Download An explanation for the apparent dissociation between clinical

ARTHRITIS & RHEUMATISM
Vol. 58, No. 10, October 2008, pp 2958–2967
DOI 10.1002/art.23945
© 2008, American College of Rheumatology
An Explanation for the Apparent Dissociation Between
Clinical Remission and Continued Structural Deterioration in
Rheumatoid Arthritis
A. K. Brown,1 P. G. Conaghan,1 Z. Karim,1 M. A. Quinn,1 K. Ikeda,1 C. G. Peterfy,2
E. Hensor,1 R. J. Wakefield,1 P. J. O’Connor,3 and P. Emery1
Objective. Achieving remission is the aim of treatment in rheumatoid arthritis (RA). This should represent minimal arthritis activity and ensure optimal
disease outcome. However, we have previously demonstrated a high prevalence of imaging-detected synovial
inflammation in RA patients who were in clinical remission. The purpose of this study was to evaluate the
long-term significance of subclinical synovitis and its
relationship to structural outcome.
Methods. We studied 102 RA patients receiving
conventional treatment who had been judged by their
consultant rheumatologist to be in remission, as well as
17 normal control subjects. Subjects underwent clinical,
laboratory, functional, and quality of life assessments
over 12 months. In addition to standard radiography
of the hands and feet, imaging of the hands and wrists
was performed with musculoskeletal ultrasonography
(US) and conventional 1.5T magnetic resonance imaging (MRI) at baseline and 12 months, using validated
acquisition and scoring techniques.
Results. Despite their being in clinical remission,
19% of the patients displayed deterioration in radiographic joint damage over the study period. Scores on
musculoskeletal US synovial hypertrophy, power Doppler (PD), and MRI synovitis assessments in individual
joints at baseline were significantly associated with
progressive radiographic damage (P ⴝ 0.032, P < 0.001,
and P ⴝ 0.002, respectively). Furthermore, there was a
significant association between the musculoskeletal US
PD score at baseline and structural progression over 12
months in totally asymptomatic metacarpophalangeal
joints (P ⴝ 0.004) and 12 times higher odds of deterioration in joints with increased PD signal (odds ratio
12.21, P < 0.001).
Conclusion. Subclinical joint inflammation detected by imaging techniques explains the structural
deterioration in RA patients in clinical remission who
are receiving conventional therapy. Our findings reinforce the utility of imaging for the accurate evaluation of
disease status and the prediction of structural outcome.
Supported by a project grant from the Arthritis Research
Campaign.
1
A. K. Brown, MB ChB, MRCP(UK), PhD, P. G. Conaghan,
MB BS, PhD, FRACP, FRCP, Z. Karim, MB BCh, MRCP, MD, M. A.
Quinn, MRCP, MBChB, K. Ikeda, MD, PhD, E. Hensor, PhD, R. J.
Wakefield, BM, MRCP, MD, P. Emery, MA, MD, FRCP: University
of Leeds, and Chapel Allerton Hospital, Leeds, UK; 2C. G. Peterfy,
MD, PhD: Synarc Inc., San Francisco, California; 3P. J. O’Connor,
BM, FRCR: Chapel Allerton Hospital, Leeds, UK.
Dr. Brown has received speaking fees and honoraria from
Schering-Plough and Abbott Laboratories (less than $10,000 each).
Dr. Quinn has received consulting fees, speaking fees, and/or honoraria from Schering-Plough and Abbott Laboratories (less than
$10,000 each). Dr. Peterfy owns stock or stock options in Synarc Inc.
Address correspondence and reprint requests to P. Emery,
MA, MD, FRCP, ARC Professor of Rheumatology, Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, Chapel Allerton Hospital, Leeds LS7 4SA, UK. E-mail:
[email protected].
Submitted for publication September 24, 2007; accepted in
revised form June 27, 2008.
Remission is the aim of treatment in patients with
rheumatoid arthritis (RA) (1). The remission state
should represent an absence of inflammation, synonymous with no clinical symptoms or signs, and should
result in optimal structural, functional, and quality of life
outcomes. Modern RA therapy now enables a more
complete suppression of inflammation, as reflected by
the increasing rates of remission that have been reported
(2–4). However, disease remission may not necessarily
be associated with a consistently good outcome. A
number of reports have suggested a disparity between
clinical state and outcome, providing evidence of progression of joint damage despite apparent remission
(5,6). This observation has been interpreted by some
investigators as evidence of dissociation between syno2958
CLINICAL REMISSION AND CONTINUED STRUCTURAL DETERIORATION IN RA
vitis and subsequent erosive joint damage (5,7). Alternatively, it may reflect the inadequate sensitivity of the
traditional clinical approaches, such as the American
College of Rheumatology (ACR; formerly, the American Rheumatism Association) remission criteria (8) and
the Disease Activity Score 28-joint assessment (DAS28)
criteria (9,10), to accurately detect synovitis and therefore assess true remission status. While these measurement techniques are composite scores based on clinical
and laboratory assessments, they have the disadvantage
of not directly measuring inflammation at the primary
site of disease and may be subject to confounding
influences (11).
