ARTHRITIS & RHEUMATISM
Vol. 64, No. 1, January 2012, pp 6776
DOI 10.1002/art.33312
2012 American College of Rheumatology
Power Doppler Ultrasound, but Not Low-Field
Magnetic Resonance Imaging, Predicts Relapse and
Radiographic Disease Progression in Rheumatoid Arthritis
Patients With Low Levels of Disease Activity
Violaine Foltz,1 Frederique Gandjbakhch,1 Fabien Etchepare,1 Carole Rosenberg,1
Marie Laure Tanguy,2 Sylvie Rozenberg,1 Pierre Bourgeois,1 and Bruno Fautrel1
Objective. Subclinical inflammation and radio-
graphic progression have been described in rheumatoid
arthritis (RA) patients whose disease is in remission or
is showing a low level of activity. The aim of this study
was to compare the ability of ultrasonography and
magnetic resonance imaging (MRI) to predict relapse
and radiographic progression in these patients.
Methods. Patients with RA of short or intermedi-
ate duration that was either in remission or exhibiting
low levels of activity according to the Disease Activity
Score (DAS) were included in the study. Over a period
of 1 year, patients underwent clinical and biologic
assessments every 3 months and radiographic assess-
ments at baseline and 12 months. Radiographs were
graded according to the modified Sharp/van der Heijde
score (SHS). At baseline, patients underwent ultra-
sonography and MRI, which were graded using binary
and semiquantitative scoring systems. Relapse was
defined as a DAS of >2.4, and radiographic progression
was defined as an increase in the SHS of >1. We tested
the association of values by multivariate logistic re-
gression.
Results. A total of 85 RA patients with a mean
Supported by a research grant from the Societe Francaise de
Rhumatologie.
1
Violaine Foltz, MD, Frederique Gandjbakhch, MD, Fabien
Etchepare, MD, Carole Rosenberg, MD, Sylvie Rozenberg, MD,
Pierre Bourgeois, MD, Bruno Fautrel, MD, PhD: University of
Paris VI and Centre Hospitalier Universitaire Pitie Salpetriere, Paris,
France; 2Marie Laure Tanguy, PhD: Centre Hospitalier Universitaire
Pitie Salpetriere, Paris, France.
Address correspondence to Violaine Foltz, MD, Rheumatol-
ogy Department, Groupe Hospitalier Pitie Salpetriere, 83 Boulevard
de lHopital, 75013 Paris, France. E-mail: violaine.foltz@psl.aphp.fr.
Submitted for publication September 14, 2010; accepted in
revised form August 25, 2011.
67
disease duration of 35.3 months were studied. RA was in
remission in 47 of these patients, and 38 had low levels
of disease activity. At 1 year, 26 of the 85 patients
(30.6%) showed disease relapse, and 9 of the 85 patients
(10.6%) showed radiographic progression. The baseline
PD synovitis count (i.e., the number of joints at baseline
for which the power Doppler [PD] signal indicated
synovitis) predicted relapse (adjusted odds ratio [OR]
6.3; 95% confidence interval [95% CI] 2.020.3), and the
baseline PD synovitis grade predicted disease progres-
sion (adjusted OR 1.4 [95% CI 1.11.9]). MRI was not
predictive of outcomes.
Conclusion. For RA patients whose disease is in
remission or who have low levels of disease activity,
PD signals on ultrasonography could predict relapse or
radiographic progression and identify those whose dis-
ease is adequately controlled, which is especially helpful
when considering treatment tapering or interruption.
For patients with rheumatoid arthritis (RA),
therapeutic objectives are remission or a low level of
disease activity and no disease evolution (13). How-
ever, the concept of remission remains complex, and
several definitions have been proposed, but no consen-
sus has been reached (414).
Previous studies have reported on the possibility
of radiographic evidence of disease progression in RA
patients considered to be in clinical disease remission or
with low levels of disease activity (1519). Moreover,
research has suggested the presence of subclinical resid-
ual inflammation in patients whose RA is in remission or
is showing a low level of activity. This inflammation
could explain the apparent discrepancy between clinical
and structural evidence of disease evolution.
