Factors determining a DMARD initiation in early inflammatory arthritis patients. The ESPOIR cohort study

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Abstract
To describe the rate and timing of DMARD start in patients with early inflammatory arthritis in France, and to determine the factors leading to this treatment start. The ESPOIR cohort study collects data on patients presenting with early arthritis. Baseline characteristics were assessed, and Cox regression analysis was performed to estimate the likelihood of starting DMARD treatment over time, adjusting for patient-, disease- and physician characteristics. Of the 775 analysed patients, 598 (77.2%) received at least 1 DMARD during the follow-up period, after a median time of 4.0 months. In general, a higher tender joint count, involvement of the hands, involvement of more than 3 joint groups, presence of abnormal CRP-levels or CCP-antibodies significantly increased the likelihood of being treated (p<0.01 for all determinants), as well as a positive result on the bilateral foot-squeeze test (p<0.04). In addition, a significant hetero-geneity in therapeutic strategy across the 14 tested French regions was found: adjusted hazard ratios for DMARD start ranged from 1 to 2.15 (p<0.01), depending on the region where a patient was followed. For anti-CCP test and swollen joint count we demonstrated a statistically significant interaction with geographic region, implying that these tests are interpreted differently across regions. The same factors that increased the likelihood to start a DMARD were related to an earlier start. Rate and timing of treatment start with DMARDs in patients with early inflammatory arthritis in France is determined by well known clinical and biochemical variables. Apart from these variables, however, unknown and intangible factors that seem to cluster geographically are responsible for important variations in practice performance.

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Clinical and Experimental Rheumatology 2009; 27: 84-91.
Factors determining a DMARD initiation in early inflammatory
arthritis patients. The ESPOIR cohort study
C. Lukas
1
, F. Guillemin
2
, R. Landewé
3
, D. van der Heijde
4
, I. Logeart
5
,
B. Fautrel
6
, J.P. Daures
7
, B. Combe
1
1
Immuno-Rhumatologie, Hôpital Lapeyronie, Montpellier, France;
2
EA 4003, Nancy-University,
Vandoeuvre-les-Nancy, France;
3
University of Maastricht and CAPHRI Institute, Maastricht,
The Netherlands;
4
Leiden University Medical Center, Leiden, The Netherlands;
5
Wyeth
Pharmaceuticals France, Paris La Défense, France;
6
Service de Rhumatologie, Groupe Hospitalier
Pitié-Salpêtrière, Paris, France;
7
Institut Universitaire de Recherche Clinique de Montpellier,
University of Montpellier I, Montpellier, France.
Abstract
Background
To describe the rate and timing of DMARD start in patients with early inflammatory arthritis in France, and to determine
the factors leading to this treatment start.
Methods
The ESPOIR cohort study collects data on patients presenting with early arthritis. Baseline characteristics were assessed,
and Cox regression analysis was performed to estimate the likelihood of starting DMARD treatment over time, adjusting
for patient-, disease- and physician characteristics.
Results
Of the 775 analysed patients, 598 (77.2%) received at least 1 DMARD during the follow-up period, after a median time
of 4.0 months. In general, a higher tender joint count, involvement of the hands, involvement of more than 3 joint groups,
presence of abnormal CRP-levels or CCP-antibodies significantly increased the likelihood of being treated (p<0.01 for all
determinants), as well as a positive result on the bilateral foot-squeeze test (p<0.04). In addition, a significant hetero-
geneity in therapeutic strategy across the 14 tested French regions was found: adjusted hazard ratios for DMARD start
ranged from 1 to 2.15 (p<0.01), depending on the region where a patient was followed. For anti-CCP test and swollen joint
count we demonstrated a statistically significant interaction with geographic region, implying that these tests are
interpreted differently across regions. The same factors that increased the likelihood to start a DMARD were related to
an earlier start.
Conclusion
Rate and timing of treatment start with DMARDs in patients with early inflammatory arthritis in France is determined by
well known clinical and biochemical variables. Apart from these variables, however, unknown and intangible factors that
seem to cluster geographically are responsible for important variations in practice performance.
Key words
Arthritis, antirheumatic agents/DMARDs, ESPOIR cohort study, physician’s practice patterns.
85
DMARD start in early inflammatory polyarthritis / C. Lukas et al.
Cédric Lukas, MD
Francis Guillemin, MD, PhD
Robert Landewé, MD, PhD
Désirée van der Heijde MD, PhD
Isabelle Logeart, MD
Bruno Fautrel, MD, PhD
Jean Pierre Daures, PhD
Bernard Combe, MD, PhD
Funding was provided by an unrestricted
grant from Merck (MSD) to the ESPOIR
cohort study. An additional grant from
INSERM (France) was obtained to support
part of the biologic database for the first 2
years. Abbott and Amgen have also
supported the ESPOIR cohort study.
