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Progression of joint damage in early rheumatoid arthritisAssociation with HLADRB1 rheumatoid factor and anticitrullinated protein antibodies in relation to different treatment strategies.

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ARTHRITIS & RHEUMATISM
Vol. 58, No. 5, May 2008, pp 1293–1298
DOI 10.1002/art.23439
© 2008, American College of Rheumatology
Progression of Joint Damage in Early Rheumatoid Arthritis
Association With HLA–DRB1, Rheumatoid Factor, and
Anti–Citrullinated Protein Antibodies in Relation to
Different Treatment Strategies
J. K. de Vries-Bouwstra,1 Y. P. M. Goekoop-Ruiterman,2 K. N. Verpoort,2
G. M. T. Schreuder,2 J. A. P. M. Ewals,3 J. P. Terwiel,4 H. K. Ronday,3
P. J. S. M. Kerstens,5 R. E. M. Toes,2 R. R. P. de Vries,2 F. C. Breedveld,2 B. A. C. Dijkmans,1
T. W. J. Huizinga,2 and C. F. Allaart2
Objective. To determine the association of HLA–
DRB1, rheumatoid factor (RF), and anti–citrullinated
protein antibody (ACPA) status with progression of
joint damage in early rheumatoid arthritis (RA) treated
according to different treatment strategies.
Methods. The present study was conducted using
data from the BeSt study (Behandelstrategieën voor
Reumatoide Artritis [treatment strategies for rheumatoid arthritis]), a randomized trial comparing 4 targeted (toward achievement of a Disease Activity Score
[DAS] of <2.4) treatment strategies: sequential monotherapy (group 1), step-up combination therapy (group
2), initial combination therapy with methotrexate, sulfasalazine, and prednisone (group 3), and initial combination therapy with methotrexate and infliximab
(group 4), in 508 patients with early RA. Multivariate
logistic regression analysis was used to predict progressive disease (increase of Sharp/van der Heijde score
over 2 years beyond the smallest detectable change
[4.6]) according to the presence or absence of the
shared epitope (SE), DERAA, RF, and ACPA, with
correction for other baseline characteristics.
Results. Progressive disease could not be predicted by presence of the SE: the odds ratio in groups 1,
2, 3, and 4, respectively, was 1.4, 2.6, 1.9, and 3.0.
DERAA carriership did not protect against progressive
disease (odds ratio 0.4, 1.4, 0.9, and 0.9 in groups 1, 2, 3,
and 4, respectively). RF positivity and ACPA positivity
predicted progressive disease in group 1 (odds ratio 4.7
[95% confidence interval 1.5–14.5] for RF and 12.6 [95%
confidence interval 3.0–51.9] for ACPA), but not in
groups 2–4 (for RF, odds ratio [95% confidence interval] 1.5 [0.5–4.9], 1.0 [0.3–3.3], and 1.4 [0.4–4.8] in
group 2, group 3, and group 4, respectively; for ACPA,
odds ratio [95% confidence interval] 3.4 [0.8–14.2], 1.7
[0.5–5.4], and 1.8 [0.5–6.8] in group 2, group 3, and
group 4).
Conclusion. In patients with early RA treated with
the goal of tight control of the DAS, no significant
association between HLA–DRB1 status and radiographic progression was found. RF and ACPA were
predictive of progressive disease only in patients
treated with sequential monotherapy. These observations suggest that effective treatment can prevent
ISRCTN: 32675862.
The BeSt study is supported by a study grant from the Dutch
College for Health Insurance; additional funding was provided by
Centocor and Schering-Plough.
1
J. K. de Vries-Bouwstra, MD, PhD, B. A. C. Dijkmans, MD,
PhD: VU University Medical Center, Amsterdam, The Netherlands;
2
Y. P. M. Goekoop-Ruiterman, MD, PhD, K. N. Verpoort, MD,
G. M. T. Schreuder, PhD, R. E. M. Toes, PhD, R. R. P. de Vries, MD,
PhD, F. C. Breedveld, MD, PhD, T. W. J. Huizinga, MD, PhD, C. F.