68
Ultrasonography (US) and magnetic resonance
imaging (MRI) are considered superior to clinical exam-
ination and radiographic assessment of arthritis because
of their direct, valid, sensitive, and specific visualization
and objective assessment of inflammatory lesions and
structural damage (2022). Indeed, Brown et al (15)
found that patients with disease considered to be in
remission according to clinicobiologic indices showed
persistent inflammation (synovitis, tenosynovitis, bone
marrow edema) on US and MRI. So, these techniques
can more accurately detect and measure RA activity and
structural progression than can the established methods,
particularly in patients with subclinical activity.
Because patients with disease in remission or
with low levels of disease activity might show residual
subclinical inflammation, we wondered whether such
findings are predictive of future relapse or progression
of structural damage. In the present study, we compared
US and MRI findings in a prospective longitudinal
evaluation of patients with RA in remission or with low
levels of disease activity that was stable (i.e., for at least
2 months) according to the Disease Activity Score
(DAS), whatever the treatment. We aimed to determine
whether subclinical activity observed by US or MRI
could predict disease relapse and/or radiographic evi-
dence of disease progression in such patients.
PATIENTS AND METHODS
Study design. This was a longitudinal observational
study in which we prospectively followed a cohort of patients
with RA whose disease was in remission or showing low levels
of activity over 1 year to assess the ability of US and MRI to
predict risk of relapse and radiographic evidence of disease
progression at 1 year.
Ethical approval for the project was obtained from the
ethics committee of the Hopital Pitie Salpetriere. Written found (27).
informed consent was obtained from all patients.
Patient population. To be included in the study, pa-
tients had to have established RA, which was defined accord-
ing to the American College of Rheumatology (ACR) 1987
criteria (23), that was of short or intermediate duration (i.e.,
6 years), and was in remission or exhibiting stable, low levels
of activity according to the DAS (i.e., DAS 2.4 at 2-month
measurements) (4). RA treatment needed to be stable for
at least 2 months, and synthetic or biologic disease-modifying
antirheumatic drugs (DMARDs) or low-dose corticosteroids
(10 mg/day) were allowed.
Patients were excluded if they had a contraindication
to gadolinium or MRI, a DAS 2.4, a modification of
DMARD therapy in the previous 2 months, or another sig-
nificant comorbid condition that could interfere with the
protocol.
FOLTZ ET AL
Data collection. At baseline and at 12 months, patients
underwent complete clinical, biologic, and radiographic assess-
ments. US and MRI were performed at baseline. In addition,
at 3, 6, and 12 months, patients underwent clinicobiologic
assessments.
Assessment of demographic and clinicobiologic char-
acteristics. The following demographic data were recorded at
baseline: sex, age, medical history, and disease duration. Data
on clinical and quality of life variables were collected, includ-
ing the duration of morning stiffness, patients assessment of
pain by visual analog scale, patients global assessment of
health and disease activity by visual analog scale, count of 44
joints for tenderness and swelling (performed by a rheumatol-
ogist [BF] who was blinded with regard to current treatment
and imaging findings), current treatment, and Health Assess-
ment Questionnaire (HAQ) score (24). Laboratory assess-
ments included a complete blood cell count, erythrocyte
sedimentation rate (ESR), C-reactive protein (CRP) level, and
serologic assessments for rheumatoid factor (RF) and anti
citrullinated protein antibody (ACPA).
Radiographic assessment. All patients underwent pos-
teroanterior radiography of the hands, wrists, and feet. Radio-
graphic changes were graded anonymously by 2 trained readers
(VF and FG), according to the modified Sharp/van der Heijde
score (SHS) (25). Intraobserver and interobserver reliability
was considered moderate to good; a preliminary exercise
provided the smallest detectable change for defining structural
disease progression (see Appendix A).
Ultrasonographic assessment. All patients underwent
US assessment of the wrists, metacarpophalangeal (MCP)
joints 2, 3, and 5, and metatarsophalangeal (MTP) joints 2, 3,
and 5. Each joint region was investigated in dorsal, ventral,
and, when possible, lateral views in grayscale (GS) and power
Doppler (PD) modes using a 7.513-MHz linear transducer
(Esaote Technos).
The presence of synovitis in GS and PD modes and the
presence of erosions were defined by the Outcome Measures
in Rheumatology (OMERACT) guidelines (26). US was per-
formed independently by 1 of 2 trained rheumatologists who
were experienced in joint US (FE and CR) and were blinded
with regard to the other data. Good interreader reliability was
The presence and location of synovitis in GS and PD
modes, as well as the presence of erosions, were evaluated.