We previously studied a cohort of RA patients
with clinically quiescent disease who were treated with
disease-modifying antirheumatic drugs (DMARDs), and
we assessed the prevalence of synovial inflammation
using validated musculoskeletal ultrasonography (US)
and magnetic resonance imaging (MRI) outcome measures (12). We demonstrated that 93% of the patients
had synovitis on MRI and that 85% had synovial hypertrophy on gray-scale (GS) and 60% had increased power
Doppler (PD) signal on musculoskeletal US, even
though the majority of the patients fulfilled the ACR
and DAS28 remission criteria. These results suggested
that satisfying conventional remission criteria may not
accurately reflect an absence of synovial inflammation.
These data generated the hypothesis that subclinical
inflammation detected by imaging techniques may explain the structural progression reported in RA patients
in clinical remission.
In the present study, we performed a longitudinal
evaluation of this DMARD-treated clinical remission
cohort. Our aim was to determine the structural significance of this subclinical inflammation and to investigate
whether imaging-detected synovitis can be used to predict subsequent progression of joint damage.
PATIENTS AND METHODS
Patients and controls. In this prospective longitudinal
cohort study, consultant rheumatologists used their clinical
judgment to identify RA patients from their outpatient clinics
whose disease was considered to be in remission while taking
conventional DMARDs. In addition, all patients satisfied the
following 6 criteria: RA classified according to the ACR
criteria (13), age ⬎18 years, disease duration of at least 12
months, no disease flare within the preceding 6 months, stable
therapy for 6 months, and no clinical indication for a change in
treatment.
A control group of 17 sex-matched normal subjects was
also studied. None of these subjects had a history of joint
disease, nor did they have any musculoskeletal symptoms or
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signs at the time of evaluation. All control subjects underwent
a clinical assessment and an MRI scan of their dominant hand
and wrist at baseline, using the same technique as used in the
RA patients (see below).
Ethical approval for the project was obtained from the
Ethics Committee of the Leeds Teaching Hospitals National
Health Service Trust. Written informed consent was obtained
from all subjects prior to study inclusion.
Study assessments. Inclusion criteria were applied at
–2 months and at 0 months (baseline). At baseline and 12
months, all patients underwent complete clinical, laboratory,
radiographic, functional, quality of life, and imaging assessments. In addition, at 3, 6, and 9 months clinical, laboratory,
functional, and quality of life assessments were performed.
Assessment of demographic and clinical characteristics. Demographic characteristics recorded at baseline included age, sex, duration of current remission, current therapy,
and previous DMARDs received. Clinical data were recorded
at every visit and included the duration of morning stiffness;
Likert and visual analog scales (VAS) for fatigue, joint pain,
physician’s assessment of disease activity, and patient’s global
impression of health and disease activity; and the number of
painful, tender, and swollen joints as assessed by an independent trained metrologist. The Health Assessment Questionnaire (HAQ) (14) and the RA Quality of Life (RAQoL)
questionnaire (15) were completed at every visit, and the
scores were calculated. Remission and disease activity scores at
each visit were calculated using the ACR remission criteria (8)
(5 of 6 criteria satisfied on separate occasions 2 months apart)
and the DAS28 criteria (10).
Laboratory assessment. A complete blood cell count,
erythrocyte sedimentation rate, and C-reactive protein level
were measured at every visit. Rheumatoid factor (RF) titers
and HLA type were determined at baseline to assess the
presence of RA susceptibility (shared epitope) alleles.
Radiographic assessment. Posteroanterior radiographs of the hands, wrists, and feet were obtained at baseline
and at 12 months using standardized techniques. Radiographic
joint damage was scored according to the Genant-modified
Sharp scoring method (16). A single experienced reader
(CGP) who was blinded to all other imaging and clinical
findings and the chronological sequence of the baseline and
followup radiographs performed this assessment.
Ultrasonographic assessment. Each patient underwent
a musculoskeletal US assessment of the joints of the dominant
hand and wrist at baseline and at 12 months using GS and PD
techniques. Eight joint regions were imaged by musculoskeletal US: metacarpophalangeal (MCP) joints 2–5 and the radiocarpal, ulnar-carpal, distal radioulnar, and intercarpal compartments of the wrist. Musculoskeletal US was performed by
a single experienced sonographer (ZK) who was blinded to all
other study findings, using an ATL HDI 3000 machine (ATL
Ultrasound, Bothell, WA) with a 10–5 MHz linear array
“hockey stick” transducer, according to the European League
Against Rheumatism (EULAR) guidelines (17). The presence
and location of any synovial hypertrophy and erosions were
recorded with reference to standardized definitions subsequently agreed upon by the Outcome Measures in Rheumatology (OMERACT) group (18).
