close

Вход

Забыли?

вход по аккаунту

?

Rheumatoid arthritis joint progression in sustained remission is determined by disease activity levels preceding the period of radiographic assessment.

код для вставкиСкачать
ARTHRITIS & RHEUMATISM
Vol. 60, No. 5, May 2009, pp 1242–1249
DOI 10.1002/art.24433
© 2009, American College of Rheumatology
Rheumatoid Arthritis Joint Progression in
Sustained Remission Is Determined by Disease Activity Levels
Preceding the Period of Radiographic Assessment
D. Aletaha,1 J. Funovits,1 F. C. Breedveld,2 J. Sharp,† O. Segurado,3 and J. S. Smolen4
Objective. Joint damage is related to disease
activity in rheumatoid arthritis (RA), but the degree of
its progression and the temporal associations between
disease activity and joint damage are unclear. The aim
of this study was to evaluate whether there is a latency
in the effect of disease activity on radiographic progression in patients with RA.
Methods. Data were obtained from the PREMIER
trial, a 2-year randomized, controlled clinical trial of
adalimumab plus methotrexate versus methotrexate
alone or adalimumab alone in early RA. Radiographic
progression of joint damage was calculated using the
modified total Sharp score in a subset of patients whose
disease was in remission (Simplified Disease Activity
Index <3.3) in the second year of the trial. The progression of damage in the second year was compared
between groups of patients whose disease was already in
remission for an additional period of 3, 6, or 9 months
during the first year. Analysis of variance was used to
test for a linear trend.
Results. Among 794 patients with early RA, 119
(15%) achieved sustained remission during the second
year, with no difference in radiographic progression
across the 3 treatment groups. Radiographic progression in the second year was significantly different between patients with 3, 6, or 9 additional months of
remission during year 1 (mean change in the modified
Sharp score 1.19 in those with 3 additional months of
remission versus 0.20 in those with 6 additional months
of remission and ⴚ0.32 in those with 9 additional
months of remission; P < 0.05). The results were
supported by similar findings in a series of sensitivity
analyses.
Conclusion. These data indicate that the level of
disease activity as well as the duration of remission
affect subsequent progression of radiographic damage
in RA. This latency between disease activity and its
effects on radiographic progression should be considered
when evaluating radiographic outcomes in trials of RA.
Supported in part by a grant from St. Anna Children’s
Hospital, Vienna, Austria.
1
D. Aletaha, MD, MSc, J. Funovits, Dipl Ing: Medical University of Vienna, Vienna, Austria; 2F. C. Breedveld, MD, PhD:
Leiden University Medical Center, Leiden, The Netherlands; 3O.
Segurado, MD, PhD: Abbott Laboratories, Abbott Park, Illinois; 4J. S.
Smolen, MD: Medical University of Vienna and Hietzing Hospital,
Vienna, Austria.
†
Dr. Sharp is deceased.
Dr. Aletaha has received consulting fees from Abbott Laboratories (less than $10,000). Dr. Breedveld has received consulting
fees, speaking fees, and/or honoraria from Wyeth, Abbott Laboratories, and Schering-Plough (less than $10,000 each). Dr. Segurado owns
stock options in Abbott Laboratories and has applied for a patent
related to Humira. Dr. Smolen has received consulting fees, speaking
fees, and/or honoraria from Abbott Laboratories (less than $10,000),
as well as grants.
Address correspondence and reprint requests to D. Aletaha,
MD, MSc, Division of Rheumatology, Medical University of Vienna,
Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail:
daniel.aletaha@meduniwien.ac.at.
Submitted for publication August 6, 2008; accepted in revised
form January 10, 2009.
Joint destruction is the major hallmark of rheumatoid arthritis (RA) (1) and is usually evaluated by
radiographic imaging (2,3). It constitutes the irreversible
component of the RA disease process (4), accumulating
with time and leading to increasing disability (5–8).
Thus, joint damage is associated with bad outcomes in
RA (5,8,9).
Several risk factors have been linked with joint
destruction (1,9–11), and it is unequivocally recognized
that joint damage increases with increasing disease
activity (6,7,11–16). However, progression of joint destruction is not always directly coupled to the signs and
symptoms of RA, since, with the advent of tumor
necrosis factor (TNF) inhibitors, it has been noted that
joint damage can be retarded or stopped even if active
disease prevails (17,18). Nevertheless, because joint
1242
PROGRESSION OF JOINT DAMAGE IN RA REMISSION
destruction is a clear sequela of disease activity, it can be
stated, in relation to the outcomes of any therapy, that
only the induction of remission can reliably halt disease
progression, and therefore this outcome should be a goal
in the treatment of RA.