Please address correspondence and
reprint requests to:
Prof. Bernard Combe,
Service d’immuno-rhumatologie,
Hopital Lapeyronie,
191 avenue du doyen Gaston Giraud,
34295 Montpellier,
Cedex 5, France.
E-mail: b-combe@chu-montpellier.fr
Received on February 28, 2008; accepted
in revised form on July 24, 2008.
© Copyright C
LINICAL AND
E
XPERIMENTAL RHEUMATOLOGY 2009.
Competing interests: none declared.
Introduction
Management of early inflammatory ar-
thritis is not yet clearly standardized,
and recommendations regarding its
diagnosis and treatment have only re-
cently been developed (1, 2). Although
consensus exists on the need for early
use of disease-modifying antirheumatic
drugs (DMARDs) in patients presenting
with inflammatory arthritis that could
evolve into persistent and erosive dis-
ease (2-5), no general rules have been
published on the optimal time to the
first introduction and the detailed clini-
cal picture of the characteristic patient
requiring DMARDs early (6). Hence,
already in patients meeting diagnostic
criteria for rheumatoid arthritis (RA),
important practice variations with re-
gard to DMARD start are regularly
noted between rheumatologists and
non-rheumatologist care providers (7,
8) and also across specialists (9). This
disparity in care, mainly investigated
through surveys, is noteworthy both
in patients with undifferentiated early
arthritis and in early RA (9-14). The
discrepancies could be related to the
difficulty in diagnosing RA at an early
stage, evaluating its prognosis and ex-
cluding a spontaneously resolving dis-
ease. Indeed, spontaneous remission is
a frequently described outcome in early
arthritis (15), and the therapeutic deci-
sion shall take it all into account to pre-
serve the risk-to-benefit ratio. Regard-
ing the start of therapy with a DMARD
in RA, former studies noted physicians’
characteristics (9, 16), the time period
of study (17) or disease characteristics
as potentially determining factors, but
these factors have not yet been exam-
ined in a cohort of patients including
patients with undifferentiated inflam-
matory arthritis. We used the data from
a French longitudinal prospective co-
hort study of adult patients with both
early undifferentiated inflammatory
arthritis and recently developed RA,
the ESPOIR cohort study (18, 19), to
describe the therapeutic behaviour of
French general practitioners (GPs) and
rheumatologists between 2002 and 2005
with regard to a decision to the rate and
timing of a DMARD start in early in-
flammatory arthritis, and to determine
the factors that contribute to this start
of DMARD therapy. In France, GPs
should be regarded as front-line physi-
cians with both an early diagnostic and
therapeutic role, together with a pivotal
referral function to specialists such as
rheumatologists. As this is a prospec-
tive observational cohort assessing
health-care delivery under non-trial
conditions, it allowed us to describe
and analyse daily practice, which may
help in explaining GP and rheumatolo-
gist’s behaviour.
Patients and methods
The ESPOIR cohort
The ESPOIR cohort (18, 19) is a
French prospective observational study
of adults over 18 and less than 70 years
old recruited from multiple regions
across France under auspices of the
French Society of Rheumatology. The
patients included had to present with
inflammatory arthritis lasting for 6
weeks up to 6 months, involving more
than 2 joints and diagnosed by the re-
ferring physician as RA or suspected
to develop into RA. Patients had never
undergone treatment with a DMARD
or steroids. Patients were excluded if
the referring physician had judged they
had other clearly defined inflammatory
rheumatic diseases or undifferentiated
arthritis (UA) which were unlikely to
develop into RA.
Patients were recruited from general
practitioners and rheumatologists from
14 regions across France, and data
were collected by the regional univer-
sity rheumatology department. Each
regional center collected data but did
not interfere with patients’ treatment.
Patients were routinely treated and fol-
lowed up by private rheumatologists
in the geographical area, but in excep-
tional cases by GPs with a special inter-
est in rheumatology. It may have hap-
pened that the investigator was also the
patient’s physician. The results of each
test carried out within the framework of
the study were periodically communi-
cated to the practitioner taking care of
the patient. All patients were followed
up by the same investigator every 6
months during the first 2 years and
every year thereafter. Data concerning
medical history, socioeconomic and
demographic characteristics, clinical,
86
DMARD start in early inflammatory polyarthritis / C. Lukas et al.
biological, radiographic and genetic
parameters, were also collected. One
biological resources center (Paris-Bi-
chat, Joelle Benessiano) was in charge
of centralising and managing biological
data collection.