Allaart, MD, PhD: Leiden University Medical Center, Leiden, The
Netherlands; 3J. A. P. M. Ewals, MD, H. K. Ronday, MD, PhD: Haga
Hospital, The Hague, The Netherlands; 4J. P. Terwiel, MD: Spaarne
Hospital, Haarlem, The Netherlands; 5P. J. S. M. Kerstens, MD, PhD:
Jan van Breemen Institute, Amsterdam, The Netherlands.
Dr. de Vries-Bouwstra has received speaking fees (less than
$10,000) from Schering-Plough. Dr. Dijkmans has received consulting
and speaking fees (less than $10,000) from Schering-Plough, Wyeth,
and Abbott. Dr. Allaart has received consulting fees, speaking fees,
and/or honoraria (less than $10,000) from Schering-Plough.
Address correspondence and reprint requests to J. K. de
Vries-Bouwstra, MD, Department of Rheumatology C1R, Leiden
University Medical Center, PO Box 9600, 2300 RC Leiden, The
Netherlands. E-mail: jeskadvb@xs4all.nl.
Submitted for publication February 23, 2007; accepted in
revised form January 18, 2008.
1293
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DE VRIES-BOUWSTRA ET AL
radiographic progression, even in patients with risk
factors for severe damage.
Positivity for certain HLA class II alleles and for
autoantibodies, notably rheumatoid factor (RF) and
anti–citrullinated protein antibody (ACPA), is known to
be associated with susceptibility to and severity of
rheumatoid arthritis (RA) (1,2). The presence of the
HLA–DRB1 alleles *0101, *0102, *0401, *0404, *0405,
*0408, *0410, *1001, or *1402, all sharing an amino acid
sequence in the third hypervariable region (HVR3)
(known as the shared epitope [SE]), is associated with
susceptibility to RA and more severely destructive RA
(2). Other studies have shown the DRB1 alleles *0103,
*0402, *1102, *1103, *1301, *1302, and *1304, all containing the DERAA motif in HVR3, to be negatively
associated with RA progression (3). The presence of RF
is not unique to RA, but has been consistently reported
to be associated with more severe joint damage in RA
(4). More recently, the presence of ACPAs was shown to
be predictive of and highly specific for RA (5). ACPAs
are also associated with more destructive disease (1).
In order to better prevent severe and destructive
disease, treatment of RA can be initiated immediately
after diagnosis, and antirheumatic drugs are more frequently being prescribed in combination. In many of the
studies demonstrating the association of autoantibodies
and/or SE alleles with more severe joint destruction,
data were derived from early arthritis inception cohorts
that included RA patients who were not treated according to current standards (6,7). Lard et al showed that
with early and aggressive treatment, the association
between SE positivity and radiographic progression disappears (8). In the BeSt study (Behandelstrategieën
voor Reumatoide Artritis [treatment strategies for rheumatoid arthritis]) (9), a comparison of 4 intensive treatment strategies in patients with newly diagnosed RA,
treatment was adjusted until low disease activity was
achieved. In all treatment groups, this resulted in remarkable suppression of radiographic progression (10).
In this unique cohort of patients, we explored the
influence of treatment strategies on the association of
joint destruction with DRB1, RF, and ACPA status.
PATIENTS AND METHODS
Patients and treatment protocol. The BeSt study was a
randomized, controlled trial of 508 patients with newly diagnosed RA that fulfilled the 1987 criteria of the American
College of Rheumatology (formerly, the American Rheumatism Association) (11). None of the patients had received
treatment with disease-modifying antirheumatic drugs. The
patients were allocated into 4 treatment groups: sequential
monotherapy (group 1; n ⫽ 126), step-up combination therapy
(group 2; n ⫽ 121), initial combination therapy including
high/tapered-dose prednisone (group 3; n ⫽ 133), and initial
combination therapy including infliximab (n ⫽ 128). Use of
prednisone was allowed only as dictated by the protocol. In all
groups the goal was to achieve good clinical response as
defined by the Disease Activity Score (DAS) (12). Every 3
months, the DAS, based on a 44-joint count, was calculated. If
the DAS was ⬎2.4, treatment was adjusted according to the
protocol for the particular treatment group. If the DAS
remained at ⱕ2.4 for at least 6 months, the numbers and
dosages of drugs were tapered until only 1 drug remained, at a
maintenance dosage. Further details on the patient population,
treatment protocol, and primary outcomes have been published elsewhere (10).
