A DAS28 “no response” corresponds to an improvement of ≤0.6
or, for those with an endpoint DAS28 N5.1, an improvement of ≤1.2. A
“moderate response” is defined as an improvement of N0.6 and ≤1.2
with an endpoint DAS28 ≤5.1 or an improvement of N1.2 with an
endpoint DAS28 of N3.2. A “good response” is reserved for patients
attaining a DAS28 of ≤3.2 and an improvement of N1.2. Additionally,
J. Polido-Pereira et al. / Autoimmunity Reviews 10 (2011) 707–713
DAS28 can classify patients in disease activity classes: remission (≤2.6),
low activity (N2.6 and ≤3.2), moderate activity (N3.2 and b5.1) and
high activity (≥5.1).
709
To define the concept of refractory a target has to be determined.
More than 60 experts from various regions of the world developed
recommendations for achieving optimal therapeutic outcomes in RA
in the Treat to Target Initiative. These recommendations assumed that
the main goal to achieve in RA is remission, being a low disease
activity state an alternative aim for those who failed to reach that
major goal. Regular follow up, every 1–3 months, for disease activity
above the target, and 3–6 months, if patients have already reached the
target, was defined as the best clinical practice (Fig. 1) [26]. According
to this initiative, refractory disease could be defined as the failure to
achieve the predetermined target. The Treat to Target recommendations did not purpose a specific composite measure of disease activity.
Applying the most widely used composite measure (DAS28) in this
setting would mean that the ideal target to reach is a DAS28 ≤2.6
and, for those who cannot achieve it, the goal would be to keep a
DAS28 ≤3.2. Remission could be delineated with more stringed
criteria, based on the recently published definition of remission in RA
proposed by ACR and EULAR: ≤ 1 tender joint, ≤1 swollen joint, CRP
≤1 mg/dl and patient global assessment ≤1 (0 to 10). Alternatively a
SDAI ≤3.3 can also classify a remission state [24].
Currently, there are no biological markers to define refractory
disease, since the concept itself is yet to be clearly defined in clinical
terms. Nevertheless, recent EULAR recommendations on the management of RA state the importance of prognostic markers in treatment decisions. Several factors seem to independently predict worse
outcome: autoantibodies (high levels of rheumatoid factor (RF)
and/or anti-citrullinated peptides antibodies (ACPA)), high disease
activity as measured by composite indices and early occurrence of
erosions. All these factors were included in the creation of a prediction
model. Still, this does not define per se refractory disease, but only
an increased risk of developing refractory RA [27,28]. In addition,
other factors can play a role in the refractoriness of RA in individual
patients, such as genetic variability affecting DMARDs metabolism
and influencing the relevance of pathogenic pathways not targeted by
the available DMARDs.
Delaying the start of treatment can lead to worse outcomes and might
reduce the likelihood of inducing remission or of attaining low disease
activity and increases the risk of refractoriness [29,30]. Indeed, the
first 3–6 months of disease in early RA patients are crucial regarding
joint damage, since around 50% of patients develop erosions during
the first year of disease course and 90% after the second year after
diagnosis [31,32]. Tight monitoring of disease activity, minimum
every 3 months, assessed by validated instruments and followed
by frequent treatment adjustments are also determinant factors to
achieve better outcomes as recently reviewed [33]. Strategies based in
treatment to target and intensive monitoring regimes such as the ones
used in the TICORA, Fransen et al., and the CAMERA studies were
clearly better than treatment decisions according to clinical judgment
and routine care follow-up [15,34,35].
Due to its good safety profile and efficacy both as monotherapy as
well as potentiating the effect of other DMARDs, MTX is nowadays
considered the preferred synthetic drug to be initiated at diagnosis of
RA patients. MTX should be started at a weekly dose of 10 to 15 mg
and increased by adding 5 mg every four weeks up to a dose of 25 mg
(rarely 30 mg), according to tolerability and efficacy. Age, comorbidities and concomitant medications can influence the rate of dose
increment and limit the maximum used dose. In refractory patients in
whom malabsorption is suspected or a dose limit has been determined by gastrointestinal intolerance, changing to parental route
should be tried [36].