However, there have been recent reports that
joint damage can accrue even in states of remission
(19,20), and several reasons for this finding have been
discussed. However, a question not sufficiently addressed is whether there is a lag time until the consequences of disease activity can be visualized as joint
damage on conventional radiographs, since resolution of
inflammation may not necessarily mean immediate halting of the destructive process.
In the majority of RA patients, joint damage
becomes visible after ⬃1–2 years of disease (21,22), long
after the occurrence of signs and symptoms of synovitis.
Moreover, in experimental models of destructive arthritis, synovitis and clinical symptoms precede the occurrence of histologic joint erosions, although osteoclasts,
the pivotal cell population involved in bony damage, are
activated even earlier (23). Thus, the evolution of joint
destruction may require the prolonged presence of
inflammatory cytokines. Vice versa, halting of progressive disease activity may require a prolonged absence of
mediators of inflammation.
In the present study, we evaluated the possibility
that disease activity levels before a baseline radiograph
is obtained might influence the progression of radiographic damage that will become visible on a subsequent
radiograph. To investigate the presence of such a “carryover” effect of disease activity on joint damage, we used
a large clinical trial database of patients with early RA
who were treated with methotrexate (MTX) monotherapy, adalimumab monotherapy, or the combination
of adalimumab plus MTX (24), with a 2-year followup of
disease activity and radiographic assessments.
PATIENTS AND METHODS
Source data. We used data from the PREMIER trial,
a multicenter, randomized, double-blind, controlled, phase III
clinical trial comparing adalimumab (40 mg every other week),
MTX (mean dosage 16.9 mg weekly), and the combination of
adalimumab and MTX in patients with early RA who had not
been previously treated with MTX (24). For the present study,
we were provided data on all patients enrolled in the trial. A
central institutional review board or independent ethics committee at each participating site had approved the study, and
all patients had provided written informed consent.
Patients enrolled in the PREMIER trial were required
to be at least 18 years of age, to have been given the diagnosis
of RA (25) within 3 years before the trial start, and to have had
1243
no prior treatment with MTX. In addition, patients had to be
either positive for rheumatoid factor or have erosions in at
least 1 joint on radiographic assessment. In addition, patients
were required to have active disease at the start of the study,
defined as ⱖ8 swollen joints, ⱖ10 tender joints, and an
erythrocyte sedimentation rate (ESR) of ⱖ28 mm/hour or a
C-reactive protein (CRP) concentration of ⱖ1.5 mg/dl.
Outcome measures. Using the source data, which
included the swollen joint count (SJC), the tender joint count
(TJC), patient’s and evaluator’s global assessments of disease
activity (PGA and EGA, respectively) on a visual analog scale
(in cm), and the ESR or CRP level (26), we were able to
calculate the Simplified Disease Activity Index (SDAI) (sum of
the SJC ⫹ TJC ⫹ PGA ⫹ EGA ⫹ CRP) (27). The SDAI has
been extensively validated and frequently used in RA outcomes research, and was therefore used as the main measure
of disease activity in the present study, since it provides a
stringent criterion for remission (28,29). The Clinical Disease
Activity Index (CDAI) (sum of the SJC ⫹ TJC ⫹ PGA ⫹
EGA) was used for validation purposes (14,27). In addition to
the CDAI, the Disease Activity Score in 28 joints using the
CRP level (DAS28-CRP), calculated as (0.56 ⫻ 公TJC28) ⫹
(0.28 ⫻ 公SJC28) ⫹ (0.36 ⫻ lognat[CRP ⫹ 1]) ⫹ (0.014 ⫻
global health) ⫹ 0.96, which is based on the traditional DAS28
(30), was used for validation purposes. The disease activity
states of remission and low, moderate, or high disease activity
have previously been defined on the basis of all of these scoring
systems (26). In the SDAI, the respective cutoff values for
remission, low disease activity, moderate disease activity, and
high disease activity are scores of ⱕ3.3, ⬎3.3–11, ⬎11–26, and
⬎26, respectively (31).
Radiographs were obtained at baseline, year 1, and
year 2. Four readers with no knowledge of the treatment
allocations were used for this study, with 2 of these readers
reviewing the radiographs of each patient and assessing joint
erosions (on a scale of 0–5) and joint space narrowing (on a
scale of 0–4), using the modified total Sharp score (2). The
readers were blinded to the sequence of the radiographic
images. Only patients with complete clinical followup data at
baseline, 3, 6, 9, 12, 15, 18, 21, and 24 months, as well as total
Sharp scores available from all 3 radiographic assessments,
were evaluated in this post hoc analysis of the trial.