The first inclusions began in December
2002, and 813 patients were included
by March 2005 when the database was
locked for the present analysis.
Study objectives
The primary objective of this study
was to describe the rate and timing of
DMARD use (excluding corticoster
-
oids), and to determine factors leading
to the start of a drug in a cohort of pa-
tients with early inflammatory arthritis
treated by rheumatologists in France.
Explanatory variables
The following clinical, biological and
sociodemographic characteristics, pos-
sibly influencing the decision to begin
DMARD treatment, were assessed:
1. Sociodemographic variables: sex,
age (tertiles), educational level (at
least high school).
2. Baseline clinical disease character-
istics: type of disease onset [acute
(symptoms appearing in less than
1 week), insidious or intermittent];
number of tender joints (28-joint
count) (tertiles); number of swol-
len joints (28-joint count) (ter-
tiles); symmetrical onset of disease;
clinical involvement of the hands;
presence of rheumatoid nodules;
involvement of more than 3 joint
groups; morning stiffness lasting for
more than 60 minutes; induced pain
by the foot-squeeze test; the latter 6
treated as binary variables.
3. Prognostic characteristics at base-
line: presence of typical erosions as
seen on hand or feet x-rays; posi-
tivity for rheumatoid factor (RF);
positivity for anti-citrullinated pep-
tide antibodies (CCP-Abs); elevated
level of C reactive protein (CRP >10
mg/l) and impaired functional status
(Health Assessment Questionnaire
[HAQ] ≥1).
4. Comorbidity (binary): presence of
at least 1 comorbid factor: ischemic
heart disease, hypertension, diabetes
mellitus, renal disease (proteinuria
or hematuria) or current cancer.
5. Time from symptom onset to first
visit to a physician (GP or rheuma-
tologist) (tertiles).
6. Observational center of the patient
(among the 14 French centers).
Statistical analysis
Outcome assessment. Time to actual
start of first DMARD was calculated
based on the date of first prescription of
a DMARD (methotrexate, leflunomide,
sulfasalazine, hydroxychloroquine, so
-
dium aurothiopropanol sulfonate, thio-
pronine, biologics or combination ther-
apy). If patients did not start a DMARD
at the last available follow-up visit, out-
come was censored (minimum follow-
up time was 12 months after inclusion
visit). Survival analysis was calculated
as the time from the first visit to a phy-
sician (either GP or rheumatologist) for
arthritis symptoms, to the time of first
DMARD prescription.
Analyses. Multivariate Cox propor-
tional hazard analysis was used to
evaluate the independent contribution
of baseline features on a decision to
start a DMARD. A forward stepwise
procedure was used to select variables
in the model. The inclusion signifi-
cance level was 0.05 and the exclusion
significance level 0.20. Heterogeneity
across observational centers was fur-
ther investigated by testing interactions
between center and each of the baseline
characteristics of the patients, in a Cox-
model including the interaction term,
and the center and the variable of inter-
est (main effects). Concerning the tim-
ing of DMARD start, median time per
category of baseline characteristics was
estimated by Kaplan-Meier analysis
and Log-rank test was used to test the
difference between categories. All sta-
tistical analyses were performed with
SPSS 13 for Windows.
The study was approved by a central
ethics committee, and written informed
consent was obtained from each par-
ticipant.
Results
Baseline characteristics
The main baseline characteristics of the
813 patients are shown in Table I. They
presented with active, recent-onset
disease: mean DAS28 of 5.1, mean dis
-
ease duration less than 15 weeks (from
first symptoms, ie any rst persistently
swollen joint, to first ESPOIR follow-
up visit). The biological patterns were
similar to those of other published data
on early inflammatory arthritis, with
42.2% of the patients having a positive
test result for RF at baseline, 39.5% for
anti-CCP ab, and elevated blood inflam-
matory criteria (mean CRP 22.2 mg/l;
mean erythrocyte sedimentation rate
(ESR) 29.4 mm). ACR criteria for RA
(20) were met by 71% of the patients at
the time of inclusion in ESPOIR.
Treatment patterns
Because one or more data required for
this analysis were missing, 38 out of
the 813 patients could not be included
in the analysis. Of the 775 analysed, a
total of 598 patients (77.2%) received
at least 1 DMARD during the follow-up
period (Fig. 1). The median time to first
DMARD introduction was 4.0 months
[95% confidence interval (CI
95%)
3.7;
4.3]. Of the 598 treated patients, 281
(47%) started their first DMARD within
3 months after the first visit to a physi-
cian, and 522 (87%) within 6 months.