Synovitis was scored using a binary scale (0 absence/1
presence; maximum score 14). Synovial blood flow in each
joint was assessed in PD mode and was scored using a binary
scale (0 absence/1 presence of PD signal) and the
semiquantitative scoring system proposed by Szkudlarek et al
(21,28) (03 scale, where 0 absent, no vascularization; 1
mild, single-vessel signal or isolated signal; 2 moderate,
confluent vessels; and 3 marked, vessel signals in more than
half of the intraarticular area [maximum score 42]). The sum of
the synovitis and PD scores was calculated for each patient.
The number of erosions at the 30 locations examined were
scored using a binary scale (0 absence/1 presence of 1
erosion; some sites had a score 1 because of the presence of
several erosions).
PD ULTRASOUND PREDICTS RELAPSE AND PROGRESSION IN RA 69

after intravenous administration of gadolinium and STIR

Figure 1. Flow chart showing the distribution of study patients
throughout the trial.
MRI assessment. All patients underwent low-field
dedicated MRI (0.2T C-Scan; Esaote) of the dominant hand,
exploring the wrist and MCP joints 25. Sequences were
chosen according to OMERACT guidelines: 3-dimensional
T1-weighted sequences in axial and coronal planes before and
sequences in axial and coronal planes. Synovitis, erosions, and
bone marrow edema were scored according to the OMERACT
RA MRI Scoring (RAMRIS) system (2931). Synovitis was
scored on a 4-point semiquantitative scale (0 normal, 1
mild, 2 moderate, and 3 severe), and a synovitis count was
obtained. Bone marrow edema was graded on a 4-point scale
(0 no edema, 1 133% edema, 2 3466% edema, and
3 67100% edema). Erosions were graded on a 10-point
scale, where each point represents a 10% loss of bone volume.
Images were interpreted by 2 experienced readers (VF and
FG), who were blinded with regard to all data, but were aware
of the chronological sequence of the images (32). Intrareader
and interreader reliability was assessed 3 months after the end
of followup. Intraobserver reliability kappa values were 0.81,
0.82, and 0.90 for the RAMRIS semiquantitative scoring of
synovitis, bone marrow edema, and erosions, respectively;
interobserver kappa values were 0.69, 0.68, and 0.84, respec-
tively.
Outcome measures. Because of lack of a consensus
definition of relapse or flare (33), we used a composite

Table 1. Baseline demographic, clinical, and laboratory characteristics of patients with RA in remission
or expressing low levels of activity*
Patients with
All RA low levels of Patients with
patients RA activity RA in remission
Characteristic (n 85) (n 38) (n 47)
Age, mean SD years 50.7 13.5 49.1 14.1 51.9 13.1
No. (%) female 69 (81.2) 33 (86.8) 36 (76.6)
Duration of RA, mean SD months 35.3 20.7 40.1 24.4 31.4 16.5
Patients global assessment, by VAS, 14.2 13.9 19.1 14.9 10.2 11.7
mean SD mm
Joint counts
No. of tender joints 1.5 1.8 2.8 1.8 0.5 0.9
No. of swollen joints 2.7 1.9 3.1 1.8 2.4 1.9
DAS, mean SD (range 03) 1.5 0.54 2.02 0.2 1.09 0.3
Laboratory
ESR, mean SD mm/hour 13.6 12.1 16.1 12.3 11.7 11.7
CRP, mean SD mg/liter 5.5 5.3 5.7 5.5 5.33 5.2
No. (%) RF positive 54 (63.5)
No. (%) ACPA positive 48 (56.5) 24 (63.2) 24 (51.1)
Radiography
No. (%) with erosions 77 (90.6) 35 (92.1) 42 (89.4)
No. (%) with SHS 1 85 (100)
Ultrasonography
No. (%) with GS-positive synovitis 74 (87.1) 33 (86.8) 41 (87.2)
No. (%) with PD-positive synovitis 24 (28.2) 17 (44.7) 7 (14.9)
Mean SD count per patient 0.6 1.3 1.0 1.6 0.4 1.0
Mean SD grade per patient 1.0 2.0 1.4 2.3 0.6 1.6
No. (%) with erosions 68 (80.0) 30 (78.9) 38 (80.9)
MRI
No. (%) with synovitis 82 (96.5) 37 (97.4) 45 (95.7)
No. (%) with bone marrow edema 27 (31.8) 13 (34.2) 14 (29.8)
No. (%) with erosions 85 (100) 38 (100) 47 (100)

* RA rheumatoid arthritis; VAS visual analog scale (0100 mm); DAS Disease Activity Score;
ESR erythrocyte sedimentation rate; CRP C-reactive protein; RF rheumatoid factor; ACPA
anticitrullinated protein antibody; SHS modified Sharp/van der Heijde score; GS grayscale image;
PD power Doppler; MRI magnetic resonance imaging.
