Efficacy and safety of combination etanercept and
methotrexate versus etanercept alone in patients with
rheumatoid arthritis with an inadequate response to
methotrexate: the ADORE study
P L C M van Riel, A J Taggart, J Sany, M Gaubitz, H W Nab, R Pedersen, B Freundlich,
D MacPeek, for the ADORE (Add Enbrel or Replace Methotrexate) Study Investigators
............................................................... ............................................................... .
See end of article for
P L C M van Riel, Radboud
Grooteplein 10, 6525 GA
Accepted 9 January 2006
Published Online First
7 February 2006
Ann Rheum Dis 2006;65:1478–1483. doi: 10.1136/ard.2005.043299
Objective: To evaluate the efficacy and safety of etanercept (ETN) monotherapy compared with
combination ETN and methotrexate (MTX) treatment in patients with rheumatoid arthritis who had an
inadequate response to MTX monotherapy. (The response was defined by the presence of Disease Activity
Score-28 joint count (DAS28) >3.2 or a combination of >5 swollen joints, >5 painful joints and
erythrocyte sedimentation rate >10 mm/h.)
Methods: Patients with active rheumatoid arthritis taking MTX >12.5 mg/week for >3 months were
included in this 16 week, randomised, open-label study. Patients were randomly assigned to either ETN
(25 mg subcutaneous injection twice weekly) added to the baseline dose of MTX or ETN monotherapy.
Results: 315 patients were randomised to ETN (n=160) or ETN plus MTX (n=155). The primary end
point, DAS28 (4) improvement of .1.2 units, was achieved by 72.8% and 75.2% of patients treated with
ETN and those treated with ETN plus MTX, respectively, with no significant difference (p=0.658) between
the two groups. The European League Against Rheumatism response criteria of good or moderate
response was attained by 80.0% of patients in the ETN group and by 82.4% of patients in the ETN plus
MTX group. American College of Rheumatology 20%, 50% and 70% response rates achieved by both
groups were also similar: 71.0% v 67.1%, 41.9% v 40.1% and 17.4% v 18.4%, respectively. The rates of
adverse and serious adverse events were similar between the treatment groups.
Conclusion: Both the addition of ETN to MTX and the substitution of ETN for MTX in patients with
rheumatoid arthritis who had an inadequate response to MTX resulted in substantial improvements in
clinical signs and symptoms and were generally well-tolerated treatment strategies for improving clinical
signs and symptoms of rheumatoid arthritis.
(MTX), one of the more effective disease-modifying antirheu-
matic drugs (DMARDs), has been a mainstay of treatment for
rheumatoid arthritis for many years.2 3A substantial number of
patients with active rheumatoid arthritis, however, do not fully
respond to MTX monotherapy.4 5
The sustained efficacy and safety of etanercept (ETN), a
tumour necrosis factor a (TNFa) receptor antagonist, has
been well documented in patients with active rheumatoid
arthritis.4–8A previous study in patients with rheumatoid
arthritis with an inadequate response to prior MTX mono-
therapy showed that the addition of ETN to MTX treatment
resulted in a significantly greater clinical improvement than
treatment with MTX alone.5In the second study, the absence
of an ETN monotherapy group did not allow for the full
evaluation of therapeutic strategies for patients having an
inadequate response to MTX monotherapy. This study was
not designed to differentiate between those patients who had
partial responses to MTX monotherapy and those who were
The purpose of the Add Enbrel or Replace Methotrexate
(ADORE) study was to evaluate the efficacy and safety of
ETN alone compared with combination ETN and MTX
treatment in patients with an inadequate response to MTX
heumatoid arthritis is a debilitating disease, with annual
incidence rates of 20–50 cases per 100 000 people in
North America and northern Europe.1Methotrexate
MATERIALS AND METHODS
This prospective, 16 week, randomised, open-label, parallel-
group, outpatient study was conducted at 60 centres in eight
Netherlands, Turkey, UK and Spain) between March 2003
and May 2004. The study protocol was approved by an
institutional review board or ethics committee in each
All patients provided written, informed consent. Patients had
to be at least 18 years of age, have active rheumatoid
arthritis, be in American College of Rheumatology (ACR)
>12.5 mg/week for a minimum of 3 months at a stable dose
for at least 6 weeks at the time of study enrolment. All
patients must have been at least 16 years of age at the onset
of rheumatoid arthritis, must not have used any DMARDs
other than MTX within 12 weeks of screening, and must have
Abbreviations: ACR, American College of Rheumatology; ADORE,
Add Enbrel or Replace Methotrexate; DAS28, Disease Activity Score-28
joint count; DMARD, disease-modifying antirheumatic drug; ESR,
erythrocyte sedimentation rate; ETN, etanercept; EULAR, European
League Against Rheumatism; GH VAS, Visual Analogue Scale of
General Health; MTX, methotrexate; TEMPO, Trial of Etanercept and
Methotrexate with radiographic Patient Outcomes; TNF, tumour necrosis
had inadequate control of rheumatoid arthritis symptoms while
Score-28 joint count (DAS28) >3.2 or a combination of >5
swollen joints, >5 painful joints and an erythrocyte sedimenta-
tionrate(ESR)>10 mm/h.The ESR >10 mm/hwas selected to
ensure a DAS >3.2 if the investigator used only swollen and
tender joints to enrol patients in the study.