The most frequently first-prescribed
DMARD was methotrexate (57.7%),
followed by hydroxychloroquine
(14.5%), sulfasalazine (12.3%), leflu-
nomide (6.3%), sodium aurothiopropa-
nol sulfonate (2.1%), and thiopronine
(0.3%). Combination therapies as first-
prescribed DMARD (methotrexate as-
sociated with hydroxychloroquine, and/
or sodium aurothiopropanol sulfonate,
leflunomide, sulfasalazine, etanercept,
adalimumab) were used in 36 patients
(6.0%) only.
Adjusted hazards ratios for
DMARD start decision
Table II displays the adjusted Haz
-
ards ratios (HR) for DMARD therapy
start from the Cox regression analysis,
which accounts for all baseline data that
might influence a physician’s decision
to start therapy. Baseline tender joint
count was closely related to DMARD
treatment (p=0.001): the adjusted
HR was 1.25 (CI
95%
1.01-1.55) for a
DMARD start of an “active disease
(tender joint count ranging from 5 to
87
DMARD start in early inflammatory polyarthritis / C. Lukas et al.
9) versus a “mild disease” (tender joint
count below 5), and 1.57 (CI
95%
1.25-
1.97) for a DMARD start of a “very
active disease” (i.e. with baseline ten-
der joint count >9) versus a “mild dis-
ease”. The swollen joint count was not
an independent predictor when tender
joint count was in the model, probably
due to the high correlation between the
two. In a model without tender joint
count however, swollen joint count
became an independent predictor. The
following disease variables were inde-
pendent contributors to DMARD start:
involvement of at least 3 distinct joint
groups, or arthritis in the hands (HRs
1.49 and 1.79 respectively), and a posi-
tive bilateral foot-squeeze test with an
HR of 1.22 (p=0.004).
Anti-CCPab positivity independently
increased the likelihood of a DMARD
start, (HR: 1.71 (CI
95%
1.44-2.03)). In a
separate model with only RF and not
anti-CCPab included, the HR of RF
was 1.60 (p<0.001) (with a better fit of
the model including anti-CCP). Elevat-
ed CRP resulted also in a significantly
more frequent DMARD start (HR 1.28,
p=0.003), while a model without CRP
resulted in a HR of 1.19 (p=0.05) for
having an elevated ESR. Finally, we
observed a marked regional diversity
in second-line therapy use (HRs from
each of the 14 observational centers
ranging from 1.02 to 2.15, p=0.006 for
comparison test), after adjustment for
patient and disease characteristics at
baseline. When further investigating
this heterogeneity across observational
centers, we identified a few charac-
teristics that contributed to explain
regional variations in DMARD start:
The interactions between observational
center and number of swollen joints
(p=0.008), and between observational
center and presence of anti-CCPab
(p=0.045) were statistically significant.
The implications of these interactions
are illustrated by an example: while in
first center (Fig. 2 lower graph) there
was an important difference between
anti-CCP positive (100% DMARD
start) and anti-CCP negative patients
(40% DMARD start), almost no dif-
ference between DMARD start in anti-
CCP positive and negative patients
could be found in the other center (Fig.
2 upper graph).
Baseline characteristics linked to
earlier DMARD start
Table III shows the univariate rela-
tionships between baseline variables
and time to DMARD start. Sociode-
mographic variables had no relevant
impact on the time to first DMARD:
gender was not found to play any role
(p=0.46), nor was the age of the pa-
tient (p=0.29) or the educational level
(p=0.65). Baseline clinical findings,
on the other hand, were determinants
Table I. Baseline characteristics of the ESPOIR patients (n=813).
Variable n (%) Mean (SD)
Sex, female, n (%) 624 (76.8%)
Age, years 48.1 (12.5)
Disease duration, months 3.39 (1.73)
Number of tender joints (28 joint count) 8.43 (7.01)
Number of swollen joints (28 joint count) 7.19 (5.37)
Rheumatoid Factor positivity, n (%) 343 (42.2%)
Anti-CCP antibodies positivity, n (%) 321 (39.5%)
Time to first general practitioner visit, days 26.4 (41.1)
Time to first rheumatologist visit, days 74.9 (76.6)
ESR (mm) 29.4 (24.5)
ESR≥28 mm 318 (40.9%)
CRP (mg/l) 22.2 (34.0)
CRP≥10mg/l 387 (50.0%)
HAQ 0.98 (0.68)
Disease Activity (Patient self-assessment, Visual Analogic 59.9 (25.6)
Scale 0-100mm)
Joint Pain at rest (Visual Analogic Scale 0-100mm) 37.2 (27.7)
DAS28 value 5.11 (1.31)
DAS28 <2.6, n (%) 21 (2.60%)
DAS28 2.6-5.1, n (%) 385 (47.4%)
DAS28 >5.1, n (%) 393 (48.3%)
At least one co-morbid factor, n (%)* 187 (23.0%)
*presence of at least 1 comorbid factor: ischemic heart disease, hypertension, diabetes mellitus, renal
disease (proteinuria or hematuria) or current cancer.