Statistical analysis. In the initial analysis of the data,
we identified the degree of radiographic progression during
the second year of the PREMIER study for patients with
different disease activity levels in the second year. We therefore used the area under the disease activity curve (AUC) of
the SDAI in the second year of the study (based on the
radiographic assessments every 3 months), and adjudicated
patients to groups according to defined disease activity levels,
with those in remission having an SDAI-AUC of ⱕ3.3, those
with low disease activity having an SDAI-AUC ⬎3.3 to ⱕ11,
those with moderate disease activity having an SDAI-AUC
⬎11 to ⱕ26, and those with high disease activity having an
SDAI-AUC ⬎26. We performed these analyses separately for
the adalimumab, MTX, and adalimumab plus MTX groups.
Based on the observations in previous studies (32), we
expected that patients whose disease was in sustained remission, irrespective of therapy, would have no radiographic
progression, and that there would be no difference between
1244
ALETAHA ET AL
the 3 treatment groups in this regard. Therefore, we pooled the
3 treatment arms to address the questions on the effects of
sustained remission on radiographic progression. To this end,
we selected only the subgroup of patients who had an SDAIAUC ⱕ3.3 during the second year of the study. In this
subgroup of patients whose disease was in remission in the
second year, we then analyzed the effect of disease activity
levels during the first year on radiographic progression during
the second year. Graphically, the results are depicted as bar
charts to compare mean progression, and we used probability
plots to compare the distribution of individual patients. Parametric methods (analysis of variance [ANOVA] with testing
for a linear trend component) were used to compare radiographic progression between the 3 groups.
The impact of disease activity in the first year on
progression of joint damage in the second year was assessed by
evaluating whether the duration of remission prior to the visit
at month 12 was relevant. For this purpose, all patients whose
disease was in remission in year 2 were used. Similar to the
definition of year 2 remission, year 1 remission was again
defined based on the SDAI-AUC, i.e., the respective period of
year 1 during which the time-integrated SDAI did not exceed
3.3. We thus compared 3 groups of patients according to the
additional number of months in remission in year 1, as follows:
1) patients whose disease was already in remission from month
9 to month 12 (3 additional months in remission), 2) patients
whose disease was in remission from month 6 to month 12 (6
additional months in remission), and 3) patients whose disease
was in remission from month 3 to month 12 (9 additional
months in remission). An analysis of 0–12 months was not
performed, because disease activity was high for all patients at
the baseline visit, given the inclusion criteria, and therefore no
patient would be ascertainable for such a group.
To test the robustness of the results, we performed
additional analyses with modified parameters. In one sensitivity analysis, we defined the disease activity categories based on
other disease activity indices, the CDAI and the DAS28. We
also investigated whether the trend observed in the pooled
group would be present if analyses were done separately in the
MTX, adalimumab, and adalimumab plus MTX groups. Finally, to further support the concept of a carry-over effect, we
investigated the year 2 progression in 3 patient groups based
on 3 tertiles of average disease activity during year 1 (defined
as the bottom, middle, or top tertile on the basis of the
SDAI-AUC from month 3 to month 12).
P values less than 0.05 were considered significant. All
analyses were performed using the SAS package, version 9.1.3
(SAS Institute, Cary, NC).
RESULTS
Patients. In the PREMIER trial, 799 patients
were randomized to receive treatment, of whom 268
were in the adalimumab plus MTX combination group,
257 were in the MTX monotherapy group, and 274 were
in the adalimumab monotherapy group. Of these, 794
patients had complete radiographic data at baseline,
year 1, and year 2. For the analyses on radiographic
progression in the second year, 501 patients had com-
Figure 1. Radiographic progression of rheumatoid arthritis joint
damage in year 2 by treatment group of patients categorized by
average disease activity level in year 2 on the basis of the Simplified
Disease Activity Index (with remission, low disease activity, moderate
disease activity, and high disease activity defined as scores of ⱕ3.3,
⬎3.3–11, ⬎11–26, and ⬎26, respectively). Radiographic progression
varied between the treatment groups, except among the patients whose
disease was in remission. Bars show the mean and SEM change in the
modified total Sharp score for radiographic progression.
plete data on SDAI scores available (190 in the combination group, 158 in the MTX group, and 153 in the
adalimumab group). Because the numbers of missing
data items were different depending on the scoring
system, the numbers of patients with complete data
varied when the CDAI or DAS28-CRP was used to
assess disease activity levels, particularly in the main
analysis that focused on the subgroups with different
duration of remission in year 1. Therefore, the demographics and clinical characteristics of the different
subsets of patients are not presented herein, but these
data can be obtained from the previously published
report on all patients studied in the PREMIER trial
(24). In our study, the characteristics of the patients in
the subgroups did not differ across the 3 treatment
groups (results not shown).