Patients who required concurrent use of prednisone
.10 mg/day, or its equivalent, were excluded from study
entry. Other exclusion criteria were presence of known
relevant concurrent medical diseases, use of bolus cortico-
steroids within 6 weeks or intra-articular corticosteroid
injections within 4 weeks of the screening visit, and previous
treatment with ETN or any other biological treatment.
Patients were randomly assigned to receive ETN in combina-
tion with MTX or ETN alone. Those patients receiving
combination therapy were treated with ETN (25 mg as a
subcutaneous injection twice weekly) added to the previously
stable baseline dose of MTX (>12.5 mg/week orally or by
injection). Patients receiving ETN alone were initially treated
with ETN concurrently with the previously administered
dose of MTX, which was decreased and discontinued over a
4-week period, following which ETN was continued as
monotherapy for an additional 12 weeks. Dose reductions
of ETN were not permitted during the study. A temporary
dose interruption of ETN of (2 weeks was permitted if a
mild or moderate toxicity event9occurred that was not
alleviated by therapeutic intervention. A single MTX dose
decrease to a minimum of 7.5 mg/week and a dose
interruption of (2 weeks were permitted after an adverse
event thought to be related to MTX.
The primary efficacy measure was the proportion of evaluable
patients in each treatment group who achieved an improve-
ment of .1.2 units in DAS28 (4) score from baseline to week
16. DAS28 and ESR were measured at screening, baseline and
weeks 4, 8, 12 and 16 (or discontinuation). The DAS28 (4)
score is a function of ESR, the patient’s Visual Analogue Scale
of General Health (GH VAS), and the number of tender and
swollen joints assessed using the 28-joint count method.10A
DAS28 (4) score .5.1 units indicated high disease activity
and a score (3.2 units indicated low disease activity.10 11The
baseline DAS28 (4) score and the week 16 DAS28 (4) score
were calculated, and the improvement from baseline to week
16 was derived.
Secondary end points included the proportion of patients
in each treatment group achieving an improvement of .1.2
units in DAS28 (3) score, which is a function of ESR, tender
joint count and swollen joint count, but not GH VAS,10 11from
baseline to week 16; time to achieve an improvement in
DAS28 (4) .1.2 units; flare of disease at week 4, defined as
worsening in DAS28 (4) .0.6 units from baseline to week 4;
and clinical remission, defined as DAS28 (4) and DAS28 (3)
of ,2.6 units at week 16. Additionally, the European League
Against Rheumatism (EULAR) response criteria for DAS28
(4) were assessed by using DAS28 (4) at week 16 (last
observation carried forward method) and improvements in
DAS28 (4) from baseline to week 1612(table 1).
The proportion of patients who achieved improvements in
ACR components was also assessed. ACR20, ACR50 and
ACR70 response rates were calculated at week 16 (or
Safety assessments included analyses of clinical chemistry,
blood counts, urine analysis, and vital signs measured at
screening, baseline and weeks 4, 8, 12 and 16. Physical
examinations were carried out at screening, baseline and
final visit. Adverse events and concomitant drugs were
recorded throughout the study.