Other synthetic DMARDs such as leflunomide and sulphasalazine
are generally placed as alternatives to MTX monotherapy in case of
intolerance or contraindications, while cyclosporine and gold have
limited use mainly due to adverse effects. Antimalarial drugs even if
able to lead to some improvement of disease manifestations are weak
inhibitors of joint damage and should be used as monotherapy only in
exceptionally mild cases, associated with intolerance to other
conventional DMARDs [28].
Glucocorticoids have an unquestionable role as an adjuvant therapy to DMARDs, used ideally for short periods of time to reduce
inflammation, as a bridging therapy at diagnosis or in refractory
patients between switches, particularly when the next treatment
option has a delayed onset of action. Additionally glucocorticoids have
showed to slow radiographic progression and are therefore qualified
as DMARDs [37]. For highly refractory patients continuous low dose
glucocorticoids, in association with other DMARDs, can be considered.
7. Mitigating refractoriness: early and optimal use of DMARDs
8. Refractoriness to synthetic DMARDs. What to do next?
Treating patients early and with the best recognized regimes of
synthetic DMARDs are important factors to mitigate refractoriness.
Synthetic DMARDs should be started in all patients upon diagnosis to
reduce disease activity, control joint damage and prevent disability.
Although combining synthetic DMARDs in patients who do not
respond to monotherapy has additional benefits demonstrated in
some clinical trials, in daily clinical practice the effective response rate
is limited by adverse effects and low compliance. Clearly the SWEFOT
trial has helped us to understand that in early arthritis patients, the
combination of MTX and infliximab is superior to the addition of SSZ
and HCQ [38]. For this reason it is recommended by EULAR task force,
that if predictors of poor outcome are present (RF, ACPA, high disease
activity, early erosions), and patients are refractory to the first synthetic DMARD they should be started on a biologic DMARD [28].
Otherwise, in the absence of severity prognostic factors switching to
another synthetic DMARD (or even to a combination of synthetic
DMARDs) might be considered.
At the moment there are nine biologic therapies approved for RA
treatment, targeting specific components of the immune system pathways, which were developed in a bench to bedside approach. All TNF
inhibitors (infliximab, adalimumab, etanercept, golimumab and
certolizumab) as well as abatacept and tocilizumab are approved by
Food and Drugs Administration (FDA) and European Medicine Agency
(EMEA) for use in DMARDs refractory patients (including MTX).
Rituximab at the moment is only approved after TNF inhibitors (TNFi)
failure, although efficacy similar to abatacept and tocilizumab has been
6. Treating a moving target
Fig. 1. Optimal management of RA [26].
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shown in DMARDs failures. Anakinra, also approved for RA treatment,
is less efficacious than the other biologics and its use is therefore
reserved for selected cases, particularly in the setting of autoinflammatory diseases [39].
The fact that TNFi were the first biologics to be approved and have
been used in clinical practice for the last 10 year has allowed the
gathering of solid data on efficacy and safety. This has contributed to
the positioning of TNFi as the first biologics to be started after
DMARDs failure [28]. However it is expected that, as biomarkers of
response to therapy become more specific and reliable, namely at the
individual level, biologic DMARDs will be selected through a more
personalized approach.
Cytokine blocking agents targeting TNF such as infliximab,
etanercept, adalimumab and more recently certolizumab and golimumab have clearly revolutionized the way moderate to severe RA is
treated. Different TNFi exhibit similar efficacy, with an ACR20, ACR50
and ACR70 response attained, respectively, by around 60%, 40% and
20% of the exposed patients [40]. It is well recognized from large
clinical trials that TNFi optimal effect is obtained if they are used in
combination with MTX. It is also possible that leflunomide can
similarly work synergistically but further studies are required [41,42].
Concomitant use of MTX reduces human anti-chimeric antibodies
(HACA) and human anti-human antibodies (HAHA) production,
minimizing immunogenicity and acute infusion reactions. Moreover,
secondary failure to anti-TNF monoclonal antibodies, which is known
to be at least in part dependent on the production of HACAs or HAHAs,
can be diminished by adding MTX [43]. When initial suboptimal
response or a secondary failure occurs during the use of infliximab
increasing the dose (up to 10 mg/kg, but more commonly up to
5 mg/kg) and/or shortening the administrations interval (up to every
4 weeks, but more commonly up to 6 weeks) can help to overcome
lack of efficacy in some cases and by this way, reduce refractoriness to
infliximab [44].