PROGRESSION OF JOINT DAMAGE IN RA REMISSION
Radiographic progression in different disease
activity states. Among the group of patients whose
disease was in sustained remission as defined by the
SDAI during the second year of the study, the extent of
radiographic progression was similar in all 3 treatment
groups (mean change in the modified total Sharp score
0.05 in the MTX group, 0.13 in the adalimumab group,
and ⫺0.14 in the adalimumab plus MTX group). Moreover, the mean radiographic progression did not significantly differ from 0, as indicated by the standard errors
of the mean for each treatment group of patients whose
disease was in sustained remission (Figure 1). This halt
of progression was not seen in patients in any other
disease activity state, although patients who received
treatment with adalimumab in combination with MTX
generally showed less radiographic progression compared with those in either the MTX monotherapy or the
adalimumab monotherapy group.
Similar results were obtained when disease activity states were defined using the CDAI or the DAS28CRP, although, on the basis of the higher stringency of
the SDAI and CDAI (29,31,33), more patients were
considered to have disease in remission and fewer were
grouped in the low disease activity state when categorized by the DAS-CRP than when categorized by the
SDAI or CDAI. Consequently, radiographic progression
of joint damage in patients considered to have disease in
1245
remission according to the DAS28-CRP was numerically
higher in the MTX monotherapy group as compared
with the other 2 treatment groups (results not shown).
As reported previously in patients receiving other TNF
inhibitors (17,18), the combination of adalimumab plus
MTX retarded progression of joint damage at all disease
activity levels and virtually halted it in those categorized
to the low disease activity state (Figure 1). Based on the
fact that there was essentially no radiographic progression in the group of patients whose disease was in
SDAI-defined remission in any of the 3 therapy groups
(Figure 1), which is consistent with previous results from
a similar study (17), we pooled the 3 treatment groups
for further analyses of joint damage progression in
patients whose disease was in remission.
Carry-over effect of previous disease activity.
Among the 794 patients with early RA, 119 (15%) (29 in
the MTX group, 66 in the adalimumab plus MTX group,
and 24 in the adalimumab group) had achieved a disease
activity level of sustained remission according to the
SDAI throughout months 12–24. In these patients, the
mean ⫾ SEM progression of the modified total Sharp
score during year 1 was 1.0 ⫾ 2.8.
To address a possible carry-over effect into year
2, we investigated whether the duration of remission
during the first year influenced the levels of radiographic
progression during the second year. As shown in Figures
Figure 2. Carry-over effect of disease activity on radiographic damage. A, Analysis of the duration of remission in year 1 (n ⫽ 14 for
9 additional months in remission, n ⫽ 22 for 6 additional months, and n ⫽ 52 for 3 additional months) in relation to radiographic
progression during the second year. Bars show the mean and SEM change (mean values over the bars) in the modified total Sharp
score for the pooled treatment group, using the Simplified Disease Activity Index (SDAI) as the disease activity instrument. P ⬍ 0.05
between groups, by analysis of variance with linear trend test. B, Analysis of the same data as in A, using probability plots to depict
the actual distribution of year 2 radiographic progression among the year 1 remission groups.
1246
ALETAHA ET AL
Figure 3. Sensitivity analyses to support the results from the main analysis with the Simplified Disease Activity Index (SDAI). Analysis of the
duration of remission in year 1 in relation to radiographic progression during the second year was carried out in the pooled treatment group using
definitions of year 1 disease activity states from A, the Clinical Disease Activity Index (CDAI), which does not include the C-reactive protein (CRP)
level as a component (n ⫽ 55 for 9 additional months in remission, n ⫽ 24 for 6 additional months, and n ⫽ 14 for 3 additional months) (P ⫽ 0.008
between groups), B, the Disease Activity Score in 28 joints using the CRP level (DAS28-CRP) (n ⫽ 130 for 9 additional months in remission, n ⫽
33 for 6 additional months, and n ⫽ 16 for 3 additional months) (P not significant [NS] between groups), or C, an approach defining the average
levels of disease activity during the first year as tertiles of the area under the SDAI curve (n ⫽ 40 in the bottom tertile, n ⫽ 41 in the middle tertile,
and n ⫽ 40 in the top tertile) (P NS between tertiles). In addition, data from the main analysis using the SDAI to define remission were analyzed
by subgroups according to the individual treatment arms of D, methotrexate monotherapy (n ⫽ 13 for 9 additional months in remission, n ⫽ 8 for
6 additional months, and n ⫽ 2 for 3 additional months) (P ⫽ 0.014 between groups), E, combination of adalimumab and methotrexate (n ⫽ 29 for
9 additional months in remission, n ⫽ 11 for 6 additional months, and n ⫽ 9 for 3 additional months) (0.1 ⬎ P ⬎ 0.05), and F, adalimumab
monotherapy (n ⫽ 10 for 9 additional months in remission, n ⫽ 3 for 6 additional months, and n ⫽ 3 for 3 additional months) (P NS between groups).