The primary analysis was based on the intent-to-treat
population. Efficacy analyses included all patients who took
the study drugs and had a valid baseline and at least one on-
therapy value for each end point. Last observation carried
forward values were used for patients who did not complete
the scheduled visits. Differences in response between the two
groups were evaluated using asymptotic 95% confidence
intervals (CIs). Mean changes in baseline of continuous and
ordinal secondary efficacy end points were summarised by
observed visit and for the last observation through week 16.
For mean improvement in DAS28 (4), DAS28 (3) and
improvement in all components of the DAS28 and ACR
criteria from baseline to week 16, an analysis of covariance
was carried out using the baseline value as a covariate. For
these end points, treatment differences and 95% CIs were
based on the adjusted means from the analysis of covariance
models. The primary end point, the DAS28 (4) improvement
score, included the GH VAS scale. As it was expected that not
all patients would complete this scale, a prespecified
sensitivity analysis, the DAS28 (3), which does not require
the GH VAS, was added to the analysis plan. The study was
powered to characterise the relative efficacy of the two
treatments rather than to declare the superiority of either
treatment. Assuming that 70% of patients in both treatment
groups improved by the DAS criteria, the two-sided 95%
confidence limits on the difference would be approximately
10%, with 150 patients per group.
A total of 315 patients with active rheumatoid arthritis were
randomly assigned to receive study drugs. In all, 160 patients
were present in the ETN group and 155 patients in the ETN
plus MTX group. One patient in the ETN group did not
receive drug and was withdrawn from the study, leaving 314
patients in the intent-to-treat analysis. Demographic and
baseline disease characteristics were generally comparable
between treatment groups (table 2).
Thirty patients (17 in ETN group and 13 in the ETN plus
MTX group) were withdrawn from the study (table 3). One
patient in the ETN group was classified as a ‘‘non-completer’’
because he stopped taking the study drugs at week 12 but
completed the week 16 visit.
With regard to concomitant use of other treatments, 74.2%
of patients in the ETN group and 81.3% of patients in the ETN
plus MTX group used non-steroidal anti-inflammatory drugs;
51.6% in the ETN group and 56.8% in the ETN plus MTX
group used corticosteroids.
response criteria categories
European League Against Rheumatism
DAS28 (4) at
DAS28 (4) improvement at week 16
.1.2 units0.6–(1.2 units
(3.2 unitsGood responseModerate
.5.1 unitsNo response
DAS28, Disease Activity Scale 28-joint count.
Combination etanercept and methotrexate versus etanercept alone1479
A total of 136 patients in the ETN group and 125 patients in
the ETN plus MTX group had data available for the DAS28
(4) analysis. In all, 156 patients in the ETN group and 151
patients in the ETN plus MTX group were included in the
DAS28 (3) analysis. The proportion of patients with an
improvement in DAS28 (4) of .1.2 units at week 16 was
similar between the ETN group and the ETN plus MTX group
(72.8% v 75.2%, respectively; difference=22.4%, 95% CI
213.1% to 8.2%; p=0.658). The proportion of patients who
experienced an improvement of .1.2 units in DAS28 (3)
scores was also similar between the ETN group and the ETN
plus MTX group (64.7% v 72.8%, respectively; differ-
ence=28.1%, 95% CI 218.4% to 2.2%; p=0.126). Despite
the slightly lower number of patients evaluated for DAS28
(4), the CIs for the difference between DAS28 (4) and DAS28
(3) were approximately 210% to +10%, as specified in the
study design. The mean improvement in DAS28 (4) scores
from baseline to week 16 was 1.95 units in the group
receiving ETN and 2.20 units in the group receiving ETN plus
MTX (difference=20.24, 95% CI 25.5 to 0.08; p=0.14). The
improvement in DAS28 (4) was rapid (as early as 4 weeks)
and sustained over the duration of the study. Scores in both
treatment groups were comparable at each time point (fig 1).
The median time to achieve DAS28 (4) improvement .1.2
units was approximately 32 days for both treatment groups.