P 0.01 versus patients with low levels of disease activity.
70 FOLTZ ET AL

definition to identify disease relapse, as follows: 1) a DAS of

2.4 at one or more followup visits; and/or 2) a dosage
increase or change in synthetic or biologic DMARDs because
of exacerbation of RA activity (loss of efficacy), excluding
change because of safety; and/or 3) an increase in the cortico-
steroid dosage 10 mg/day.
Radiographic evidence of disease progression was de-
fined as an increase in the SHS greater than the smallest
detectable change between baseline and 1 year (i.e., SHS 1
degree).
Statistical analysis. The sample size calculation was
based on the ability of the regression model to discriminate
between progression and nonprogression of disease by receiver
operating characteristic (ROC) curve analysis. Assuming that
30% of patients would show radiographic evidence of disease
progression (34), the inclusion of 84 patients would produce an
area under the ROC curve of 0.75 with a P value of less than
0.05.
Univariate analysis involved Mann-Whitney tests for
continuous variables and chi-square or Fishers exact tests for
categorical variables. Independent predictors of relapse and
radiographic evidence of disease progression were identified
by forward multivariate logistic regression. Variables with
P values of less than 0.20 on univariate analysis were included Figure 2. Ultrasound evidence of synovitis at baseline. Synovitis is
in the model. P values less than 0.05 were considered statisti- present in 2 different metacarpophalangeal joints, one with no power
cally significant. All analyses were performed with the use of Doppler signal (A) and the other hypervascularized (i.e., positive
SAS v8.2 software (SAS Institute). power Doppler signal) (B).

RESULTS Evidence of residual inflammation. Baseline US

Patient characteristics at baseline. We included
85 patients in the study (Figure 1). The main demo-
graphic, clinical, and laboratory data obtained at base-
line are shown in Table 1. A total of 30 patients (35.3%)
were receiving low-dose steroids (10 mg/day), 82
(96.5%) were receiving conventional DMARD mono-
therapy, with methotrexate being the most common
agent, and 17 (20%) were receiving combination ther-
apy with biologic agents (15 taking tumor necrosis fac-
tor blockers, 1 taking antiinterleukin-6 receptor, and
1 taking rituximab). Three of the patients whose disease
was in remission had not received DMARDs for several
months. As expected, we found low levels of disease
activity, with low values for the patients global assess-
ment of health and disease activity, the joint counts, the
DAS, the ESR, and the CRP level. In addition, because
of the low levels of disease activity and the short disease
duration, the HAQ score was also low (mean SD
0.27 0.33), which corresponded to no or mild dis-
ability, except for 2 patients, whose HAQ scores were
1.
findings revealed 74 patients (87.1%) with GS-positive
synovitis and 24 (28.2%) with PD-positive synovitis
(Table 1 and Figure 2). GS-positive synovitis was pre-
dominantly observed at the wrist, MCP2, MTP2, and
MTP3 joints (39.4%, 27.1%, 40.6%, and 40.9%, respec-
tively). PD-positive synovitis was observed at the wrist
(17.2% of patients) and equally at each MTP joint. The
mean SD GS-positive synovitis count per patient
was 3.4 2.6, the mean SD PD-positive synovitis
count was 0.6 1.3, and the mean SD PD-positive
grade was 1.0 2.0. A total of 68 patients (80.0%) had
at least 1 erosion, but the mean SD number of
erosions per patient was low at 2.6 2.6.