Synovial hypertrophy on GS images was graded according to a semiquantitative scoring method (0–3 scale, where
2960
0 ⫽ no synovial hypertrophy, 1 ⫽ mild synovial hypertrophy,
2 ⫽ moderate, and 3 ⫽ severe) (19,20). The area of maximum
enhancement on PD images was recorded using a previously
described semiquantitative technique (0–3 scale, where 0 ⫽
normal/minimal vascularity, 1 ⫽ mild hyperemia, 2 ⫽ moderate, and 3 ⫽ marked) (21). Erosions were scored according to
their location and severity/size using a similar 0–3 semiquantitative scale (22). Each patient’s total musculoskeletal US
score for each pathologic feature (GS/PD/erosion) was calculated by summing the corresponding scores for each joint
region.
Magnetic resonance imaging assessment. MRI of the
dominant hand and wrist was performed at baseline and 12
months using a conventional 1.5T Phillips MRI scanner (Philips, Surrey, UK). The same joint regions were imaged by MRI
as for musculoskeletal US. The subjects were placed in a
supine position with their arm outstretched in a “superman”
position. A dual-coil approach was used in order to image the
hand and wrist in a single sitting. T1 and T1 spectral presaturation with inversion recovery (SPIR; a method of fat suppression) sequences were recorded in the axial and coronal planes
after intravenous administration of gadolinium.
Synovitis, bone marrow edema (BME), and erosions
were defined according to OMERACT guidelines (23). Images
were graded by a single experienced reader (PGC) who was
blinded to all other imaging and clinical findings, using the
OMERACT RA MRI Scoring (RAMRIS) system (23). Synovitis was scored semiquantitatively (0–3 scale, where 0 ⫽
normal, 1 ⫽ mild, 2 ⫽ moderate, and 3 ⫽ severe), with each
point representing one-third of the maximum volume of
enhancing tissue in the synovial compartment. A similar
method was used to score BME, corresponding to the proportion of each bone containing edema (0–3 scale, where 0 ⫽ no
edema, 1 ⫽ 1–33% of bone edematous, 2 ⫽ 34–66%, and 3 ⫽
67–100%). Erosions were graded on a scale of 0–10, with each
point representing a 10% loss of bone volume. Each patient’s
total MRI score for each pathologic feature (synovitis/BME/
erosion) was calculated by summing the corresponding scores
for each joint region.
Statistical analysis. Data evaluation and statistical
analysis were performed using SPSS version 14.0 software
(SPSS, Chicago, IL). Analyses were conducted at the patient
and individual joint level. Patients were also stratified according to standard clinical remission criteria (ACR and DAS28) as
well as signs and symptoms (“asymptomatic” patients had
clinically normal joints without any evidence of pain, tenderness, or swelling). Normally distributed continuous data were
analyzed using parametric tests (independent t-test) and were
summarized with means and 95% confidence intervals (95%
CIs). Non-normally distributed and ordinal data were analyzed
using nonparametric tests (Wilcoxon’s signed rank test, MannWhitney U test) and were summarized with medians and
interquartile ranges (IQRs). Categorical data were analyzed
using chi-square tests, with continuity correction where necessary if the expected frequency for a cell in a cross-table was ⬍5.
Binary logistic regression was used to examine which baseline
factors were associated with radiologic progression. HAQ and
RAQoL data were Rasch-transformed to linearity (24). Intrareader reliability of radiographic scoring was assessed using
the Bland-Altman plot technique (25). The smallest detectable
BROWN ET AL
change (SDC) for paired radiographic change scores was
calculated according to the following formula:
SDC ⫽ 1.96 ⫻ SDdifference in change scores/冑2 ⫻
冑k
where k represents the number of readings over which one wants
to average the analyses of the trial (in this case, k ⫽ 1) (26).
RESULTS
Patient population. A total of 102 RA patients
who satisfied the inclusion criteria were evaluated. Full
sets of radiographs at both time points (baseline and 12
months) were available for 90 patients; these formed the
core dataset for the imaging analysis. Patients who did
not have a complete set of films did not differ significantly from those with complete data in terms of age,
sex, shared epitope, RF positivity at baseline, or ACR/
DAS28 remission status throughout the study. Due to
patient migration and contraindications or intolerance
of scanning procedures, complete MRI and musculoskeletal US data at both time points were not available
for all patients.
Demographic, clinical, and laboratory characteristics at baseline. The baseline demographic, clinical,
and laboratory characteristics of the RA patients are
shown in Table 1. The study population was predominantly female (67%) and had a mean age of 57 years;
64% of were RF positive, and 61% were shared epitope
positive. The median disease duration was 7 years, and
the median period of remission at the baseline assessment was almost 2 years. During the course of their
disease, 99% of the patients had received DMARD
therapy, and the majority had received ⬎1 such drug. At
baseline, 91% of the cohort were currently taking
DMARDs, with oral methotrexate and sulfasalazine
being the most commonly used medications. Twenty-one
percent of the patients were taking combination
DMARD therapy, and 2 of the patients had previously
received biologic agents. Thirty-nine percent were currently receiving a nonsteroidal antiinflammatory drug
(NSAID), and 2% were taking oral prednisolone (all ⱕ5
mg/day).