Datasets from registries (e.g., British Society for Rheumatology
Registry, Swedish Registry, German Registry) have highlighted a small
but increased risk of serious infections in comparison with synthetic
DMARDs which seem to be higher in the first 6 months of therapy.
Furthermore patients are more prone to intracellular bacterial
infections such as those caused by Mycobacterium tuberculosis and
this risk is higher in antibody treated patients than in etanercept
exposed individuals [45]. The implementation of preventing strategies has reduced the incidence of latent tuberculosis [46]. Other
preventive strategies like influenza and pneumococcal vaccination,
careful review of dental hygiene, early diagnosis and treatment of
respiratory, urinary tract and skin infections can also contribute to a
safer use of TNFi. All these prophylactic measures can lead to a higher
TNFi retention rate and thus to a decrease in treatment refractoriness.
Recently, two new TNFi, golimumab and certolizumab, have
became available [47,48]. Both were developed based on strategies
aiming at reducing immunogenicity. Golimumab was created upon
human TNF immunization of transgenic mice expressing human
immunoglobulins, being so a fully human monoclonal antibody.
Certolizumab is a humanized antibody without the Fc fragment,
which was substituted by a pegylated tail. Golimumab in association
with MTX is efficacious in MTX inadequate responders, TNFi failures
and MTX naïve patients. In phase III studies golimumab 100 mg was
not superior to 50 mg subcutaneous, neither golimumab monotherapy 100 mg was superior to MTX alone, leading to a final approved
regime of 50 mg subcutaneous once a month [49–52]. Certolizumab
has showed efficacy in MTX (RAPID1 and RAPID2) and in DMARDs
(FAST-4WARD) refractory patients [53–55]. Certolizumab has a quick
onset of action and should be administrated according to an induction
regime of 400 mg at 0, 2 and 4 weeks and 200 mg every two weeks
thereafter.
The addition to RA therapeutic armamentarium of two new
potentially less immunogenic TNFi holds the promise of improving
the chances of response at the individual level, contributing to minimize refractory cases in clinical practice.
9. Refractoriness to TNF inhibitors. What to do next?
The percentage of patients for whom the first TNFi is inefficient
(primary failure) has been estimated to be around 1/3 of the patients
[56]. Furthermore, a significant percentage of patients will also lose
efficacy latter on (secondary failure). For both these subgroups of
patients different treatment options are now available, including
switching to an alternative TNFi or changing to an agent with a different
mechanism of action.
Switching to another TNFi is supported by arguments related to
pharmacology, disease mechanisms and immunogenicity. First of all,
TNFi differ in their half-lives and affinities and this might be translated
into a different duration of TNF neutralization, leading to different
response patterns in individual patients. In addition, in spite of similar
efficacy in RA and Spondyloarthritis the differences in the mechanism
of action between monoclonal antibodies and the TNF receptor fusion
protein is reflected, for instance, in a low effect of etanercept in Crohn's
Disease and in other granulomatosis diseases, and this might be relevant in some nonresponding patients, given the individual heterogeneity of RA physiopathology. Finally, the appearance of neutralizing
antibodies against monoclonal antibodies in nonresponding patients
might be an extra argument for switching.
Therefore lost of efficacy to a TNFi can potentially be recaptured by
switching to another TNFi. The response to a second TNFi has been
reported to be slightly lower in comparison to TNFi naïve patients but
it is clearly reduced with further switches [57]. Additionally, the reason
for switch might also influence the outcome, with discontinuation due
to adverse events and due to secondary failure being predictors of
better response to a second TNFi than when the switch is made after a
primary failure [57,58]. These data suggest that switching to a second
TNFi can be considered, with the possible exception of primary
failures. However, switching to another biologic with a different
mechanism of action is clearly advisable if a second response failure
occurs.
Our armamentarium and experience with the use of other biologics
has markedly increased in recent years. Specifically, rituximab,
tocilizumab and abatacept have proven their efficacy in anti-TNF
refractory patients in large randomized clinical trials (RCT) [59–62].