Baseline MRI findings revealed 82 patients
(96.5%) with synovitis. Synovitis was predominantly
observed at the wrist, MCP2, and MCP3 joints (76.5%,
21.2%, and 22.4%, respectively). The mean SD syno-
vitis count per patient was 4.5 2.0 (maximum 7), and
the mean SD synovitis grade was 5.6 3.9. A total of
27 patients (31.8%) had at least 1 case of bone marrow
edema, with a mean SD of 1.0 2.6 bone marrow
edemas (maximum 23) and a mean SD grade of 1.8
4.4 (maximum 69) (Appendix B). Bone marrow edemas
PD ULTRASOUND PREDICTS RELAPSE AND PROGRESSION IN RA
Figure 3. Magnetic resonance imaging evidence of structural progression of rheumatoid arthritis at baseline. Bone marrow edema appears as a
hyposignal of the trapezium (white arrow) on the T1-weighted sequence image (A) and as a hypersignal of both the trapezium and the first
metacarpal bone (black arrows) on the STIR sequence image (B).
were predominantly observed at the wrist (21.2%) and
MCP5 (10.6%) joints (Figure 3). MRI revealed erosions
in all patients, with a mean SD number of 7.2 3.7
erosions and a mean SD grade of 11.4 7.9 erosions.
The maximum inflammation (synovitis or bone marrow
edema) was noted at the wrist at locations that were less
accessible and less efficient for US evaluation (for
synovitis, wrist 76.4% versus MCP joints from 9.4% to
21.2%; for bone marrow edema, wrist 21.2% versus
MCP joints 0%).
Comparison of patients whose RA was in remis-
sion with those whose RA showed low levels of activity at
baseline. A subanalysis of patients with disease in remis-
sion or with low levels of activity according to the DAS
at baseline (Table 1) revealed 38 patients with low levels
of activity and 47 with disease in remission. The values
for the clinical variables used for the DAS calculation
were lower in patients whose RA was in remission than
in patients with low levels of RA activity, and those with
low levels of RA activity more often had at least 1
PD-positive case of synovitis (44.7% versus 14.9%; P
0.005), a higher mean PD-positive synovitis count (1.0
1.6 versus 0.4 1.0; P 0.01), and grade (1.4 2.3
versus 0.6 1.6; P 0.01).
Relapse during followup. Data concerning re-
lapse were available for 81 patients (95.3%) (Figure 1).
At 12 months, 26 patients (32.1%) experienced disease
relapse: treatment had increased in 7 patients (i.e.,
dosage increase or change in synthetic or biologic
71
DMARDs because of RA exacerbation), the DAS had
increased to 2.4 in 15 patients (3 at 3 months, 4 at 6
months, and 8 at 12 months), and both the treatment
and the DAS had increased in 4 patients (3 at 6 months)
(Table 2). Eleven of these 26 patients had been in
remission at baseline (2 receiving biotherapies) and 15
showed low levels of activity (4 receiving biotherapies);
3 of these 26 patients had radiographic evidence of
disease progression at baseline.
Patients with relapse differed from those without
relapse in terms of ACPA positivity (96.2% versus
35.2%; P 0.02), the number of joints at baseline where
a positive PD signal indicated synovitis (mean SD
1.3 1.8 versus 0.4 0.9; P 0.004), the grade of joints
at baseline where a positive PD signal indicated synovitis
(mean SD 1.9 2.7 versus 0.6 1.4; P 0.005), and
the MRI-positive synovitis grade (8.4 4.4 versus 6.0
4.4; P 0.03).
Multivariate analysis of variables found to be
significant on univariate analysis (duration of RA, use
of corticosteroids, the DAS, the ESR, RF and ACPA
positivity, baseline PD-positive synovitis count and
grade, and MRI-positive synovitis grade) revealed a
significant association between only the baseline PD-
positive synovitis count and relapse (adjusted odds ratio
[OR] 6.3; 95% confidence interval [95% CI] 2.020.3).