Clinical and laboratory measures of disease activity all showed low activity, as measured by VAS
assessments, the duration of early morning stiffness, the
formal joint counts, and levels of acute-phase reactants.
The study group had generally low levels of functional
impairment, as measured by the HAQ (median 0.31
[IQR 0.14–0.57]), and had mild-to-moderate quality of
life impairment, as measured by the RAQoL (median
7.5 [IQR 3.5–13.5]). A total of 54% fulfilled the ACR
CLINICAL REMISSION AND CONTINUED STRUCTURAL DETERIORATION IN RA
Table 1.
2961
Demographic, clinical, and laboratory features of the 102 RA patients at baseline*
Age, mean (range) years
Sex, % female/male
Duration of RA, median (range) years
Duration of remission, median (range; IQR) months
% RF positive (median titer)
% shared epitope positive
Homozygotes
Heterozygotes
Current medications, % of patients
DMARDs
No. of DMARDs received, median (range)
None
1 DMARD (specific agent received, %)
2 DMARDs (specific agents received, %)
3 DMARDs (specific agents received, %)
Oral steroids (daily dose)
Assessments by VAS (0–100 scale), median (IQR) score
Fatigue
Joint pain
Patient’s global assessment
Physician’s global assessment
Morning stiffness, median (IQR) minutes
Joint counts, median (IQR)
Painful joints (80 assessed)
Tender joints (28 assessed)
Swollen joints (28 assessed)
ESR, median (IQR) mm/hour
CRP, median (IQR) mg/liter
% meeting ACR remission criteria
DAS28 remission criteria
Mean score
% in remission (score ⬍2.6)
% with low disease activity (score 2.6–3.2)
% with moderate disease activity (score 3.2–5.1)
% with high disease activity (score ⬎5.1)
57 (24–81)
67/33
7 (2–38)
22 (6–144; 12–36)
64 (134)
61
14
47
1 (0–3)
9
70 (41 oral MTX; 22 SSZ)
15 (10 SSZ/MTX)
6 (6 SSZ/MTX/HCQ)
2 (ⱕ5 mg)
20 (8–33)
14 (5–25)
14 (7–25)
10 (5–15)
0 (0–0)
0 (0–1)
0 (0–2)
1 (0–4)
10 (6–18)
5 (0–9)
54
2.53
56
20
23
1
* RA ⫽ rheumatoid arthritis; IQR ⫽ interquartile range; RF ⫽ rheumatoid factor (positive titer ⬎40 IU);
DMARDs ⫽ disease-modifying antirheumatic drugs; MTX ⫽ methotrexate; SSZ ⫽ sulfasalazine; HCQ ⫽
hydroxychloroquine; VAS ⫽ visual analog scale; ESR ⫽ erythrocyte sedimentation rate; CRP ⫽
C-reactive protein; ACR ⫽ American College of Rheumatology; DAS28 ⫽ Disease Activity Score 28-joint
assessment.
remission criteria, and 56% satisfied the DAS28 remission criteria (DAS28 score ⬍2.6). The mean ⫾ SD
DAS28 score in the entire cohort was 2.53 ⫾ 0.96 (95%
CI 2.34, 2.72).
Findings of imaging assessments at baseline.
The majority of patients (57 of 90 [63%]) had evidence
of radiographic joint damage, as assessed using the
Genant-modified Sharp technique (60% with erosions
and 51% with joint space narrowing [JSN]; median total
joint damage score 2.000 [IQR 0.000–12.625]). On musculoskeletal US (n ⫽ 88), 68% of patients had erosions,
89% had evidence of synovial hypertrophy, and 63% had
increased PD signal. Using MRI (n ⫽ 76), 96% of patients
had erosions, 92% had synovitis, and 53% had BME.
Of the patients who satisfied the ACR remission
criteria, 87% (39 of 45) had synovial hypertrophy and
56% (25 of 45) had increased PD signal on musculoskeletal US, and 95% (36 of 38) had detectable synovitis on
MRI. Similarly, of the patients who fulfilled the DAS28
remission criteria, 84% (41 of 49) and 51% (25 of 49)
had synovial hypertrophy and increased PD signal, respectively, on musculoskeletal US, and 88% (36 of 41)
had demonstrable synovitis on MRI.