DAS28: disease activity score 28; ESR: erythrocyte sedimentation rate; CCP: citrullinated peptide
antibodies; CRP: C-reactive protein.
Fig. 1. Cumulative proportion of treated patients over time, in each of the 14 observational center.
88
DMARD start in early inflammatory polyarthritis / C. Lukas et al.
in the decision of starting a DMARD
earlier: initial hand involvement led
to earlier treatment start (p<0.0001),
as did a positive bilateral foot-squeeze
test result (p<0.0001). Baseline dis-
ease activity, reflected by the counts
of tender or swollen joints (tertiles),
was also a strong determinant of ear-
lier DMARD start: Patients with low-
est number of tender joints (less than
5) received a second-line therapy later
than those from the remaining catego-
ries (i.e. with 5 to 9, and more than 9
tender joints, p≤0.02 for all pairwise
comparisons). Similar results were ob-
tained when comparing timing of treat-
ment start in patients with low (less
than 4), intermediate (4 to 8), or high
(more than 8) number of swollen joints
(p<0.003 for all pairwise comparisons).
A symmetrical arthritis also led to an
earlier start of treatment (
p=0.0001),
as did an involvement of more than 3
joint groups (p<0.0001) or a duration
of morning stiffness exceeding 60 min-
utes (p=0.009).
Among characteristics considered to
have prognostic value, a high acute
phase response led to earlier DMARD
treatment (p<0.001 for patients with
high, i.e. over 10 mg/l, vs. normal level
of CRP). The treatment start was also
significantly earlier in patients having a
positive RF- and anti-CCPab-test result
as compared to those with negative tests
(p<0.0001 for both comparisons). An
early erosive disease (erosions seen on
first evaluation-radiographs) was also
related to an earlier start of treatment,
but the statistical significance was weak
(p<0.04), probably due to the small
number of patients showing structural
abnormalities at inclusion according to
the referring doctor (less than 15%). A
marked functional impairment, as re-
flected by a HAQ≥1 at the time of the
first medical evaluation of the patient,
was also related to an earlier DMARD
initiation (p<0.001).
Presence of at least one comorbid fac-
tor was not found to influence the tim-
ing of treatment (p=0.87), and the lag
time between symptom onset and the
first visit to a doctor (general practi-
tioner or rheumatologist) also did not
have an impact (p=0.36).
The time to DMARD start was also
found to be substantially heterogene-
ous across the 14 observational centers
(p<0.001).
Discussion
This is the first report of French rheu
-
matologists’ performance concerning
DMARD therapy initiation in early
inflammatory arthritis in daily prac-
tice, both for outpatients of university
centers and private care practice. An
important observation is the heteroge-
neity we found across regions within
a single European country with regard
to the decision of starting a specific
therapy, even after controlling for activ-
ity- or severity-related (prognostic) fac-
tors which are expected to guide such
a decision. Theoretically, the adjust-
ment for these factors such as the level
Table II. Adjusted hazard ratio for starting a DMARD after first medical visit.
HR [95% CI] p
Anti-CCP test (positive vs. negative) 1.71 [1.44-2.03] <0.001
Observational center (range of HR) range of HRs: 0.006
(reference = center with lowest HR) 1.02 – 2.15
Number of tender joints 0.001
Second tertile (5-9) vs. first tertile (≤4) 1.25 [1.01-1.55] 0.042
Third tertile (>9) vs. first tertile (≤4) 1.57 [1.25-1.97] <0.001
Involvement of at least 3 joint groups 1.49 [1.15-1.93] 0.003
CRP (>10 mg/l vs. <10mg/l) 1.28 [1.09-1.52] 0.003
Initial hand involvement (yes vs. no) 1.79 [1.16-2.76] 0.009
Foot-squeeze test (positive vs. negative) 1.22 [1.01-1.46] 0.035
HR: Hazards ratio; DMARD: disease-modifying antirheumatic drug, CI: confidence interval.
Fig. 2. Cumulative
proportion of treated
patients over time
following first medi-
cal consultation, in 2
independent observa-
tional centers (lower
and upper graphs),
depending on results
of the anti-CCP test
(positive: continued
curves, negative: dot-
ted curves).