Radiographic evidence of disease progression at
1 year. Data concerning radiographic evidence of dis-
ease progression were available for 80 of the 85 patients
72 FOLTZ ET AL

(94%) (Figure 1). Among the 9 patients (11.3%) with Table 3. Baseline demographic, clinical, and laboratory characteris-
radiographic evidence of disease progression at 1 year, tics of the RA patients, according to radiographic evidence of disease
progression at 1 year*
at baseline 4 (5% of the entire population) had been in
remission (P 0.73) and 5 (6.2% of the entire popula- No
Progression progression
tion) had low levels of disease activity; 3 showed disease
Chacteristic (n 9) (n 71)
relapse. Only the mean GS-positive synovitis count per
patient was significantly higher in patients with than in Age, mean SD years 51.9 10.3 51.0 13.5
Duration of RA, mean SD months 29.4 17.2 36.5 20.6
those without radiographic evidence of disease progres- Treatment, no. (%)
sion (4.8 2.3 versus 3.2 2.6; P 0.04) (Table 3). Biologic agents 0 (0) 15 (21.1)
Multivariate analysis of variables found to be Oral corticosteroids 3 (33.3) 24 (33.8)
DAS, mean SD (range 03) 1.6 0.3 1.5 0.6
significant on univariate analysis (therapy with biologic Laboratory
agents, GS-positive and baseline PD-positive synovitis ESR, mean SD mm/hour 12.8 7.1 13.4 12.4
count, baseline PD-positive synovitis grade, and MRI- CRP, mean SD mg/liter 5.3 2.4 5.6 5.6
No. (%) RF positive 6 (66.7) 51 (71.8)
positive synovitis grade) revealed a significant associa- No. (%) ACPA positive 6 (66.7) 37 (52.1)
tion between only the baseline PD-positive synovitis Ultrasonography, mean SD per
grade and radiographic evidence of disease progression patient
GS-positive synovitis count 4.8 2.3 3.2 2.6
(OR 1.4 [95% CI 1.11.9]). PD-positive synovitis
Count 1.8 2.8 0.5 0.9
Grade 2.8 4.0 0.8 1.5
Erosion count 3.0 3.0 2.6 2.6
MRI, mean SD per patient
Table 2. Baseline demographic, clinical, and laboratory characteris- Synovitis
tics of the RA patients, according to relapse or no relapse at 1 year* Count 5.0 1.5 4.4 2.1
Grade 8.1 3.1 6.5 4.7
Relapse No relapse Bone marrow edema grade 0.9 2.0 2.5 6.4
Characteristic (n 26) (n 55) Erosions grade 12.1 10.5 9.7 6.7

Age, mean SD years 53.7 12.7 50.0 13.1 * RA rheumatoid arthritis; DAS Disease Activity Score; ESR
Duration of RA, mean SD months 44.1 27.1 32.5 15.9 erythrocyte sedimentation rate; CRP C-reactive protein; RF
Treatment, no. (%) rheumatoid factor; ACPA anticitrullinated protein antibody; GS
Biologic agents 6 (23.1) 10 (18.2) grayscale image; PD power Doppler; MRI magnetic resonance
Oral corticosteroids 12 (46.2) 15 (27.2) imaging.
DAS, mean SD (range 03) 1.7 0.6 1.5 0.5 P 0.04 versus patients who experienced progression.
Laboratory
ESR, mean SD mm/hour 15.5 10.4 12.3 12.6
CRP, mean SD mg/liter 5.5 4.1 5.6 6.0
No. (%) RF positive 20 (76.9) 38 (69.1) DISCUSSION
No. (%) ACPA positive 25 (96.2) 19 (34.6)
Ultrasonography, mean SD per Our study demonstrated that in a sample of 85
patient
GS-positive synovitis count 3.6 2.1 3.3 2.8 patients who were followed up prospectively over a
PD-positive synovitis period of 1 year, the baseline PD-positive synovitis count
Count 1.3 1.8 0.4 0.9 and grade were predictive of disease relapse and radio-
Grade 1.9 2.7 0.6 1.4
Erosion count 2.3 2.1 2.8 2.9 graphic evidence of disease progression. In the same
MRI, mean SD per patient sample, MRI had no predictive value. To our knowl-
Synovitis
Count 4.8 1.8 4.3 2.1
edge, this is the first longitudinal study over 1 year
Grade 8.4 4.4 6.0 4.4 conducted in RA patients with low levels of disease
Bone marrow edema grade 3.5 8.4 2.0 4.8 activity or remission according to validated tools, with
Erosions grade 12.2 10.8 9.6 7.1
homogenous disease duration and followup with classic
* RA rheumatoid arthritis; DAS Disease Activity Score; ESR clinicobiologic data as well as imaging data.
erythrocyte sedimentation rate; CRP C-reactive protein; RF The main strength and originality of our study
rheumatoid factor; ACPA anticitrullinated protein antibody; GS
grayscale image; PD power Doppler; MRI magnetic resonance are the identification of factors that predict relapse.
imaging. Previous studies have shown that up to 52% of patients
P 0.02 versus patients who experienced relapse. with disease in remission experience disease exacerba-
P 0.004 versus patients who experienced relapse.