Considering the completely asymptomatic and
clinically normal joints (i.e., no pain, tenderness, or
swelling) in the dominant hand or wrist, 38% (145 of
378) had synovial hypertrophy and 15% (56 of 378) had
increased PD signal on musculoskeletal US, and 50%
(160 of 322) had detectable synovitis on MRI, despite
the normal clinical findings. High levels of intra- and
interobserver reliability for imaging scoring have previously been reported in this cohort (12).
2962
BROWN ET AL
Table 2. Percentages of patients whose total joint damage scores deteriorated over 12 months, according
to assessment technique, and significance of the differences from baseline*
Score
All patients
No. of patients
% with erosion
P versus baseline
% with JSN
P versus baseline
Total radiographic score
P versus baseline
Asymptomatic patients
No. of patients
% with erosion
P versus baseline
% with JSN
P versus baseline
Total radiographic score
P versus baseline
Dominant-hand MCP joints 2–5
Radiography of
both hands and feet
Radiography
US
MRI
90
9
0.012†
17
0.003†
19
0.001†
102
6
0.038†
3
0.109
7
0.016†
95
24
0.082
NA
–
NA
–
74
20
0.002†
NA
–
NA
–
25
4
0.577
16
0.066
16
0.131
30
7
0.157
7
0.180
10
0.109
27
22
0.366
NA
–
NA
–
20
25
0.034†
NA
–
NA
–
* MCP ⫽ metacarpophalangeal; US ⫽ ultrasonography; MRI ⫽ magnetic resonance imaging; JSN ⫽ joint
space narrowing; NA ⫽ not applicable.
† Significantly different versus baseline. All P values were determined by Wilcoxon’s signed rank test.
Findings of clinical and imaging assessments in
the control group. All control subjects had normal
findings on clinical examination. Three control subjects
(18%) had evidence of synovitis on MRI. This comprised a total of 4 joints (3%), all of which were graded
as mild. BME was not seen in any joints of the control
subjects.
Change in RA disease activity over 12 months.
There were no statistically significant differences in the
results of disease activity measures between the baseline
and outcome assessments. At 12 months, 45% of the
patients (38 of 85) fulfilled the ACR remission criteria
and 61% (52 of 85) fulfilled the DAS28 remission
criteria. The mean change in the DAS28 score was
–0.016 (95% CI –0.255, 0.223) (t ⫽ 0.134, P ⫽ 0.894
Student’s paired t-test). Only 5% of patients required a
change in therapy due to increased disease activity
throughout the study period, despite regular clinical
assessments at 3-month intervals.
Progression of structural changes in each patient
over 12 months. The calculated SDC for the erosion
score (both hands and feet) and for the total radiographic score (combined erosion and JSN scores in both
hands and feet) was 1. The SDC for the JSN score (both
hands and feet) and for the erosion/JSN/combined score
(dominant-hand MCP joints 2–5) did not exceed the
smallest unit of change in the scale, which was 0.5.
A total of 19% of patients (17 of 90) experienced
a deterioration in their total radiographic joint damage
scores that exceeded the SDC over the study period. The
quantitative change in the total radiographic damage
score was statistically significant (Z ⫽ –3.26, P ⫽ 0.001
by Wilcoxon’s signed rank test) (Table 2). The probability plot shown in Figure 1 illustrates the proportion of
patients with a change in the total radiographic score, as
well as a quantitative measure of the difference in
scores, over the 12-month study period.
Musculoskeletal US and MRI scanning detected
changes in the total erosion score in the dominant-hand
MCP joints in a larger proportion of patients (24% [23
of 95] and 20% [15 of 74], respectively) than did
radiography (6% [5 of 90]) (Table 2). There were
significant quantitative changes in the total erosion
scores in the dominant hand and wrist, as measured by
musculoskeletal US (n ⫽ 82) (median change 0 [IQR
0–1]; Z ⫽ ⫺2.41, P ⫽ 0.016 by Wilcoxon’s signed rank
test) and by MRI (n ⫽ 66) (median change 0 [IQR 0–1];
Z ⫽ ⫺3.37, P ⫽ 0.001). The change in dominant-hand
MCP score was statistically significant only for the MRI
assessment (n ⫽ 74) (median change 0 [IQR 0–0]; Z ⫽
⫺3.12, P ⫽ 0.002), although US showed a trend toward
significance (n ⫽ 95) (median change 0 [IQR 0–0]; Z ⫽
⫺1.74, P ⫽ 0.082) (Table 2).
We performed univariate binary logistic regression analyses to investigate the association between
baseline factors and radiographic progression and found
that in addition to known predictive factors, such as RF
(borderline significant; odds ratio [OR] 2.95, P ⫽ 0.054)
CLINICAL REMISSION AND CONTINUED STRUCTURAL DETERIORATION IN RA
Figure 1. Cumulative probability distribution of the percentages of
symptomatic and asymptomatic patients with a given change in total
radiographic (x-ray [XR]) score (smallest detectable change [SDC]).
and ACR remission (borderline significant; OR 0.33,
P ⫽ 0.054), the total baseline PD score was also associated with an adverse structural outcome radiographically (increase in OR per unit increase in score 1.36, P ⫽
0.038). The PD score for the dominant-hand MCP joints
was also significantly associated with radiographic progression in any joint anywhere in the hands and feet
(increase in OR per unit increase in score 1.64, P ⫽
0.036) (Table 3).