Bars show the mean and SEM change (mean values over the bars) in the modified total Sharp score for radiographic progression.
2A and B, the low level of radiographic progression seen
in patients considered to have disease in sustained
remission throughout the second year further decreased
with an increase in the period of remission during the
first year (P ⬍ 0.05 by ANOVA with linear trend)
(Figure 2A).
The average disease activity between month 12
and month 24, which, if it had been dissimilar, could
have accounted for differences in the radiographic progression rate, was similar between the 3 groups of
patients whose disease had additional time in remission
during year 1 (mean SDAI 1.8, 1.5, and 1.4 in those with
3, 6, and 9 additional months of remission in year 1,
respectively; P not significant). Thus, these data indicate
that carry-over effects governed the differences in the
progression rates among patients whose disease was in
remission.
Validation of main results using different definitions. We validated the results from the main analysis of
the average disease activity during the first year in a
series of additional analyses. When we used the CDAI
instead of the SDAI to assess disease activity states, and
PROGRESSION OF JOINT DAMAGE IN RA REMISSION
thus eliminated the potential influence of the CRP level,
results similar to those observed using the SDAI were
obtained in the 3 groups of patients whose disease had
additional time in remission according to the CDAI
(Figure 3A). Likewise, when using the DAS28-CRP
definition of remission (Figure 3B), a similar trend was
found among the 3 groups.
Furthermore, when the effect of average disease
activity according to the SDAI during year 1 was analyzed with the use of tertiles of average disease activity
from month 3 to month 12 (using the SDAI-AUC),
similar patterns were observed; namely, patients in the
lowest tertile of year 1 disease activity had less progression during the second year compared with those in the
second and third tertiles (Figure 3C), although all of
these patients had disease in remission during year 2.
Finally, similar effects were also present within
the individual treatment groups, i.e., the MTX monotherapy group (Figure 3D), the adalimumab plus MTX
group (Figure 3E), and the adalimumab monotherapy
group (Figure 3F). Although these individual treatment
group analyses were stratified, and the numbers remaining in each of the subgroups were very small, the results
taken together support the initial finding that the
achievement of a state of remission and the duration of
that state, rather than the type of therapy, were responsible for the halt of radiographic progression.
DISCUSSION
In this post hoc analysis of data from the PREMIER trial, we addressed the question of whether joint
damage can be generally arrested in states of sustained
remission. This has not been resolved hitherto, because
progression of radiographic changes is known to be
associated with disease activity; however, several reports
have indicated that joint destruction can progress even
in patients who achieve longer-term remission (19,
20,34). To address this issue, we evaluated the scores of
radiographic progression at baseline, year 1, and year 2
in patients from the PREMIER study.
Given the high disease activity in all patients at
entry into the PREMIER study, and considering the
period of time necessary to reduce or halt disease
activity even under the most favorable circumstances, an
evaluation of radiographic changes during the first year
would have provided only limited insights, since the
initial period in active disease may already have driven
joint damage. Analyzing changes in radiographic scores
in the second year using the year 1 radiographs as a
baseline measure, however, ensured that at the time of
1247
the year 1 radiographs, disease in many patients had
already reached low activity or remission. Stringent
criteria for sustained remission were applied by using the
remission definition of the SDAI and by requiring that
remission was sustained throughout the period analyzed.
