High-resolution ultrasound confirms reduced synovial hyperplasia
following rituximab treatment in rheumatoid arthritis
Hans-Rudolf Ziswiler1, Daniel Aeberli1, Peter M. Villiger1and Burkhard Mo ¨ ller1
Objective. To assess the response of RA patients to rituximab (RTX) treatment using a sensitive imaging technique for synovitis.
Methods. Twenty-three RA patients were treated with two 1000-mg infusions of the B-cell depleting antibody, RTX, in an observational
protocol. Clinical response was assessed by the European League Against Rheumatism (EULAR) response criteria. High-resolution
grey-scale and colour-coded power Doppler (PD) ultrasonography was performed at baseline and 6 months after RTX. The second to
fifth MCP and PIP joints were bilaterally examined with joints in a neutral 0 position from a palmar view and scored from 0 to 3.
Results. Median disease activity score (DAS28) improved from 5.03 to 3.56 (P¼0.001), which corresponded to a EULAR moderate
response in 11 of 23 patients and a EULAR good response in another 6 patients. Improved control of disease activity by RTX was also
indicated by tapering of median daily corticosteroid doses from 10 to 5mg, without flare ups. Mean grey-scale scores correlated with the
swollen joint count at baseline (r¼0.484, P¼0.022) and month 6 (r¼0.519, P¼0.011). Mean grey-scale scores improved upon RTX from
a 0.90 median (range 0.13–1.87) to 0.75 (range 0.19–1.50, P¼0.023). Frequency of PD positive joints was low (6.1%) at baseline and did
not significantly change following RTX treatment.
Conclusions. High-resolution grey-scale ultrasonography (US) examination confirmed reduced synovial hyperplasia, but the applied PD
method displayed no significant changes. Therefore, only grey-scale US is recommended in follow-up examinations after RTX treatment.
KEY WORDS: Arthritis, B cell, Depletion, Doppler, Grey scale, Hyperplasia, Rheumatoid, Rituximab, Synovitis, Vascularity.
Rituximab (RTX) is a chimeric monoclonal antibody directed
against the CD20 antigen expressed on pre-B and mature
B cells. RTX belongs to the new ‘beyond anti-TNF’ biologics.
Clinical efficacy of RTX for the treatment of active RA has
been documented in randomized controlled trials for patients
with inappropriate response to conventional DMARDs, such as
low-dose MTX, as well as TNF blocking agents [1–3]. B cells
provide multiple important functions by antigen presentation,
co-stimulation of T cells and antibody production related to
their derivates, the plasma cells [4, 5]; yet, the predominant
mode of action of RTX in autoimmunity is still unclear.
Recent radiographic data proved for the first time that
RTX ameliorates structural damage in RA in terms of erosions
and joint space narrowing . Macroscopic changes in synovitis
upon anti-TNF treatment could be accurately graded by MRI and
high-resolution ultrasonography (US). The data obtained by these
methods correlated with subsequent disease progression in
conventional X-rays [7–12]. To date, no studies have addressed
the short-term effect of RTX treatment on the morphological level
of synovitis with either one of these modern imaging techniques.
In this study, we monitored synovial morphology in therapeutic
B-cell depletion with US and compared the results with estab-
lished clinical parameters for response.
Patients and methods
Twenty-three patients diagnosed with RA according to the
ACR classification criteria  were treated with two infusions
of 1000mg chimeric anti-CD20 antibody RTX (Roche Pharma,
Reinach, Switzerland) 14 days apart from each other in an
observational protocol. All patients had previously failed to
respond to at least one conventional DMARD. In addition,
all but three patients also failed to respond to at least one TNF
blocking agent, in agreement with the Swiss licence for RTX
in RA. Clinical disease activity was assessed by swollen joint
count (SJC), tender joint count (TJC), ESR, serum CRP and
disease activity composite score DAS28  at baseline and
6 months after treatment with RTX. The European League
Against Rheumatism (EULAR) response criteria were calculated
prednisolone (80mg intravenously, Pfizer Zurich, Switzerland),
5mg levocetirizin-dihydrochloride (UCB-Pharma AG, Bulle,
Switzerland) and 1000mg acetaminophen tablets (Bristol-Myers
Squibb, Baar, Switzerland) were concomitantly given with RTX
infusions. Subcutaneous low-dose MTX was used in 21 of
23 patients; it was kept stable for at least 6 weeks, in maximal
tolerated doses up to 25mg/week, before RTX infusions
and during the observational phase. TNF blocking agents were
discontinued at least one treatment interval before B-cell
depletion. Orally administered corticosteroids were continued in
a stable dose and then carefully tapered, according to improved
disease activity. Local corticosteroid injections into the joints of
interest were prohibited. The patient cohort is described in
more detail in Table 1. Written informed consent was obtained
according to the Declaration of Helsinki from all participants.