Baseline characteristics. The following parameters
were assessed in all patients at study entry: age, sex, current
smoking status, duration of symptoms, time between diagnosis
and study enrollment, DAS, C-reactive protein (CRP) level,
morning stiffness assessed by the patient on a visual analog
scale, radiographic damage score (see below), presence of
erosions, and functional ability as measured with the Health
Assessment Questionnaire (HAQ) (13).
HLA genotyping. HLA class II typing was performed
in all patients who provided written informed consent for
sampling of DNA material (n ⫽ 113, 102, 115, and 111 in
groups 1, 2, 3, and 4, respectively). HLA–DRB1 subtyping was
performed by polymerase chain reaction using specific primers
and hybridization with sequence-specific oligonucleotides. All
patients carrying DRB1*0101, *0102, *0401, *0404, *0405,
*0408, *0410, *1001, or *1402 were considered to be SE
positive; all patients carrying DRB1*0103, *0402, *1102,
*1103, *1301, *1302, and *1304 were considered DERAA
positive. Based on the subtyping, information on SE carriership was obtained in 417 patients (95% of typed patients).
Thirteen patients were homozygous for the SE (n ⫽ 1, 4, 6, and
2 in groups 1, 2, 3, and 4, respectively). DERAA status was
determined in 383 patients (87% of typed patients).
Autoantibody determination. The presence of RF was
determined at baseline at the laboratories of the centers
participating in the BeSt study (n ⫽ 19), based on the validated
cutoff value at the particular laboratory. At the time of
enrollment, testing for ACPA was not commonly performed in
the participating centers, and different commercial kits were
used (Euro-Diagnostica, Arnhem, The Netherlands and Axis
Shield, Dundee, UK). The presence of ACPA was determined
using baseline sera from 119 patients. In 309 patients, the
presence of ACPA was determined from serum samples
obtained during followup. Recent evidence indicates that
presence or absence of ACPA is a stable characteristic (14).
Therefore, all 428 patients (84%) with available data on ACPA
status from either time point were included in the analysis (104
[83%] from group 1, 104 [86%] from group 2, 109 [82%] from
group 3, and 111 [87%] from group 4).
Determination of radiographic progression. Radiographs of both hands and both feet, obtained at baseline and
after 2 years, were available in 455 patients (90%) (111 [88%]
from group 1, 105 [87%] from group 2, 123 [92%] from group
3, and 116 [91%] from group 4). Radiographic progression
over 2 years was determined independently by 2 observers.
GENETIC AND ANTIBODY ASSOCIATIONS WITH RA PROGRESSION, BY TREATMENT
1295
Table 1. Baseline characteristics of the 508 patients with early RA*
Treatment group
Age, median (IQR) years
Female
Duration of symptoms, median (IQR) weeks
Time between diagnosis and enrollment,
median (IQR) weeks
HAQ score, median (IQR)
DAS, median (IQR)
SHS, median (IQR)†
Erosive disease†
Rheumatoid factor positive
ACPA positive‡
Shared epitope positive§
DERAA positive¶
Smoker#
Sequential
monotherapy
Step-up
combination
therapy
Initial
combination
therapy with
prednisone
Initial
combination
therapy with
infliximab
54 (45–63)
86 (68)
23 (14–54)
2 (1–5)
54 (45–64)
86 (71)
26 (14–56)
2 (1–4)
55 (43–65)
86 (65)
23 (15–52)
2 (1–4)
54 (45–63)
85 (66)
23 (13–46)
3 (1–5)
1.4 (1.0–1.9)
4.5 (3.9–5.2)
3.5 (1.5–9.5)
89 (72)
84 (67)
68 (65)
69 (64)
19 (19)
45 (37)
1.4 (0.9–1.9)
4.4 (3.9–5.1)
5.0 (1.5–8.1)
82 (70)
77 (64)
61 (59)
60 (62)
10 (11)
44 (39)
1.4 (1.0–2.0)
4.3 (3.8–5.0)
3.5 (1.5–8.5)
93 (71)
86 (65)
60 (55)
75 (69)
16 (16)
44 (35)
1.4 (0.9–1.8)
4.2 (3.7–4.9)
4.0 (1.5–8.5)
93 (73)
82 (64)
72 (65)
74 (71)
22 (23)
40 (32)
* Except where indicated otherwise, values are the number (%). RA ⫽ rheumatoid arthritis; IQR ⫽ interquartile range; HAQ ⫽
Health Assessment Questionnaire; DAS ⫽ Disease Activity Score; SHS ⫽ Sharp/van der Heijde score; ACPA ⫽ anti–citrullinated
protein antibody.