2963
In the completely asymptomatic patients, who
had no painful, tender, or swollen joints, 16% (4 of 25)
experienced radiographic progression, as reflected by an
increased total joint damage score exceeding the SDC in
the hands and feet. In the dominant-hand MCP joints,
7% (2 of 30) had a worse erosion score on radiography,
22% (6 of 27) had a worse erosion score on musculoskeletal US, and 25% (5 of 20) on MRI (Table 2 and
Figure 1).
At 12 months, 11% of the patients who satisfied
the ACR remission criteria and 12% of the patients who
satisfied the DAS28 remission criteria also showed radiographic progression (data not shown).
Progression of structural changes in individual
joints and association with baseline parameters. SDC
values were calculated for the radiographic erosion
score, JSN score, and the combined score for individual
dominant-hand MCP joints. For each of the scores, the
calculated SDC did not exceed the smallest unit of
change in the scale (0.5).
Associations between baseline clinical joint assessments and structural progression in individual joints
were evaluated. The dominant-hand MCP joints were
used for this purpose since comparable data for each
imaging modality were available for each patient at
these anatomical sites. While the clinical characteristics
were associated with an increased likelihood ratio of
structural progression, particularly for joint pain and
tenderness (OR 3.32 and OR 2.17, respectively), none of
these parameters reached statistical significance (Table
4). In contrast, baseline imaging findings were associated
with a statistically significant likelihood of subsequent
structural deterioration in the MCP joints. In particular,
a positive PD signal (OR ⫽ 12.21, P ⬍ 0.001) as well as
Table 3. Associations between clinical, laboratory, and imaging findings at baseline and radiographic progression in
both hands and feet over 12 months*
Baseline variable
No
radiographic
progression
(n ⫽ 73)
Radiographic
progression
(n ⫽ 17)
OR
(95% CI)
P
No. (%) RF positive
ESR, median (IQR) mm/hour
CRP, median (IQR) mg/liter
No. (%) meeting ACR remission criteria
No. (%) in DAS28 remission (score ⬍2.6)
DAS28 score, mean (95% CI)
Total US PD score, median (IQR)
Dominant-hand US PD score, median (IQR)
28 (38)
10 (6–18)
5 (0–9)
41 (56)
44 (60)
2.48 (2.26, 2.71)
1 (0–2)
0 (0–0.75)
11 (65)
13 (8–18)
0 (0–12)
5 (29)
6 (35)
2.89 (2.40, 3.38)
1 (0–3.5)
0 (0–2)
2.95 (0.98, 8.86)
1.01 (0.96, 1.06)
1.01 (0.93, 1.10)
0.33 (0.10, 1.02)
0.36 (0.12, 1.08)
1.54 (0.89, 2.65)
1.36 (1.02, 1.81)
1.64 (1.03, 2.61)
0.054
0.667
0.765
0.054
0.068
0.122
0.038
0.036
* OR ⫽ odds ratio; 95% CI ⫽ 95% confidence interval; RF ⫽ rheumatoid factor; ESR ⫽ erythrocyte sedimentation
rate; IQR ⫽ interquartile range; CRP ⫽ C-reactive protein; ACR ⫽ American College of Rheumatology; DAS28 ⫽
Disease Activity Score 28-joint assessment; US ⫽ ultrasonography; PD ⫽ power Doppler.
2964
BROWN ET AL
Table 4. Associations between the clinical and imaging findings at baseline and radiographic progression in individual joints (dominant-hand MCP joints) over 12 months*
Baseline variable
Clinical findings, no. (%) of patients
Painful joint count
Tender joint count
Swollen joint count
Imaging findings
US SH score, median (IQR)
US PD score, median (IQR)
MRI synovitis score, median (IQR)
MRI BME score, median (IQR)
No. (%) US SH positive
No. (%) US PD signal positive
No. (%) MRI synovitis positive†
No. (%) MRI BME positive†
No radiographic
progression
(n ⫽ 370)
Radiographic
progression
(n ⫽ 10)
OR
(95% CI)
12 (3)
18 (5)
75 (20)
1 (10)
1 (10)
3 (30)
3.32 (0.39, 28.30)
2.17 (0.26, 18.10)
1.69 (0.43, 6.67)
0.273
0.473
0.457
1 (0–1)
0 (0–0)
0 (0–1)
0 (0–0)
203 (55)
28 (8)
160 (48)
20 (6)
1 (0–2)
0.5 (0–2)
2.5 (0–3)
0 (0–0)
7 (70)
5 (50)
5 (63)
1 (13)
2.31 (1.06, 5.52)
4.00 (1.98, 8.08)
2.98 (1.49, 5.97)
2.26 (0.98, 5.22)
1.92 (0.49, 7.54)
12.21 (3.34, 44.73)
1.79 (0.42, 7.62)
2.23 (0.26, 19.00)
0.032
⬍0.001
0.002
0.057
0.350
⬍0.001
0.430
0.464
P
* MCP ⫽ metacarpophalangeal; OR ⫽ odds ratio; 95% CI ⫽ 95% confidence interval; US ⫽
ultrasonography; SH ⫽ synovial hypertrophy; IQR ⫽ interquartile range; PD ⫽ power Doppler; BME ⫽
bone marrow edema.