The proportion of patients who experienced an improve-
ment of .1.2 units in DAS28 (3) scores was also similar
between the ETN group and the ETN plus MTX group (64.7%
v 72.8%, respectively; difference=28.1%, 95% CI 218.4% to
‘‘Flare’’ of the disease at week 4, defined as worsening of
the DAS28 (4) score to .0.6 units, was not observed in any
patients receiving ETN and was observed in only one patient
(0.9%) receiving ETN plus MTX treatment. The proportion of
patients who experienced a clinical remission as measured by
a DAS28 (4) score of ,2.6 units at week 16 was similar
between the ETN-treated and the ETN plus MTX-treated
groups (14.6% v 17.3%, respectively; difference=22.7%, 95%
CI 210.9% to 5.5%; p=0.52). Similarly, the proportion of
patients with a clinical remission as defined by DAS28 (3)
score ,2.6 units at week 16 was similar between the ETN
group and the ETN plus MTX group (15.2% v 15.1%,
respectively; difference=0.1%, 95% CI 27.9% to 8.0%;
The proportion of patients in both treatment groups with a
‘‘good’’ or ‘‘moderate’’ EULAR response at week 16 was
similar: 80.0% in the ETN group compared with 82.4% in the
ETN plus MTX group.
We found no significant difference in the proportion of
patients achieving ACR20, ACR50 and ACR70 response
criteria at week 16 between the treatment groups (fig 2).
The proportion of patients who achieved ACR20 was 71.0%
and 67.1% in the ETN group and the ETN plus MTX group,
respectively (difference=3.9%, 95% CI 26.4% to 14.2%;
p=0.46). The proportion of patients who achieved ACR50
was 41.9% in the ETN group and 40.1% in the ETN plus MTX
group (difference=1.8%, 95% CI 29.2% to 12.8%; p=0.75).
The corresponding proportion of patients in each group who
achieved ACR70 was 17.4% and 18.4%, respectively (differ-
ence=21.0%, 95% CI 29.6% to 7.6%; p=0.82). Final mean
ESR was 26.4 mm/h in the ETN group and 20.8 mm/h in the
ETN plus MTX group, which reflects a significant mean
improvement of 7.8 and 14.6 mm/h, respectively (differ-
ence=26.1, 95% CI 29.6 to 22.7; p=0.001).
Baseline characteristics of study patients (intent-
Mean age, years
Ethnic origin, n (%)
Sex, n (%)
Mean time since primary diagnosis,
Rheumatoid factor positive, %
Prior corticosteroid use, n (%)
Prior NSAID use, n (%)
Mean ESR, mm/h
Mean duration of morning stiffness,
Mean DAS28 (4)
Median MTX dose, mg/week
Mean no of prior DMARDs
Mean no of total joint replacements
Mean general health VAS (0–100)
Mean pain VAS (0–100)
Global assessment of RA activity
Mean HAQ (0–3)
Mean no of swollen joints
Mean no of tender joints
DAS28, Disease Activity Score-28 joint count; DMARD, disease-
modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; ETN,
etanercept; HAQ, Health Assessment Questionnaire; MTX, methotrexate;
NSAID, non-steroidal anti-inflammatory drug; RA, rheumatoid arthritis;
VAS, Visual Analogue Scale.
Patients withdrawn from study (intent-to-treat
Primary reason for
Number of patients withdrawn, n (%)
ETN (n=159)ETN plus MTX (n=155)
ETN, etanercept; MTX, methotrexate.
ETN + MTN
Week 4Week 8Week 12
count (DAS28) (4).1.2) over time. Last observation carried forward
(LOCF) at week 16. ETN, etanercept; MTX, methotrexate.
Percentage of responders (Disease Activity Score-28 joint
1480van Riel, Taggart, Sany, et al
One or more adverse events were experienced by 62.9% (100/
159) of the ETN group compared with 70.3% (109/155) of the
ETN plus MTX group (table 4).
The most frequently reported adverse event in the ETN
group was headache, experienced by 14 patients (8.8%), and
that in the ETN plus MTX group was nasopharyngitis,
experienced by 20 patients (12.9%). Most adverse events
were mild to moderate in intensity in both groups.