Although there was a virtual arrest of progression
of radiographic scores at the group level in patients who
maintained remission between month 12 and month 24,
some patients in all 3 treatment groups who showed
progression of radiographic scores despite being in
clinical remission throughout the second year, as depicted in the probability plots in Figure 2B. When we
analyzed whether expanding the duration of remission
into the first treatment year would have an effect on
radiographic changes in the second year, we found that,
indeed, a proportion of patients in whom joint damage
progressed during the second year had attained their
state of remission only shortly, i.e., ⱕ3 months, before
the year 1 radiograph was obtained. This also translated
into progression of radiographic scores at the group
level. In contrast, in 80% of patients who had already
achieved remission for 9 months before the first radiograph was assessed, joint destruction did not progress,
and in the remainder of patients, maximal progression
was numerically lower than that in those with shorter
periods of remission. Therefore, joint damage in RA
does not progress in states of sustained remission in the
majority of patients. However, to fully confirm this fact,
remission has to be present for a prolonged period of
time before the first radiograph is obtained. Thus, we
were able to show that preceding disease activity is a
relevant determinant for radiographic progression between 2 time points.
Several explanations for this finding could be
considered. One explanation would be that disease
activity was misclassified and, rather than remission, low
disease activity prevailed during the observation period,
at least in some patients. However, this is unlikely, since
among patients receiving MTX monotherapy, joint damage was halted only in those whose disease was in
longstanding remission; if remission had been misclassified in these patients, the halt in progression would not
have occurred, given their progression of joint damage
during low disease activity. It might, however, be the
case that subclinical joint inflammation prevails for an
additional period of time after clinical remission has
been achieved (20), leading to smouldering progression
of damage; in this case, the lag time observed in our
study would be overestimated.
As another explanation, joint damage could be an
event that is totally separate from inflammation, at least in
1248
ALETAHA ET AL
a subset of RA patients. However, this would not explain
the results presented, particularly the difference between
shorter- and longer-term remission. Moreover, in light of
the compelling information on the effects of cytokines
involved in RA pathogenesis (35–37) as well as the association of disease activity with joint damage in RA, it is
unlikely that induction of joint destruction can be completely separated from the processes of inflammation.
Yet another explanation for our findings could be
methodologic in nature, in that joint damage may need a
certain amount of time to become visible by radiographic
assessment. Indirect evidence for this hypothesis stems
from data obtained using other imaging techniques, especially magnetic resonance imaging (MRI). Several authors
have suggested that joint damage can be seen much earlier
by MRI than radiologically (20,38). Thus, any identification
of joint damage in the course of remission would be the
consequence of such a lag period in detection.
Finally, our findings could be related to the
biology of joint destruction. In an experimental model of
arthritis, joint damage identified by histology did not
concur with the development of osteoclasts, since the
evolution of erosions takes more time (23); this has also
been observed in clinical practice (21,22). Conversely,
stopping the function of osteoclasts, once they have been
activated, may require a longer time than would the
reversal of inflammation. Regardless of the underlying
mechanism, our finding of reduced joint damage progression in patients with lower disease activity before the
baseline radiograph was assessed supports the hypothesis that joint destruction, at least as detected by traditional radiographs, is subject to a carry-over effect.
In summary, sustained remission is associated
with a halt of joint damage irrespective of the type of
therapy. The shorter the period of remission, the more
likely some mild progression may be found, and this is
likely a consequence of a carry-over effect of past
periods of inflammation. Thus, sustained remission is
the ultimate goal to prevent the occurrence of joint
destruction and, consequently, the accrual of irreversible
disability in RA. Moreover, in the process of therapeutic
decision-making, the assessment of radiographic progression of joint damage will have to account for these
observations regarding the latency of radiographic manifestations in patients with RA.
ACKNOWLEDGMENT
We dedicate this manuscript to our dear friend and
esteemed colleague Dr. John Sharp, who recently passed away,
and to Dr. Sharp’s family. Dr. Sharp’s spirit will continue to
enrich our scientific work.
AUTHOR CONTRIBUTIONS
Dr. Aletaha 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. Aletaha, Smolen.
Acquisition of data. Sharp, Segurado.
Analysis and interpretation of data. Aletaha, Funovits, Breedveld,
Smolen.
Manuscript preparation. Aletaha, Breedveld, Segurado, Smolen.
Statistical analysis. Aletaha, Funovits.
REFERENCES
1. Scott DL, Symmons DP, Coulton BL, Popert AJ. Long-term
outcome of treating rheumatoid arthritis: results after 20 years.
Lancet 1987;1:1108–11.
2. Sharp JT, Young DY, Bluhm GB, Brook A, Brower AC, Corbett
M, et al. How many joints in the hands and wrists should be
included in a score of radiologic abnormalities used to assess
rheumatoid arthritis? Arthritis Rheum 1985;28:1326–35.
3. Van der Heijde DM, van Riel PL, Nuver-Zwart IH, Gribnau FW,
van de Putte LB. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis.
Lancet 1989;1:1036–8.