89
DMARD start in early inflammatory polyarthritis / C. Lukas et al.
of disease activity and the presence or
absence of anti-CCP/RF should result
in a very consistent pattern in treatment
strategies, not only with regard to the
lag-time between symptom onset and
treatment start, but also with regard to
the proportion of patients with early ar-
thritis in which DMARDs are actually
started. However, the remaining dis-
crepancies across French regions dem-
onstrate that similar results of diagnostic
and prognostic procedures may result in
different consequences with regard to
DMARD start, which probably depends
on differences in opinions, beliefs and
interpretations of the treating physician.
A prerequisite is that the greater part of
the relevant patient’s disease character-
istics can be captured and summarized
(21). It is rational to assume that several
determinants of the therapeutic decision
to start DMARDs can not be assessed,
but we still believe that the most impor-
tant diagnostic and prognostic factors
in early inflammatory arthritis, about
which broad consensus exists in the
rheumatological community, were used
in the present analysis.
The independent significant variation in
medical practice across observational
centers revealed a geographical hetero-
geneity in practice performance among
French rheumatologists. The ESPOIR
Table III. Median time (months) to first DMARD as per baseline characteristics of the patients, and results of the Log-Rank test for the
respective comparison.
Compared categories Median time (months) p
Sociodemographics Sex Female 4.04 [3.69-4.39] 0.455
Male 3.94 [3.43-4.45]
Age
<43 years 4.11 [3.59-4.62] 0.134
*
43-55 years 3.84 [3.38-4.31]
>55 years 4.11 [3.69-4.52]
Education < high school 4.24 [3.89-4.58] 0.654
≥ high school 3.94 [3.58-4.30]
Clinical disease characteristics Initial hand involvement Yes 3.84 [3.38-4.31] <0.001
No 14
Type of onset Symmetrical 3.81 [3.54-4.09] <0.001
Asymmetrical 5.22 [4.37-6.08]
Rheumatoid nodules Present 4.37 [1.43-7.32] 0.853
Absent 4.01 [3.69-4.33]
Type of onset Acute 3.98 [3.25-4.70] >0.886
*
Progressive 4.01[3.51-4.51]
Intermittent 4.04 [3.68-4.40]
Tender joint count
≤4 tender joints 4.96 [4.30-5.62] <0.015
*
5-9 tender joints 4.24 [3.78-4.70]
>9 tender joints 3.32 [2.84-3.79]
Swollen joint count
≤3 swollen joints 5.45 [4.42-6.49] <0.003
*
4-8 swollen joints 4.11 [3.69-4.52]
>8 swollen joints 3.25 [2.86-3.65]
Foot-squeeze test Positive 3.58 [3.26-3.90] <0.001
Negative 4.96 [4.30-5.62]
Involvement of at least 3 joint groups Yes 3.78 [3.51-4.04] <0.001
No 6.90 [4.15-9.65]
Duration of morning stiffness > 60 minutes 3.94 [3.65-4.24] <0.01
< 60 minutes 5.06 [3.98-6.14]
Prognosis-related factors Radiographic erosions Present 3.98 [3.35-4.60] <0.04
Absent 4.04 [3.71-4.37]
CRP ≥10 mg/l 3.42 [2.97-3.87] <0.001
<10 mg/l 4.57 [4.02-5.12]
Anti-CCP antibody test Positive 3.29 [2.93-3.64] <0.001
Negative 4.73 [4.18-5.29]
Rheumatoid Factor test Positive 3.42 [3.07-3.77] <0.001
Negative 4.80 [4.24-5.35]
HAQ ≥1 3.42 [3.03-3.81] <0.001
<1 4.70 [4.22-5.18]
Referral Lagtime from symptom onset <1 week 4.14 [3.54-4.74] >0.213
*
to first physician
2-4 weeks 4.21 [3.87-4.54]
>4 weeks 3.68 [3.21-4.15]
Observational center Observational center <0.001
(14 centers) Range : 3.19 – 5.68
Comorbidity At least one comorbidity Yes 3.91 [3.34-4.48] 0.650
No 4.04 [3.71-4.37]
Log-Rank test;
Tertiles;
Confidence interval not computable; DMARD: disease-modifying antirheumatic drug; CRP: C-reactive protein; CCP: citrullin-
ated peptide antibodies.
*
For all pairwise comparisons.
90
DMARD start in early inflammatory polyarthritis / C. Lukas et al.
patients are most often treated and fol-
lowed up by private rheumatologists,
but these rheumatologists generally col-
laborate with the observational center
in their region, which is also the center
in which they usually were trained, and
with which they tune their performance
in clinical practice, thus explaining the
geographical rather than individual var-
iation. This formerly reported source of
variation (16, 17) should strongly en-
courage initiatives for improving the
management of early inflammatory ar-
thritis. In particular, development and
implementation of guidelines (like the
recently formulated recommendations
for the management of patients with
early arthritis (1) could help practition-
ers propose the most appropriate strat-
egy in individual patients.