A total of 15 patients (4.8%) experienced one or more
serious adverse events during this study. Eight patients
(5.0%) experienced 13 serious adverse events in the ETN
group, and 7 patients (4.5%) experienced 8 serious adverse
events in the ETN plus MTX group. These events represented
various organ systems and did not indicate clustering of any
single event. None of the serious adverse events were
considered to be related to ETN or MTX, with the exception
of three events in two patients (one patient from each
treatment group). One case of dizziness and one case of
blurred vision in the same patient were considered to be
related to ETN, although these were not considered by the
investigator to be due to demyelinating disease. One case of
dyspnoea was considered to be related to ETN plus MTX
treatment. No cases of tuberculosis, opportunist infections or
deaths were reported in the ETN group. Three deaths were
reported in the ETN plus MTX group, one of which was due
to a cardiac arrhythmia that occurred 1 month after the
patient discontinued study drugs, another was due to cardiac
arrest and the third was due to a massive cerebral
haemorrhage. All the deaths in this group were considered
to be unrelated to study drugs by the investigator.
Non-biological DMARDs, such as sulfasalazine, hydroxy-
chloroquine and MTX, are often used as initial treatment in
patients with rheumatoid arthritis. Unfortunately, many
patients on these drugs do not achieve an adequate response
or cannot maintain a therapeutic response due to toxicity.
The question often arises as to whether one should add or
substitute an anti-TNF agent.5 8This study was initiated to
help answer this question with the use of ETN.
Current study versus TEMPO
It has been shown that patients with rheumatoid arthritis
who had not been previously exposed to MTX or who had not
failed to respond to MTX had greater clinical and radio-
graphic responses to combination ETN and MTX treatment
compared with either ETN or MTX monotherapy (Trial of
Etanercept and Methotrexate with radiographic Patient
Outcomes (TEMPO)).4It has also been shown clinically that
combination therapy was better than MTX plus placebo in
patients who had experienced an inadequate response to
MTX.5In the study of inadequate responders to MTX, there
was no ETN monotherapy arm, leaving unanswered the
question of whether there was an added benefit of using
combination therapy as opposed to ETN alone.
Results from this open-label study indicated that, in these
patients, the improvement seen when adding ETN was
principally a function of ETN alone and not of the
combination with MTX. The clinical responses as measured
by DAS.1.2, change in DAS, DAS remission rates and ACR
scores were similar for the patients treated with either ETN
monotherapy or combination therapy. The results showed
that .70% of patients in this study met the primary end
point of a DAS28 improvement .1.2, representing at least a
moderate EULAR response. This response was rapid, occur-
ring within approximately 1 month, and was sustained for
the next 3 months. The lack of disease flare on tapering of
MTX in the ETN monotherapy group was consistent with the
rapid response following replacement of MTX by ETN, and
supports the treatment option of discontinuing MTX in
patients in whom the drug is providing inadequate efficacy.
There are no generally accepted criteria that determine a
partial or inadequate responder as opposed to a resistant or
refractory responder to MTX. Studies on biological agents in
patients who have been previously treated with MTX have
required various numbers of swollen and tender joints and
differing prior MTX dosages for inclusion of patient.4 5 13 14In
the design of this study, patients with a broad range of
disease severity were evaluated, including at least some
patients with less severe rheumatoid arthritis, by setting the
DAS28 inclusion criterion at .3.2. The mean baseline DAS28
was, in fact, higher than that in TEMPO (approximately 6.2
for ADORE v 5.5 for TEMPO).4
In TEMPO, most patients were MTX-naive (60%) or off
MTX for at least 6 months (40%), and were started on ETN or
combination therapy earlier than is usually done in clinical
practice when patients have often failed at least one DMARD,
usually including MTX, before starting anti-TNF treatment.
Patients in the ADORE study had already been on MTX
treatment at reasonably high doses (median 15 mg/week in
ADORE v 10 mg/week in TEMPO at baseline) for at least
3 months and, therefore, more closely resembled patients
ETN (n = 155)
ETN + MTN (n =152)
Rheumatology (ACR)20, ACR50 and ACR70 at week 16 (last
observation carried forward). ETN, etanercept; MTX, methotrexate.
Proportion of patients achieving American College of
Incidence of adverse events >5% of patients by
Any adverse event, n (%)
Most common adverse events,
Any adverse event causing
withdrawal, n (%)
Any serious adverse event,
Infections, n (%)
100 (62.9) 109 (70.3)
8 (5.0) 7 (4.5)
ETN, etanercept; MTX, methotrexate.
*On the basis of number of adverse events rather than number of
subjects; n=317 for ETN; n=365 for ETN+MTX.
Combination etanercept and methotrexate versus etanercept alone 1481
often seen in clinical practice for whom doctors would
consider starting an anti-TNF agent. These differences in the
populations may have contributed to the different results
seen in the combination therapy groups of the two studies.