† Magnetic resonance imaging (MRI) was performed in 340 joints (332 without radiographic progression
and 8 with radiographic progression).
the scores for the PD (OR ⫽ 4.00, P ⬍ 0.001) and
synovial hypertrophy (OR ⫽ 2.31, P ⫽ 0.032) by musculoskeletal US, as well as synovitis (OR ⫽ 2.98, P ⫽
0.002) by MRI, were associated with significantly higher
odds of progression (Table 4).
Progression of structural changes in asymptomatic joints and association with findings of imaging
assessments at baseline. As shown in Figure 2, similar
proportions of asymptomatic and symptomatic MCP
joints demonstrated structural progression. We assessed
whether baseline imaging data were associated with
longitudinal radiographic progression in these asymptomatic joints. Despite a relatively small number of
joints with radiographic structural deterioration, PD
findings were significantly associated with radiographic
progression, as measured either by the difference in the
PD score (median score 1 [IQR 1–1] in joints without
progression and median score 1 [IQR 1–2] in joints with
progression; increase in OR per unit increase in score
6.41 [95% CI 1.81, 22.74], P ⫽ 0.004) or by the number
of joints with increased PD signal (4% of joints without
progression versus 29% of joints with progression; OR
8.77 [95% CI 1.54, 49.89], P ⫽ 0.014) (data not shown).
DISCUSSION
Figure 2. Percentages of dominant-hand metacarpophalangeal
(MCP) joints with structural deterioration over 12 months, as determined by radiography (x-ray [XR), ultrasonography (US), and magnetic resonance imaging (MRI), in symptomatic and asymptomatic
MCP joints. Asymptomatic MCP joints were those without pain,
tenderness, or swelling. Symptomatic MCP joints were those with pain
and/or tenderness and/or swelling.
In this prospective longitudinal study, we found
that structural progression occurs in RA patients receiving conventional therapy despite the presence of clinical
remission and that such deterioration is associated with
synovitis detected by imaging techniques. We also demonstrated that subclinical inflammation in asymptomatic
CLINICAL REMISSION AND CONTINUED STRUCTURAL DETERIORATION IN RA
joints as detected by imaging techniques predicts the
progression of joint damage in patients with RA.
Over the study period, one-fifth of the RA patients, who were in clinical remission as determined by a
physician, experienced deterioration in their total radiographic joint damage score that exceeded the SDC.
Applying the established measures of RA remission,
such as the ACR and DAS28 criteria, 12% of these
patients still showed radiographic deterioration, and
moreover, a similar proportion of patients had radiographic progression despite the complete absence of
clinical signs and symptoms in their joints. With moresensitive imaging techniques, such as musculoskeletal
US and MRI, the proportion with subsequent structural
deterioration was greater in each of these groups.
These data suggest that the current measures
used to assess disease activity in RA, which largely rely
on subjective clinical symptoms, joint examination findings, and laboratory measures of acute-phase reactants,
are not sufficiently sensitive to exclude ongoing inflammation in patients with low levels of disease activity. This
observation is corroborated by the results of a receiver
operating curve analysis to investigate the threshold by
which the DAS28 score may be used to predict radiographic progression at 1 year. The resulting area under
the curve value of 0.699 (data not shown) supports the
relative inaccuracy of the DAS28 score to accurately predict radiographic structural outcome no matter where
the cutoff point for remission is set. This has important
implications and suggests that traditional measures of
RA disease activity may also lack predictive validity
since they are unable to accurately predict subsequent
structural deterioration as early as 1 year later.
To our knowledge, this is the first study to demonstrate a direct association between synovitis, as detected by musculoskeletal US (GS synovial hypertrophy
and PD signal) and radiographic progression in individual joints in a large cohort of RA patients. These data
also confirm previous reports of the relationship between imaging-detected synovitis and subsequent structural damage (27,28). In addition, this study is the first to
demonstrate that subclinical inflammation detected by
imaging techniques may predict subsequent radiographic
outcome in clinically asymptomatic joints. These data
support our hypothesis that subclinical inflammation,
which is undetectable by traditional measurement techniques, is the pathophysiologic mechanism for continued
structural progression in RA despite apparent clinical
remission. This phenomenon has been observed in this
cohort and by other cohorts evaluated by other investigators (5,6), but it has previously defied explanation.