† n ⫽ 455.
‡ n ⫽ 428.
§ n ⫽ 417.
¶ n ⫽ 383.
# n ⫽ 487.
Paired (in random order) radiographs of the hands and feet
were scored according to the Sharp/van der Heijde method
(15), under blinded conditions. The intraobserver coefficients
were 0.90 and 0.91, and the interobserver coefficient was 0.94.
The mean score from the 2 observers was used for all analyses.
Erosive disease was defined as a mean erosion score of ⱖ0.5.
Progressive disease was defined as a change in the total
Sharp/van der Heijde score (SHS) over 2 years greater than the
smallest detectable change (i.e., 4.64) (10).
Statistical analysis. Baseline characteristics were compared among subgroups of patients by analysis of variance or
Kruskal-Wallis test for comparison of means and medians, and
chi-square test for comparison of proportions. Progression of
radiographic damage was compared between subgroups of
patients, defined based on the presence or absence of SE,
DERAA, RF, and ACPA, in each of the 4 treatment groups.
Logistic regression analysis was performed to evaluate
whether progressive disease was significantly influenced by the
presence of SE, DERAA, RF, or ACPA in any of the
treatment groups after correction for characteristics significantly associated with radiographic outcome and/or presence
of SE, DERAA, RF, or ACPA. The following baseline characteristics were analyzed for possible association with SE
carriership, DERAA carriership, presence of RF, presence of
ACPA, or progressive disease: sex, age, smoking status, duration of symptoms, DAS, CRP level, duration of morning
stiffness, HAQ score, SHS, and erosive disease. All variables
shown to be significantly different between patients with and
those without the characteristic of interest were entered into
the regression analyses as possible confounders (with cutoffs
for continuous variables defined by the mean value in the
population under study).
RESULTS
At baseline, disease characteristics of patients in
the 4 groups were comparable (Table 1). Sixty-seven
percent of the patients were SE carriers and 17% were
DERAA carriers, with equal distribution among the
treatment groups. Sixty-five percent of the patients were
RF positive and 61% were ACPA positive, also with
equal distribution among the 4 groups. Over 2 years of
followup, radiographic progression (beyond the smallest
detectable change) was observed in 44 patients in group
1 (40%), 36 in group 2 (34%), 23 in group 3 (19%), and
21 in group 4 (18%) (P ⬍ 0.001 for comparison of all
groups).
Radiographic progression was compared between patients with and patients without the SE,
DERAA, RF, or ACPA, in each of the treatment
groups. Over 2 years of followup, radiographic progression was not significantly different between patients with
and those without the SE (Figure 1A), or between
patients with and those without DERAA. The median
(interquartile range [IQR]) change in the SHS in SE-
1296
DE VRIES-BOUWSTRA ET AL
Figure 1. Radiographic progression (Sharp/van der Heijde score;
probability plots) over 2 years among rheumatoid arthritis patients in
the 4 treatment groups, according to the presence (solid symbols) or
absence (open symbols) of the shared epitope (A), rheumatoid factor
(B), and anti–citrullinated protein antibody (C). combi ⫽ combination
therapy.
negative and SE-positive patients, respectively, was 1.0
(⫺0.5, 5.0) and 3.8 (0.1, 11.6) in group 1, 1.0 (0.0, 3.0)
and 3.0 (0.5, 10.0) in group 2, 2.1 (0.5, 4.8) and 1.0 (0.0,
5.5) in group 3, and 0.0 (⫺0.5, 1.1) and 1.5 (0.0, 4.0) in
group 4 (P ⬎ 0.05 for all comparisons). The change in
the SHS in DERAA-negative and DERAA-positive
patients, respectively, was 3.3 (0.0, 10.9) and 1.5 (⫺0.5,
5.0) in group 1, 2.0 (0.5, 9.5) and 3.8 (0.8, 10.3) in group
2, 1.0 (0.0, 3.0) and 0.8 (0.0, 3.9) in group 3, and 1.5 (0.0,
4.0) and 1.0 (0.0, 4.0) in group 4 (P ⬎ 0.05 for all
comparisons) (probability plots not shown because of
the small number of DERAA carriers).