Whereas the combination of MTX and ETN in patients who
were relatively MTX-naive may have been additive, this did
not seem to be the case with regard to patients on
combination therapy in this study who had inadequate
response to MTX.
It is mechanistically difficult to explain the different
findings between TEMPO and the current study. A clinical
pharmacology trial by Zhou et al15failed to show changes in
the pharmacokinetics of ETN when administered concur-
rently with MTX in patients with rheumatoid arthritis.
Clinical evidence of an obvious subpopulation of patients
who respond better to combination therapy is also lacking in
both this study and the TEMPO study. The mechanisms of
action for ETN and MTX are known to be somewhat
Other previous studies
The findings from this study are consistent with results from
previous ETN studies.5 8
In a recent trial of ETN monotherapy versus ETN plus
sulfasalazine in patients who had inadequate response to
sulfasalazine alone, both ETN monotherapy and combination
therapy provided superior efficacy compared with sulfasala-
zine alone.17Also, the efficacy of ETN alone was comparable
to that of combination therapy over 2 years of study. In a
randomised, double-blind study of DMARD-naı ¨ve patients,
no difference was found between the single-treatment arms
of sulfasalazine and MTX compared with the combination
arm of these two drugs18; however, in an open-label study of
inadequate responders to sulfasalazine, the combination of
MTX and sulfasalazine was superior to the MTX single-
Both regimens in this study were well tolerated during the
course of the trial, and treatment with ETN, either alone or in
combination with MTX, did not result in any unexpected
safety findings compared with previous ETN studies. No
cases of tuberculosis, systemic lupus erythematosus or
demyelinating disease were reported in the safety database.
The incidence of severe infections was small and comparable
in both treatment groups (5.0% for ETN and 4.5% for
Clinical implications and other considerations
The findings of this trial need to be viewed in the context of
its open-label study design, short duration and lack of
radiographic data. The duration, although short, was based
on the results of previous trials in which most of the clinical
improvement with ETN was achieved within 3 months.4–6The
lack of radiographs in this study limits the interpretation of
these data. Although there was a decrease in ESR in both
treatment groups in this study, this improvement was
significantly greater in the combination group. This leaves
open the possibility that the combination group may have
experienced less radiographic progression over time, as a
higher ESR may indicate continued underlying joint inflam-
mation and joint damage.20 21
Studies of rheumatoid arthritis have shown inhibition of
radiographic progression by ETN monotherapy.4 6Some
studies have shown that clinical disease activity may not
whereas other studies have found such a relationship,
especially in early rheumatoid arthritis.23–25Another study
showed that, although radiologic progression was related to
assessmentof disease,20 22
disease activity, clinical remission did not fully protect
against progressive joint damage.20ESR and C reactive
protein were among the prognostic markers found to be
significantly associated with severe joint damage in patients
with early rheumatoid arthritis in two long-term studies.24 26
This study may have practical implications for doctors who
are confronted with a patient who has an inadequate
response to MTX, a situation that often occurs in clinical
practice. If the addition of an anti-TNF agent is under
consideration, ETN can be added to or substituted for MTX.
Furthermore, the discontinuation of MTX does not seem to
affect the potent clinical response provided by ETN, nor does
it result in flare of disease. The findings of this study may be
relevant to patients who have had toxicity or tolerability
issues with MTX or to those who have had minimal or no
response to MTX, allowing for more flexibility of treatment
regimens. In conclusion, this study presents additional data
that MTX may be safely replaced by or complemented with
ETN in certain patients with rheumatoid arthritis, providing
We thank all patients who participated in the trial and all
investigators and nursing staff of all participating centres.
P L C M van Riel, Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands
A J Taggart, Musgrave Park Hospital, Belfast, Northern Ireland
J Sany, Service d’Immuno-Rhumatologie, Montpellier Cedex, France
M Gaubitz, Klinikum der Westfalischen Wilhelms-Universitat, Mu ¨nster,
H W Nab, Wyeth Pharmaceuticals, Hoofddorp, The Netherlands
R Pedersen, B Freundlich, D MacPeek, Wyeth Research, Collegeville,
Funding: This study was funded by a research grant from Wyeth
Competing interests: None declared.
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