The rational for the use of rituximab in the treatment of RA is based
in the ability to reduce autoreactive antibodies synthesis, such as RF
and ACPA, and impair antigen presentation to T cells, as well as
cytokine production. Patients with inadequate response to TNFi can
benefit from initiating B cell depleting therapies namely rituximab.
Finckh et al. in a longitudinal cohort study have shown that the
improvement of DAS28 score was better in patients that received
rituximab after the failure of one TNFi than those who were switched
to another TNFi [63]. When the reason for switching was considered
in a later study it was demonstrated that the magnitude of DAS28
improvement between groups was higher in those who switched due
to inefficacy of the TNFi comparing to those who changed due to other
reasons [63,64]. Well known predictors of response to rituximab (RF
and/or ACPA+) have to be taken into account in the selection of
patients, even if a few patients who are not positive for RF or ACPA
might also respond favorably [65]. Furthermore, experience with the
use of rituximab has showed that retreatment might potentiate
efficacy in responders and secondary lost of response is generally rare
[66,67]. However, for primary failures to RTX, switching to a biologic
DMARD targeting other immunologic pathways should be preferred.
At the moment, retreatment using a “treat to target” strategy instead
of an on-demand regime seems to be more effective but longer
follow-ups are needed to clarify this issue and the possible requirements for a fixed schedule are being evaluated [68].
J. Polido-Pereira et al. / Autoimmunity Reviews 10 (2011) 707–713
Encouraging data from five phase III RCT lead to the approval of
tocilizumab both in the US (TNFi failures) and in Europe (DMARDs and
TNFi failures). Blocking the effect of the pleiotropic IL6 cytokine in RA
patients is translated into similar efficacy to TNFi, regarding disease
activity and radiographic progression and clear superiority to MTX [69].
The possibility of using tocilizumab as monotherapy in patients that are
refractory or intolerant to MTX is a distinctive feature of this drug.
Abatacept is a soluble recombinant fully human protein comprises the
extracellular domain of CTLA4 and the Fc portion of an IgG1 molecule that
has been modified to prevent complement activation. The principle of its
use in RA is dependent on the induction of T cell anergy by blocking the
second signal between CD28 and CD80/86 necessary for T cell activation.
Based in data from in vivo experiments it is assumed that abatacept
develops its action by decreasing T cell activation, migration and secretion
of cytokines [70]. Particularly, abatacept is able to reduce progression to
RA in a subgroup of patients with undifferentiated/early rheumatoid
arthritis, highlighting its efficacy in early treatment [71].
Despite the increased number of biologics available, until now
there is not enough evidence that would help clinicians to position
non-TNFi biologics according to disease phenotypes or to helpful
specific biomarkers. Therefore, clinicians are still basing their decisions
on personal experience and on the safety profile of each biologic drug.
10. Could biologics used as a first line therapy reduce
refractoriness in rheumatoid arthritis?
The question if using biologic DMARDs as first line therapy early in the
disease course could reduce refractoriness is still not clearly answered.
Early intervention with biologic agents seems to offer a significant
advantage in the magnitude of their benefits. TNFi including infliximab
(ASPIRE), etanercept (COMET), adalimumab (PREMIER), and golimumab
(Go-Before) have proved that when used in early disease in MTX naïve
patients they were superior to MTX in monotherapy, particularly in their
capacity to arrest radiographic progression [49,72–74]. Similar results
would be expected if certolizumab had been tested in this same
population. Furthermore, recent analysis of the 4 year follow up of the
BeSt study revealed that first line use of infliximab led to a more sustained
remission as compared to patients that received this drug in latter stages
of the treatment strategy [75]. Similarly, the SWEFOT study highlighted
benefits from the combination of infliximab plus MTX in comparison with
triple synthetic DMARDs therapy [38]. Recent data from a prospective
open study suggests that although a faster reduction in DAS28 in patients
starting MTX and adalimumab as first line treatment is observed at
12 weeks, the clinical and radiographic outcomes at 52 weeks did not
differ from those who were changed to the same regime after 3 months, if
they were refractory to MTX [76]. Therefore this data needs further
analysis.