Among patients treated with sequential monotherapy, step-up combination therapy, and initial combination therapy including infliximab (groups 1, 2, and 4,
respectively), radiographic progression scores were sig-
nificantly higher in RF-positive patients compared with
RF-negative patients, and in ACPA-positive patients
compared with ACPA-negative patients (Figures 1B and
C). The median (IQR) change in the SHS in RFnegative and RF-positive patients, respectively, was 0.0
(⫺0.5, 3.9) and 4.8 (0.5, 20.0) in group 1, 1.0 (0.0, 4.0)
and 2.5 (0.5, 11.1) in group 2, and 0.5 (0.0, 1.5) and 1.5
(0.0, 4.3) in group 4. In ACPA-negative and ACPApositive patients, respectively, these values were 0.0
(⫺0.5, 2.1) and 5.0 (0.5, 21.5) in group 1, 0.8 (0.0, 3.9)
and 3.0 (1.0, 11.5) in group 2, and 0.0 (0.0, 1.5) and 2.0
(0.0, 4.5) in group 4 (P ⬍ 0.05 for all comparisons).
Among patients treated with initial combination therapy
including prednisone (group 3), radiographic progression scores were comparable between RF-negative and
RF-positive patients and between ACPA-negative and
GENETIC AND ANTIBODY ASSOCIATIONS WITH RA PROGRESSION, BY TREATMENT
1297
Table 2. Risk (OR [95% confidence interval]) for progressive disease with presence of the shared
epitope, DERAA, rheumatoid factor, or ACPA*
Treatment group
Shared epitope
DERAA
Rheumatoid factor
ACPA
Sequential
monotherapy
Step-up
combination
therapy
Initial
combination
therapy with
prednisone
Initial
combination
therapy with
infliximab
1.4 (0.4–5.0)
0.4 (0.1–1.2)
4.7 (1.5–14.5)
12.6 (3.0–51.9)
2.6 (0.8–8.7)
1.4 (0.3–5.5)
1.5 (0.5–4.9)
3.4 (0.8–14.2)
1.9 (0.5–7.4)
0.9 (0.2–3.7)
1.0 (0.3–3.3)
1.7 (0.5–5.4)
3.0 (0.7–13.0)
0.9 (0.2–3.1)
1.4 (0.4–4.8)
1.8 (0.5–6.8)
* All odds ratios (ORs) corrected for presence of erosions at baseline. OR for shared epitope corrected
for anti–citrullinated protein antibody (ACPA) status and C-reactive protein level at baseline; OR for
DERAA corrected for age; OR for rheumatoid factor and ACPA corrected for sex, smoking status, shared
epitope status, and Disease Activity Score.
ACPA-positive patients (Figures 1B and 1C) (median
[IQR] change 0.8 [0.0, 2.0] and 1.0 [0.0, 3.0] in RFnegative and RF-positive patients, respectively, and 1.0
[0.0, 2.5] and 1.0 [0.0, 2.8] in ACPA-negative and
ACPA-positive patients, respectively) (P ⬎ 0.05 for both
comparisons).
Next, logistic regression analyses were performed
to correct for possible confounders. SE carriership (corrected for ACPA status, CRP level, and erosions at
baseline) did not predict progressive disease in any of
the treatment groups. DERAA carriership (corrected
for age and erosions at baseline) did not protect against
progressive disease. RF and ACPA (both corrected for
sex, smoking status, SE, DAS, and erosions at baseline)
were predictive of progressive disease in patients treated
with sequential monotherapy, but not in the other
treatment groups (Table 2).