P 0.005 versus patients who experienced relapse. tion within 24 months, which suggests that residual
P 0.03 versus patients who experienced relapse. inflammation may persist even in the presence of clini-
PD ULTRASOUND PREDICTS RELAPSE AND PROGRESSION IN RA
cally undetectable disease activity (17). Nevertheless, no
predictive factors for relapse have been identified until
recently (35). In that study of RA patients with mean
disease duration of 3.8 months, relapse was defined as a
DAS 1.6 independently of potential modification of
treatment: 43 patients achieved remission after 18
months, and 14 showed disease relapse during the next
6 months. PD-positive synovitis (at least at 1 site) was
the main predictor of disease relapse, even after adjust-
ment for steroid medication (dosage not reported). PD
positivity therefore had a sensitivity of 85.7% and a
specificity of 82.8% for detecting early relapse and a
positive and negative predictive value of 70.6% and
92.3%, respectively.
Our study corroborates those results, showing
a rate of relapse of 31% at 1 year and a positive
predictive value of baseline PD-positive synovitis for
disease relapse. These results underscore the sensitivity
of PD analysis even at 1 joint and demonstrate that
persistent PD-positive synovitis is a good predictor of
unstable remission. US could thus be a useful examina-
tion to perform before reducing therapy in patients with
adequately controlled RA.
Our results revealed that a high percentage of
patients with RA in remission or with low levels of RA
activity had subclinical inflammation in asymptomatic
joints detected by US (87.1%) and MRI (96.5%). More-
over, we revealed PD-positive synovitis and bone mar-
row edema in more than one-fourth of the patients
(28.2% and 31.8%, respectively). Indeed, these 2 lesions
are considered to be aggressive for bone and increase
the risk of future disease progression as seen on radiog-
raphy (36,37). The persistence of such subclinical in-
flammation observed in our study and in other studies
(15,17,18) could explain why we found patients whose
RA was in remission or exhibited low levels of activity to
have radiographic evidence of disease progression. Ra-
diographic evidence of disease progression could also be
explained by the weak stringency of the indices used in
practice (e.g., the DAS, the Clinical Disease Activity
Index) in terms of cutoff values and their lack of stability
over time (6,13,38). Whatever the index that is used, it
reflects a transverse assessment state, rather than real
disease activity, over a long period, which introduces the
notion of a fluctuating disease activity state (39,40).
Recent studies by Brown et al (15,16) showed
results similar to ours. Nevertheless, comparisons are
difficult because the criteria for remission used in the
previous studies were different, less stringent, and less
precise: remission was based on the physicians judg-
73
ment. Indeed, among the 102 patients included, the
ACR and DAS 28-joint assessment (DAS28) criteria for
remission applied to only 54% and 56% patients, re-
spectively. Moreover, patients had a long disease dura-
tion (7 years), and the more advanced the disease, the
more difficult it is to quantify progression of structural
damage. Those investigators showed a disease progres-
sion rate of 11% at 12 months in patients who satisfied
the ACR criteria for remission and 12% for those who
satisfied the DAS28 criteria (16). Interestingly, among
the 25 patients who were asymptomatic (no painful,
tender, or swollen joints), 4 (16%) showed radiographic
evidence of disease progression (16).
The results reported by Brown et al, along with
our findings from the present study, support the hy-
pothesis that radiographic evidence of disease progres-
sion is directly linked to persistent subclinical inflamma-
tion. We suggest that among all factors we studied,
baseline PD-positive synovitis is the most robust deter-
minant of future erosive damage; the presence of GS-
positive synovitis is not sufficient (41).
The MRI findings were not associated with ra-
diographic evidence of disease progression in our study.