All current biologics (TNFi, tocilizumab, abatacept and rituximab)
have increased benefits when used combined with MTX in DMARDs
naïve patients [77–79].
Despite the ongoing discussion, at the moment there in not
enough evidence to support generalized use of biologics in association
with MTX as fist line therapy. By doing so, we would be over treating
at least 15% to 40% of patients who would respond to MTX
monotherapy [80]. This approach can be however considered in
selected cases, when clear unfavorable prognostic factors are present
and disease activity is very high.
11. Refractoriness to approved therapies. What to do next?
Despite the efficacy and increased number of biologic therapies
available it has been reported that the ACR70 response rate to a second
biologic is of 5–15% and the DAS28 remission is reached by 9–15% of this
patients, leaving the proposed treatment targets clearly unmet [81].
Many exciting new biological agents are in development for the
treatment of RA. Inclusion of selected patients that became refractory
711
to all approved biologics in ongoing clinical trials according to clinical
judgment can bring potential benefits for disease control. For example
new cytokine antagonists, namely blocking IL6, IL17 and GM-CSF are
being studied [82–88]. Other anti-CD20 antibodies including the fully
human ofatumumab and the humanized ocrelizumab and veltuzumab
are in phase II/III trials [89–91]. Neutralization of the B cell survival
and activation cytokines BLyS (or BAFF) and APRIL is an approach that
is in development, despite the disappointing results obtained with
atacicept (which blocks both BLyS and APRIL and could therefore
reversibly suppress B cell function across maturation stages). Signaling pathways including NF-kB and p38 MAPK pathways are being
targeted by small molecules, as is also the case of JAK and Syk kinases
[92,93]. Possible complementary approaches arresting the effects of
inflammation in bone metabolism such as inhibiting osteoclast
differentiation are particularly attractive [94].
The treatment potential of using stem cell transplantation (SCT) for
severe refractory RA patients at risk of high mortality and previously to
irreversible damage should not be forgotten. SCT is relatively well
tolerated by most of the patients, with transplant related mortality after
100-days of 1% and a general survival of 94%. It is associated with
improvement of disease activity and function and inhibition of joint
destruction. Peripheral blood is the most commonly used source of stem
cells and autologous transplant preferred. High doses of cyclophosphamide led to superior disease control than lower doses [95]. Relapses are
however rather frequent with a progression-free rate of 23% at 3-year
and 18% at 5 years and DMARDs such as MTX, cyclosporine and
rituximab are required to maintain disease activity controlled [96]. Since
the advent and broad use of biologic therapies SCT has indeed become
less commonly used for RA treatment as compared to other rheumatic
diseases, such as systemic sclerosis, reflecting the increase of treatment
options, but it can still be considered as a salvage treatment.
Furthermore, mesenchymal stromal cells (MSC) have showed in
vitro and in vivo anti-proliferative and anti-inflammatory properties
that support the rational for their use in inflammatory arthritis [95].
MSC effects on collagen induced arthritis models have been
contradictory, but their potential immunoregulatory effects might
be translated into a valuable therapeutic approach [97].
12. Conclusions
Despite the enthusiastic progresses in the field of RA pharmacotherapy, few patients are reaching sustained remission and refractory
patients continue to be a problem. However, we have the tools to
perform at a higher level. We have now well defined and accepted
composite measures for monitoring RA disease activity, consensual
treatment targets, a managing strategy that has been progressively
updated and a vast option of highly effective drugs. We should now
put the emphasis on the human factor and assume that managing RA
in the 21st century is a complex and highly differentiated task that
should be taken care by specialized and externally certified centers,
through a benchmark approach, where the best balance between
efficacy, safety and costs will be required.
Take-home messages
• Refractoriness can be mitigated by early diagnose of RA patients,
tight monitoring using appropriate tools to measure disease activity,
identification of patients with worse prognosis and starting early
and adequate treatment strategy aiming remission at each individual patient.
• In spite of the increased number of biologics available, until know
there is not enough evidence that would help clinicians to position
biologics according to disease phenotypes or to helpful specific
biomarkers, therefore, clinicians are still basing their decisions on
personal experience and on the safety profile of each biologic drug.
712
J. Polido-Pereira et al. / Autoimmunity Reviews 10 (2011) 707–713
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