Expectedly, clinical and biochemical
features, particularly those indicating
a possible early RA, such as involve-
ment of more than 3 joint groups of the
hands, and the presence of anti-CCP an-
tibodies, were most relevant in the final
therapeutic decision to start DMARDs.
Apart from these factors typical of the
classical RA presentation (22), and after
adjustment for them in a multivariate
model, we still found other independent
determinants of the start of antirheu-
matic therapy. Baseline disease activity,
reflected by the tender joint count in our
study, is known as a prognostic tool in
early RA (23-27) and as a predictor of
disease persistence in UA (25, 28-30)
and was thus expected to be closely
related to DMARD treatment start in
early inflammatory arthritis. This hy-
pothesis was clearly confirmed by our
results showing an independent and sig-
nificant link between illness activity and
a prompt treatment start. Another deter-
minant of an early DMARD start was
the bilateral foot-squeeze test. This sim-
ple clinical test, implying a transversal
compression of the metatarsophalange-
al joints that may cause pain (a positive
test), was previously suggested to be a
predictor of disease persistence (22, 31).
This test was independently contribu-
tory to a DMARD start, and a positive
test apparently reflects the perception of
the physician that this patient will run a
chronic and destructive disease course
(see Table II). Its assessment in early
arthritis is thus recommended (1, 31),
especially when formal clinical evalua-
tion of RA (by 28-joint counts) does not
take into account the patients’ feet.
A positive test result for anti-CCP an-
tibodies at disease onset independently
contributed to starting DMARD ther-
apy. This observation is understand-
able, and in accordance with results of
other studies showing that a positive
anti-CCP antibody test is an independ-
ent predictor of disease persistence and
radiographic evolution (22, 24, 32-35).
Far less understandable from an evi-
dence-based point of view, however, is
the geographical heterogeneity in per-
formance that we demonstrated with
regard to the consequences of a posi-
tive anti-CCP test: in some geographi-
cal areas, a positive test dominated the
decision to start DMARDs in a patient,
while in other geographical areas such
a decision was completely independ-
ent of the test result. A similar kind
of geographical heterogeneity could
be demonstrated for the swollen joint
count. These examples illustrate that
care providers handle and interpret the
available prognostic information differ-
ently in their practice with individual
patients, and as such contribute to im-
portant differences in practice perform-
ance across regions. Ideally, practice
variation should be largely explained
by true differences in individual prog-
nosis rather than by differences in the
interpretation of prognostic literature or
lack of knowledge of these.
We have here described the French
practice of DMARD therapy in early in-
flammatory arthritis within the context
of the concept of a “window of oppor-
tunity,” that is supported by the results
of several trials and meta-analyses (6,
36-49), and underscores an early treat-
ment start in recent-onset RA. Prospec-
tively following up patients in the ES-
POIR cohort will enable us to establish
whether such a strategy – with inherent
geographical variation will have an
impact on long-term clinical, radiologi-
cal, functional and social outcomes.
Aknowledgements
We thank the other members of the
steering committee and the main in
-
vestigator of each observational center:
F. Berenbaum, M.C. Boissier, A. Can-
tagrel, M. Dougados, P. Fardellone, P.
Bourgeois, R.M. Flipo, P. Goupille, F.
Liote, X. Le Loet, X. Mariette, O. Mey-
er, P. Ravaud, A. Saraux, T. Schaever-
beke, J. Sibilia. We also wish to thank
Nathalie Rincheval, from the coordinat-
ing center in Montpellier, who did ex-
pert monitoring and data management.