The study was approved by the cantonal ethics committee of Bern.
with RTX. Methyl-
Grey-scale (synonymous for brightness or B mode), as well as
colour-coded power Doppler (PD) US were performed on the
first day of RTX infusion and again 6 months later with an
Esaote MyLab 70 x-vision (Esaote S.p.a., Genova, Italy) supply
using the 4-cm linear-array transducer 6–18MHz (L4 35). MCP
and PIP joints of digits 2–5 on both hands were examined
according to the method of Scheel et al.  from a palmar
view, with joints in neutral 0 or in maximal extended position.
The colour box in PD was adjusted to the region of interest.
The pulse repetition frequency was set to 750 MHz, with wall
filter and persistence at the lowest possible level; colour priority
included all colours. The colour gain was adapted according to
published recommendations . Grey-scale and PD images with
Immunology and Allergology, Bern, Switzerland.
Bern UniversityHospital, Clinics forRheumatology,Clinical
Submitted 21 October 2008; revised version accepted 23 April 2009.
Correspondence to: Burkhard Mo ¨ller, Inselspital, Bern University Hospital,
Clinics for Rheumatology, Clinical Immunology and Allergology, Freiburgstrasse,
3010 Bern, Switzerland. E-mail: email@example.com
Advance Access publication 2 June 2009
? The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: firstname.lastname@example.org
by guest on November 14, 2015
maximal colour activity of each joint were saved as digital images
and scored from 0 to 3 by one of the participating experienced
assessors who was blind to the clinical data. Excluded from
evaluation were joints with extension deficits >208, replaced
joints as well as those with radiographic evidence for ankylosis
or major joint deformations, such as large osteophytes. Sublu-
xation, luxation and mutilation were also excluded. Synovitis
of PIP joints was defined according to reference images .
Reference photographs used in this study for MCP scoring
are shown in Fig. 1. PD-Mode images were scored in a semi-
quantitative manner from 0 to 3 according to a previous
Data were evaluated on single joint and patient levels. The
frequency of results in percentage was calculated on the basis of
all joints in evaluation at baseline and after 6 months set to 100%.
Data on patient level are given as the mean of all joints in
evaluation at baseline and month 6. Unless otherwise stated,
non-parametric data were presented by the median and range.
Spearman’s coefficient of correlation. The relationship of nominal
parameters was presented by likelihood ratios (LRs) with
indicated degrees of freedom (DFs). Significance of differences
between two tailed groups was calculated by Wilcoxon’s test of
the median and of two untailed groups by Mann–Whitney U-test.
Prediction of clinical response was estimated by calculating linear
regression models based on baseline parameters for the change of
DAS28 over time and by ordinal regression for no, moderate
and good EULAR response. Statistical analysis was performed
with SPSS version 15.0.
Clinical baseline characteristics
Median DAS at baseline was 5.03 (range 3.41–7.69). Of the
evaluated MCP and PIP joints, 27.6% were judged as tender
and 34.6% were swollen, with significant coincidence of these
items (LR¼59.0, DF¼1, P<0.001). Comparison of individual
left and right hand joints indicated symmetry for swollen
(LR¼31.9, DF¼1, P<0.001).
DF¼1,P<0.001)as wellas tender joints
Sonography at baseline
Of the 184 theoretically available joints, 158 MCP (85.9%) and
167 PIP (90.8%) were selected, after application of the exclusion
criteria, and evaluated at baseline and after 6 months. At baseline,
138 of these joints (42.5%) were free of any detectable synovial
thickening (score 0), according to corresponding reference images
for PIP joints as previously published , and for MCP joints as
presented in Fig. 1. Seventy-nine joints (24.3%) showed 18,
88 joints (27.1%) 28 and 20 joints (6.2%) 38 synovitis. The
median of baseline grey-scale scores per individual was 0.902
(range 0.00–1.87). Grey-scale scoring of single joints correlated
significantly with tenderness (LR¼12.71, P¼0.005) and more
closely with swollen joint status (LR¼43.64, P<0.001). Mean
grey-scale scores of patients correlated significantly with SJC
(Fig. 2; r¼0.484, P¼0.022), but not with TJC, DAS28, ESR or
CRP. Eighteen joints (5.5%) showed 18 and two joints (0.6%)
showed 28 hyperperfusion signals in PD at baseline. These flow
signals were only demonstrable in joints with 28 and 38 grey-scale
scoring. Positive PD results were correlated with joint tenderness
(LR¼7.26, DF¼1, P¼0.026). It is interesting to note that
synovial hyperplasia detected by grey scale (LR¼24.10, DF¼1,
P¼0.004), but not the pathological perfusion signals in PD, were
TABLE 1. Patient baseline characteristics (n¼23)
Number of female patients
CCP antibody positive
RF and anti-CCP positive
Age at disease onset, yearsa
Disease duration at inclusion, monthsa
Previous conventional DMARDb
aThe median value is given.bThe mean value is given. CCP: cyclic
FIG. 1. Reference grey-scale photographs of MCP joints taken from a palmar
longitudinal view with joints in maximal extension. (A) Score 0¼no synovial
membrane detectable or at most as a very thin, usually discontinuous hypoechoic
line. Small intra-articular effusions are an/hypoechoic and undistinguishable from
synovial hyperplasia. This thin line may become somewhat more prominent during
joint flexion. (B) Score 1¼synovial membrane is clearly detectable palmar to the
metacarpal diaphysis. Superficial and basal synovial boundaries take a parallel
course or may be slightly distended, but collapse at the epiphysis of the proximal
phalanx. (C) Score 2¼superficial and deep synovial margins form an ellipse and
synovial structures do not reach the base of the proximal phalanx. (D) Score
3¼superficial and deep synovial boundary form an ellipse and distal synovial
structures are clearly identifiable at the base of the proximal phalanx.