2965
The superiority of sensitive imaging methods over conventional clinical measures and established remission
criteria as a predictor of structural outcome demonstrated in this study provides further evidence to support
this theory. The results of our investigation suggest that,
in the majority of RA patients who are treated with conventional DMARDs, joint damage is closely related to
subclinical inflammation, which in states of low disease
activity, can only be accurately detected by imaging
techniques such as musculoskeletal US and MRI.
The differences in the capacities of imaging modalities to predict joint damage progression enable us to
hypothesize about the pathogenesis of erosive joint
damage in RA. Gray-scale musculoskeletal US primarily
detects hypertrophy of the synovium, which may become
chronically thickened and less reversible in established
RA, whereas an increased power Doppler signal may be
more likely to signify increased vascularity associated
with active inflammation. Gadolinium-enhanced MRI
provides information relating to both synovial thickness
and increased blood flow. Our data suggest that increased PD signal is the most robust predictor of erosive
damage, emphasizing the potentially important role of
increased vascularity in the development of subsequent
structural progression in patients with established RA.
In contrast, bone marrow edema reflects the presence of
an inflammatory infiltrate (29), which has been shown to
be associated with adverse structural and functional
outcomes (30,31). The relative lack of association between the baseline BME score and radiographic progression in our study may be attributed to the relatively
small number of joint regions with radiographic deterioration, particularly in the carpus, where the predictive
value of BME has been most frequently demonstrated
(30,31). However, when the MRI erosion score was used
as a more sensitive outcome measure, this resulted in a
statistically significant association between the baseline
BME score and structural deterioration seen on MRI at
the patient and individual joint level (P ⫽ 0.008 and P ⬍
0.001, respectively, by Mann-Whitney U test) (data not
shown). This observation supports our subclinical
inflammation–based hypothesis and provides further
evidence regarding the relative insensitivity of established radiographic measures for assessing structural
outcomes.
While plain radiographs remain the conventional
measure accepted by regulatory authorities for the assessment of structural outcome in RA, there is increasing evidence to support the validity of modern imaging
modalities such as musculoskeletal US and MRI in this
role (22,32–35). Our study demonstrates the enhanced
2966
sensitivity of musculoskeletal US and MRI for the
detection of structural damage as well as their superior
sensitivity to change as compared with radiography.
Furthermore, both musculoskeletal US and MRI allow
the valid and reliable assessment of both ongoing inflammatory disease activity and structural outcome in
RA at the same time. These observations are endorsed
by the data from our normal control population, which
are consistent with published findings (36), and confirm
the specificity of the imaging findings in this RA cohort.
Our results demonstrate that objective imaging
techniques definitively identify inflammation and the
potential for further joint damage across the boundaries
of the current remission classification systems, with no
differences in the proportion of patients with subclinical
synovitis who were judged by physicians to be in remission, regardless of whether they fulfilled the ACR/
DAS28 criteria. This suggests that satisfying the ACR/
DAS28 definitions is a no more valid assessment than
that made by an experienced physician. In addition,
remission classified according to established clinical
criteria may not represent an inflammation-free, nondamaging disease state. So, while the current criteria
may confer a safer disease activity level than not, they
may still allow persistent, active disease and subsequent
structural damage to go unnoticed, thus raising legitimate questions regarding their accuracy.
These data have a number of important clinical
implications. Our threshold for additional intervention
in such patients may need to be lowered, since even in
states of low disease activity, patients may benefit from
additional therapy. The effects of dosage titration and
treatment strategies involving additional or combination
therapy with traditional DMARDs or biologic agents
merit further investigation in this population. Monitoring treatment-resistant synovial inflammation with imaging studies in such patients may enable the appropriate selection of patients in whom further therapy may
result in a more-effective prevention of structural damage.
The present study supports the use of sensitive
imaging techniques for the accurate evaluation of disease status and the prediction of outcome in patients
with RA, even when the findings of standard clinical
measures of inflammatory activity have returned to
normal. Furthermore, an objective imaging assessment
improves the sensitivity of inflammation detection, enabling more-informed treatment decisions and an accurate definition of the remission state, which is most likely
to correlate with optimal long-term structural outcome.
BROWN ET AL
AUTHOR CONTRIBUTIONS
Dr. Brown 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. Brown, Conaghan, Karim, Quinn, Wakefield, Emery.
Acquisition of data. Brown, Conaghan, Karim, Emery.
Analysis and interpretation of data. Brown, Conaghan, Karim, Ikeda,
Peterfy, Hensor, Wakefield, O’Connor, Emery.
Manuscript preparation. Brown, Conaghan, Karim, Quinn, Ikeda,
Peterfy, Wakefield, Emery.
Statistical analysis. Ikeda, Hensor, Emery.
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