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    • "First, therapeutic decisions were not protocolbased in the ESPOIR cohort, and patients received treatment according to standard care by their rheumatologist. Patients with the most active or structurally aggressive disease were more likely to receive the most effective drugs such as MTX or TNF blockers, which highlights a channeling bias [4,40]. Four gross therapeutic strategies can be distinguished: no DMARD during the first year in the cohort, DMARDs without demonstrated structural efficacy such as hydroxychloroquine, DMARDs with demonstrated structural benefit such as MTX or leflunomide, or biologics such as TNF blockers. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction Early rheumatoid arthritis (RA) patients may show rapid radiographic progression (RRP) despite rapid initiation of synthetic disease-modifying anti-rheumatic drugs (DMARDs). The present study aimed to develop a matrix to predict risk of RRP despite early DMARD initiation in real life settings. Methods The ESPOIR cohort included 813 patients from the community with early arthritis for < 6 months; 370 patients had early RA and had received methotrexate or leflunomide during the first year of follow-up. RRP was defined as an increase in the van der Heijde-modified Sharp score (vSHS) ≥ 5 points at 1 year. Determinants of RRP were examined first by bivariate analysis, then multivariate stepwise logistic regression analysis. A visual matrix model was then developed to predict RRP in terms of patient baseline characteristics. Results We analyzed data for 370 patients. The mean Disease Activity Score in 28 joints was 5.4 ± 1.2, 18.1% of patients had typical RA erosion on radiographs and 86.4% satisfied the 2010 criteria of the American College of Rheumatology/European League Against Rheumatism. During the first year, mean change in vSHS was 1.6 ± 5.5, and 41 patients (11.1%) showed RRP. A multivariate logistic regression model enabled the development of a matrix predicting RRP in terms of baseline swollen joint count, C-reactive protein level, anti-citrullinated peptide antibodies status, and erosions seen on radiography for patients with early RA who received DMARDs. Conclusions The ESPOIR matrix may be a useful clinical practice tool to identify patients with early RA at high risk of RRP despite early DMARD initiation.
    Full-text · Article · Nov 2012
    • "Across the 14 participating French regions, the adjusted hazard ratios for DMARD start ranged from 1 to 2.15 (P < 0.01), depending on the region where a patient was living. When exploring the time until initiation of DMARDs further, a significant interaction was found between both anti-CCP and swollen joint count with geographic region, implying that these tests are interpreted differently across regions [91,92]. These variations in practice performance according to region might reflect variations in availability (number of rheumatologists and waiting times) as well as in the acceptability dimensions of access. "
    [Show abstract] [Hide abstract] ABSTRACT: In this chapter, we discuss challenges in collecting data on outcomes of patients who receive usual rheumatology care. We present results of the multinational Quantitative Monitoring of Patients with Rheumatoid Arthritis (QUEST RA) study which is a successful example of quantitative clinical measuring of RA as part of routine clinical care in a large number of centres across more than 30 countries. We further elaborate on what we can learn from these data about inequalities and inequities, both within and between countries. Frameworks to understand socioeconomic determinants of health are presented and, in addition to the QUEST RA data, the literature is summarised to provide further evidence on how socioeconomic determinants can contribute to health disparities of patients within and between countries.
    Full-text · Article · Oct 2012
    • "The larger difference between the expected progression and observed progression in the DAS-driven group suggests that the suppression of joint damage progression was better in this group than in routine care patients, albeit not to a level of significance (p=0.126).10 The lack of difference in our study could be explained by the fact that the investigators of the ESPOIR cohort were aware of early RA.11 Therefore, in the ESPOIR cohort, baseline tender joint count (>9), abnormal CRP levels and anti-CCP antibodies were closely related to DMARD treatment11 In addition, it is likely that the publication of the preliminary results from the TICORA study in 2003, by underlining the interest of tight control, had influenced the therapeutic care of patients of the ESPOIR cohort.12 "
    [Show abstract] [Hide abstract] ABSTRACT: To compare the efficacy of disease activity score in 28 joints (DAS28ESR)-driven therapy with anti-tumour necrosis factor (patients from the GUEPARD trial) and routine care in patients with recent-onset rheumatoid arthritis (patients of the ESPOIR cohort). After matching GUEPARD and ESPOIR patients on the basis of a propensity score and a 1:2 ratio, at baseline all patients had comparable demographic characteristics, rheumatoid factor, anticyclic citrullinated peptide antibody positivity and clinical disease activity parameters: erythrocyte sedimentation rate, C-reactive protein, mean DAS (6.26±0.87), Sharp/van der Heijde radiographic score (SHS), health assessment questionnaire (HAQ). Disease duration was longer in GUEPARD patients (5.6±4.6 vs 3.5±2.0 months, p<0.001). After 1 year, the percentage of patients in remission with an HAQ (<0.5) and an absence of radiological progression was higher in the tight control group (32.3% vs 10.2%, p=0.011) as well as the percentage of patients in low DAS with an HAQ (<0.5) and an absence of radiological progression (36.1% vs 18.9%, p=0.045). However, there was no difference in the decrease in DAS, nor in the percentage of EULAR (good and moderate), ACR20, ACR50 and ACR70 responses. More patients in the tight control group had an HAQ below 0.5 (70.2% vs 45.2%, p=0.005). Overall, pain, patient and physician assessment and fatigue decreased more in the tight control group. The mean SHS progression was similar in the two groups as was the percentage of patients without progression. In patients with recent onset active rheumatoid arthritis, a tight control of disease activity allows more patients to achieve remission without disability and radiographic progression.
    Full-text · Article · Mar 2011
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