DISCUSSION
This analysis of data from the BeSt study showed
no significant association between HLA–DRB1 status
and radiographic progression in patients with early,
active RA who were treated according to closely monitored strategies with protocol-based therapy adjustments. These findings are consistent with earlier observations by Lard et al (8). An association between the
presence of RF or ACPA and radiographic progression
was observed only in patients treated with sequential
monotherapy.
Given the relatively small numbers of patients
with progressive disease (progression greater than the
smallest detectable change), the observed lack of association between radiographic progression and genetic
and antibody status could be due to a lack of power
(Type II error). However, in groups 1 and 2, a considerable number of patients exhibited progressive disease
(44 patients and 36 patients, respectively). In addition, to
further confirm our observations, we repeated the regression analyses with radiographic progression defined
as a 2-year change in the SHS of ⬎0.5. Fifty-nine percent
(n ⫽ 66), 67% (n ⫽ 70), 54% (n ⫽ 66), and 54% (n ⫽
63) of the patients in groups 1, 2, 3, and 4, respectively,
had radiographic progression of ⬎0.5. Results of regression analyses were comparable with those obtained using
the smallest detectable change as the cutoff: only among
patients in group 1 did the presence of ACPA and RF
predict radiographic progression (odds ratio 2.8 [95%
confidence interval 1.0–7.9] and odds ratio 3.4 [95%
confidence interval 1.2–9.4], respectively).
Although several hypotheses have been formulated to explain the contribution of biologic pathways to
disease induction and progression, current data suggest
that with early and aggressive intervention, a selfperpetuating state of the autoimmune response can be
interrupted or even prevented, resulting in less severe
joint damage. This could also include a drug-specific
effect on antibody-related disease processes.
Given the intensive treatment protocol in the
BeSt study, involving adjustments of therapy every 3
months as necessary to achieve a DAS of ⱕ2.4, it is
difficult to evaluate drug-specific effects in the current
context. However, the majority of patients in groups 3
and 4 exhibited good clinical response to the initially
prescribed combinations, and radiographic progression
was the least frequent in these groups (10). Thus, one
could speculate that either high-dose prednisone or the
combination of a tumor necrosis factor inhibitor and
methotrexate is essential for most effective inhibition of
1298
DE VRIES-BOUWSTRA ET AL
joint destruction. By combining methotrexate with a
tumor necrosis factor inhibitor, RANK activation is
inhibited via at least 2 different pathways (16). Recent
basic and clinical research has also demonstrated impressive protective effects of glucocorticoids on development of erosions (17).
A significant protective effect of DERAA carriership was not observed in the present study. However,
only a small minority of patients in the cohort (67
patients [17%]) were DERAA positive. In the analysis of
DERAA, the odds ratio of radiographic progression was
0.4 (95% confidence interval 0.1–1.2) among patients
receiving sequential monotherapy (group 1). Consequently, the possibility cannot be ruled out that a
protective effect would have been observed among
patients receiving this treatment had the group included
more patients who were positive for DERAA.
In conclusion, no significant association between
HLA–DRB1 status and radiographic progression was
found in patients with early RA treated with the goal of
tight control of the DAS. Autoantibodies were predictive of progressive disease only among patients who
received sequential monotherapy. The current observations thus suggest that effective treatment can prevent
radiographic progression in RA, even among patients
who might be otherwise prone to more severe damage.
AUTHOR CONTRIBUTIONS
Dr. de Vries-Bouwstra had full access to all of the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study design. De Vries-Bouwstra, Kerstens, Breedveld, Dijkmans,
Huizinga, Allaart.
Acquisition of data. De Vries-Bouwstra, Goekoop-Ruiterman, Verpoort, Schreuder, Ronday, Ewals, Terwiel, Kerstens, Toes, de Vries,
Dijkmans, Allaart.
Analysis and interpretation of data. De Vries-Bouwstra, GoekoopRuiterman, Kerstens, de Vries, Breedveld, Huizinga, Allaart.
Manuscript preparation. De Vries-Bouwstra, Kerstens, de Vries,
Breedveld, Dijkmans, Huizinga, Allaart.
Statistical analysis. De Vries-Bouwstra.
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progressive, treatment, antibodies, relations, strategia, joint, hladrb1, different, damage, early, anticitrullinated, factors, protein, arthritisassociation, rheumatoid
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