4. Van der Heijde D, Simon L, Smolen J, Strand V, Sharp J, Boers
M, et al. How to report radiographic data in randomized clinical
trials in rheumatoid arthritis: guidelines from a roundtable discussion. Arthritis Rheum 2002;47:215–8.
5. Scott DL, Pugner K, Kaarela K, Doyle DV, Woolf A, Holmes J, et
al. The links between joint damage and disability in rheumatoid
arthritis. Rheumatology (Oxford) 2000;39:122–32.
6. Drossaers-Bakker KW, de Buck M, van Zeben D, Zwinderman
AH, Breedveld FC, Hazes JM. Long-term course and outcome of
functional capacity in rheumatoid arthritis: the effect of disease
activity and radiologic damage over time. Arthritis Rheum 1999;
42:1854–60.
7. Welsing PM, van Gestel AM, Swinkels HL, Kiemeney LA, van
Riel PL. The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid
arthritis. Arthritis Rheum 2001;44:2009–17.
8. Aletaha D, Smolen J, Ward MM. Measuring function in rheumatoid arthritis: identifying reversible and irreversible components.
Arthritis Rheum 2006;54:2784–92.
9. Sherrer YS, Bloch DA, Mitchell DM, Young DY, Fries JF. The
development of disability in rheumatoid arthritis. Arthritis Rheum
1986;29:494–500.
10. Van Gaalen FA, van Aken J, Huizinga TW, Schreuder GM,
Breedveld FC, Zanelli E, et al. Association between HLA class II
genes and autoantibodies to cyclic citrullinated peptides (CCPs)
influences the severity of rheumatoid arthritis. Arthritis Rheum
2004;50:2113–21.
11. Van Leeuwen MA, van Rijswijk MH, Sluiter WJ, van Riel PL,
Kuper IH, van de Putte LB, et al. Individual relationship between
progression of radiological damage and the acute phase response
in early rheumatoid arthritis: towards development of a decision
support system. J Rheumatol 1997;24:20–7.
12. Kirwan JR. Links between radiological change, disability, and
pathology in rheumatoid arthritis. J Rheumatol 2001;28:881–6.
13. Van der Heijde DM, van Riel PL, van Leeuwen MA, van ’t Hof
MA, van Rijswijk MH, van de Putte LB. Prognostic factors for
radiographic damage and physical disability in early rheumatoid
arthritis: a prospective follow-up study of 147 patients. Br J
Rheumatol 1992;31:519–25.
14. Aletaha D, Nell VP, Stamm T, Uffmann M, Pflugbeil S, Machold
K, et al. Acute phase reactants add little to composite disease
activity indices for rheumatoid arthritis: validation of a clinical
activity score. Arthritis Res Ther 2005;7:R796–806.
PROGRESSION OF JOINT DAMAGE IN RA REMISSION
1249
15. Smolen JS, van der Heijde DM, St.Clair EW, Emery P, Bathon
JM, Keystone E, et al, for the Active-Controlled Study of Patients
Receiving Infliximab for the Treatment of Rheumatoid Arthritis
of Early Onset (ASPIRE) Study Group. Predictors of joint damage in patients with early rheumatoid arthritis treated with highdose methotrexate without or with concomitant infliximab: results
from the ASPIRE trial. Arthritis Rheum 2006;54:702–10.
16. Plant MJ, Williams AL, O’Sullivan MM, Lewis PA, Coles EC,
Jessop JD. Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid
arthritis. Arthritis Rheum 2000;43:1473–7.
17. Smolen JS, Han C, Bala M, Maini RN, Kalden JR, van der Heijde
D, et al for the ATTRACT Study Group. Evidence of radiographic
benefit of infliximab plus methotrexate in rheumatoid arthritis
patients who had no clinical improvement: a detailed subanalysis
of data from the Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy study. Arthritis Rheum
2005;52:1020–30.
18. Landewe R, van der Heijde D, Klareskog L, van Vollenhoven R,
Fatenejad S. Disconnect between inflammation and joint destruction after treatment with etanercept plus methotrexate: results
from the trial of etanercept and methotrexate with radiographic
and patient outcomes. Arthritis Rheum 2006;54:3119–25.
19. Molenaar ET, Voskuyl AE, Dinant HJ, Bezemer PD, Boers M,
Dijkmans BA. Progression of radiologic damage in patients with
rheumatoid arthritis in clinical remission. Arthritis Rheum 2004;
50:36–42.
20. Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy
CG, et al. An explanation for the apparent dissociation between
clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 2008;58:2958–67.