This lack of ability of MRI to predict disease progression
in our study may be explained by several factors. MRI
is known to be a sensitive examination, and in our
cohort, a large number of patients with a weak grade of
synovitis (grade 1) probably did not display patho-
genicity. Patients were then classified as having either
no synovitis (grade 0 or 1) or synovitis (grade 2 or 3).
The analysis did not change our results. Second, on
MRI, the maximum inflammation was detected at the
wrist, which suggests that the maximum radiographic
evidence of progression would be observed at this site.
Nevertheless, we observed minor radiographic evidence
of deterioration in the wrists over the 12 months.
Indeed, as has previously been shown, radiography is
insensitive in revealing or following up on erosions at the
wrist (42). Third, the lack of an association between
bone marrow edema and future lesions could be ex-
plained by the low sensitivity of low-field MRI for
detecting bone marrow edema (43). Nevertheless,
Brown et al (16) used high-field MRI and did not find an
association between bone marrow edema and radio-
graphic evidence of disease progression. Fourth, in light
of the high sensitivity of MRI, the delay between the
2 radiographic assessments may have been too short.
There is no consensus on the optimum delay between 2
radiographic assessments in observing disease progres-
sion in RA patients in remission (44). Finally, the lack of
74
predictive power of MRI may be explained by a lack of
statistical power. Indeed, we determined a need for a
sample size of 85 patients in order to yield 30% radio-
graphic evidence of disease progression. However, we
found only 11% of patients with such evidence.
This study has some limitations. The first is
related to the US examination itself. It is known to be
operator dependent and was performed by 2 different
operators. However, they performed several tests, and
good reliability between them was confirmed, thus di-
minishing the risk of error in practice and interpretation.
Second, we did not perform two US assessments as we
did for the radiographic and MRI assessments. US
readings were performed during examination of the
patient because recording the images and reading them
with complete blinding is technically difficult. Third, we
used a low-field dedicated MRI, which is considered to
have good sensitivity and specificity, as compared with
high-field MRI, for detecting synovitis, tenosynovitis,
and erosions (43,4547). Nevertheless, Ejbjerg et al (43)
showed that low-field MRI could detect only about 40%
of bone marrow edema lesions as compared with high-
field MRI.
In conclusion, radiography remains the conven-
tional measure of structural progression of disease in
RA according to regulatory authorities. Increasing evi-
dence supports the necessity of including US and MRI
in the assessment of RA, especially when the disease is
considered to be in remission or exhibiting low levels of
activity. We revealed that US could be used to predict
disease relapse and structural progression by detecting
baseline PD-positive synovitis. In such patients, adjust-
ment of therapy and/or tight control of RA are neces-
sary, with no tapering of treatment. Future studies are
necessary to confirm our results with other US operators
and to determine whether US assessment should be
included in routine practice.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Foltz 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 conception and design. Foltz, Gandjbakhch, Etchepare,
Rosenberg, Bourgeois, Fautrel.
Acquisition of data. Foltz, Gandjbakhch, Etchepare, Rosenberg,
Rozenberg, Bourgeois, Fautrel.
Analysis and interpretation of data. Foltz, Gandjbakhch, Etchepare,
Rosenberg, Tanguy, Rozenberg, Bourgeois, Fautrel.
FOLTZ ET AL
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decrease in total radiographic joint damage scores exceeded the SDC
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APPENDIX B: MAXIMUM SCORES FOR VARIABLES
STUDIED BY US AND MRI
APPENDIX A: INTRAOBSERVER RELIABILITY AND US
RADIOGRAPHIC EVIDENCE OF
DISEASE PROGRESSION B mode PD mode MRI
Synovitis
First, 2 experienced readers (VF and FG) who were blinded
Count 14 14 7
with regard to all other imaging and clinical findings, performed a pilot
Grade NA* 42 21
study of all radiographs. Both readers were aware of the chronological
Erosions
sequence of baseline and followup radiographs. The intraobserver Count No limit 23
reliability (intraclass correlation coefficient [ICC]) for each reader Grade No limit 230
was, respectively, 0.96 and 0.96 for erosions, 0.94 and 0.71 for joint Bone marrow edema
space narrowing, and 0.93 and 0.78 for the SHS. The ICCs were 0.77 Count 23
for erosions, 0.6 for joint space narrowing, and 0.67 for the SHS. Grade 69
Interobserver reliability assessments were considered moderate to
good. * NA not applicable.