21. Plant MJ, Jones PW, Saklatvala J, Ollier WE, Dawes PT. Patterns
of radiological progression in rheumatoid arthritis: results of an 8
year prospective study. J Rheumatol 1998;25:417–26.
22. Van der Heijde DM. Joint erosions and patients with early
rheumatoid arthritis. Br J Rheumatol 1995;34 Suppl 2:74–8.
23. Hayer S, Redlich K, Korb A, Hermann S, Smolen J, Schett G.
Tenosynovitis and osteoclast formation as the initial preclinical
changes in a murine model of inflammatory arthritis. Arthritis
Rheum 2007;56:79–88.
24. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka
K, van Vollenhoven R, et al, for the PREMIER Investigators. The
PREMIER study: a multicenter, randomized, double-blind clinical
trial of combination therapy with adalimumab plus methotrexate
versus methotrexate alone or adalimumab alone in patients with
early, aggressive rheumatoid arthritis who had not had previous
methotrexate treatment. Arthritis Rheum 2006;54:26–37.
25. Arnett FC, Edworthy SM, Block DA, McShane DJ, Fries JF,
Cooper NS, et al. The American Rheumatism Association 1987
revised criteria for the classification of rheumatoid arthritis.
Arthritis Rheum 1988;31:315–24.
26. Aletaha D, Smolen JS. The definition and measurement of disease
modification in inflammatory rheumatic diseases. Rheum Dis Clin
North Am 2006;32:9–44.
27. Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl
G, et al. A simplified disease activity index for rheumatoid arthritis
for use in clinical practice. Rheumatology (Oxford) 2003;42:
244–57.
28. Aletaha D, Smolen JS. Remission of rheumatoid arthritis: should
we care about definitions? Clin Exp Rheumatol 2006;24(6 Suppl
43):S045–51.
29. Mierau M, Schoels M, Gonda G, Fuchs J, Aletaha D, Smolen JS.
Assessing remission in clinical practice. Rheumatology (Oxford)
2007;46:975–9.
30. Van der Heijde DM, van ’t Hof MA, van Riel PL, Theunisse LA,
Lubberts EW, van Leeuwen MA, et al. Judging disease activity in
clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis 1990;49:916–20.
31. Aletaha D, Ward MM, Machold KP, Nell VP, Stamm T, Smolen
JS. Remission and active disease in rheumatoid arthritis: defining
criteria for disease activity states. Arthritis Rheum 2005;52:
2625–36.
32. Smolen JS, Han C, van der Heijde DM, Emery P, Bathon JM,
Keystone E, et al. Radiographic changes in rheumatoid arthritis
patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of
remission and TNF-blockade. Ann Rheum Dis 2008. E-pub ahead
of print.
33. Van der Heijde D, Klareskog L, Boers M, Landewe R, Codreanu
C, Bolosiu HD, et al. Comparison of different definitions to
classify remission and sustained remission: 1 year TEMPO results.
Ann Rheum Dis 2005;64:1582–7.
34. Mulherin D, FitzGerald O, Bresnihan B. Clinical improvement
and radiological deteriorartion in rheumatoid arthritis: evidence
that pathogenesis of synovial inflammation and articular erosion
may differ. Br J Rheumatol 1996;35:1263–8.
35. Kudo O, Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Blood
2003;32:1–7.
36. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M,
Kotake S, et al. Tumor necrosis factor ␣ stimulates osteoclast
differentiation by a mechanism independent of the ODF/RANKLRANK interaction. J Exp Med 2000;191:275–86.
37. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum
SL. TNF-␣ induces osteoclastogenesis by direct stimulation of
macrophages exposed to permissive levels of RANK ligand. J Clin
Invest 2000;106:1481–8.
38. Ostergaard M, Ejbjerg B, Szkudlarek M. Imaging in early rheumatoid arthritis: roles of magnetic resonance imaging, ultrasonography, conventional radiography and computed tomography. Best
Pract Res Clin Rheumatol 2005;19:91–116.
DOI 10.1002/art.24667
Erratum
In the article by Keystone et al in the November 2008 issue of Arthritis & Rheumatism (pages 3319–3329),
there was an error in the data on serious adverse events leading to death in the group treated with
certolizumab pegol 400 mg plus methotrexate. The incidence rate per 100 patient-years was correctly shown
as 1.3; however, the actual number of deaths should have been listed as 4.
We regret the error.
Документ
Категория
Без категории
Просмотров
7
Размер файла
273 Кб
Теги
progressive, level, radiographic, joint, disease, remission, period, determiners, preceding, arthritis, activity, sustained, assessment, rheumatoid
1/--страниц
Пожаловаться на содержимое документа