FIG. 2. Grey-scale scores are correlated with SJC. Cross-sectional data were
accumulated from all 23 patients at both time points.
940Hans-Rudolf Ziswiler et al.
by guest on November 14, 2015
Single parameters of RA disease activity improved significantly
P¼0.001) despite tapering of the daily corticosteroid intake
from a median of 10mg at baseline to a median of 5mg,
6 months after RTX. When breaking down the cumulative data
to single joints, the swollen joint status was stable in 68.3%,
improved in 27.1% and worsened in 4.6% of evaluated joints.
A similar distribution of stable (64.6%), improved (28.6%) and
worsened (6.8%) joints was seen in respect to tenderness. DAS28
improved in accordance with the single items from a 5.03 median
at baseline to 3.56 (range 1.38–6.65) in therapeutic B-cell depletion
(Z¼?4.076, P<0.001). Of the 23 patients, 11 patients thereby
met the EULAR criteria for moderate clinical response and
another 6 patients met the criteria for good response. DAS28
improved by a 0.52 median in the remaining six EULAR
In B-cell depletion, 158 joints (47.6%) were free of significant
synovial thickening (score 0); whereas 100 joints (30.1%)
showed 18, 65 joints (19.6%) 28 and 9 joints (2.7%) 38 synovitis.
Grey-scale scoring remained unchanged in 175 (53.7%) joints,
improved by 1 point in 70 joints, by 2 points in 20 joints and by
3 points in 7 joints. In contrast, the grey-scale scoring worsened by
1 point in 44 joints, by 2 points in 8 joints and by 3 points in
1 joint. The median of grey-scale scores on patient level improved
from 0.902 to 0.75 (range 0.19–1.50, Z¼?2.582, P¼0.010). As at
baseline, PD positivity of 18 in 11 (3.3%) and of 28 in 5 joints
(1.5%) was limited to joints with at least 28 grey-scale scoring.
The mean grey-scale scores correlated with SJC (Fig. 2, r¼0.519,
P¼0.011). In contrast to the results at baseline, we found addi-
tional significant correlations of mean grey-scale scores in B-cell
depletion with DAS28 (r¼0.529) and ESR (r¼0.416, P¼0.048).
No predictability of clinical response to RTX
Based on sonography and clinical and laboratory parameters
at baseline, we were not able to identify any significantly contri-
buting parameter in linear regression models for the development
of DAS28, or for the best achieved level of EULAR response
in ordinal regression models.
This study shows for the first time that therapeutic B-cell deple-
tion leads to reduced synovial hyperplasia and that this process
can be displayed by grey-scale US. Implications and consequences
of these findings are discussed here.
First, remission of RA and halt of radiographic progression
are linked mechanisms  that can be disconnected under
poorly defined conditions [19, 20]. Grey-scale US provides new
information, which may lead to a better understanding of
the relationship between immune mediated inflammatory disease
processes and joint inflammation.
Secondly, it has been shown that RTX treatment can lead
to both clinical improvement and reduced radiographic disease
progression [1–3, 6]. It is not known whether the recommended
RTX re-treatment intervals, which are highly variable when based
on an individual’s disease activity , will result in optimal con-
trol of disease progression. The applied grey-scale US method
provides information on synovial morphology, which may con-
tribute to rational disease monitoring after RTX. A prospective
longitudinal study, with repeat courses of RTX, would be neces-
sary to determine if this method is useful in predicting ongoing
Thirdly, post-marketing data from RA patients with rather low
DAS28, when starting RTX, suggested that improvement in SJC
might be less with RTX than that reported from clinical trial
cohorts with substantially higher baseline disease activity .
Therefore, it is important to note that the proportion of patients
in our study clinically responding to RTX after 6 months was
similar to controlled trials [1–3, 22], despite rather low baseline
activity. Thus, in less active arthritis, lack of response to RTX
could be ruled out by applying a novel imaging technique .
It is important to note that the present data are limited to a single
time point 6 months after RTX treatment that was selected after
consideration of delayed synovial B-cell depletion [23–25].
Changes in grey-scale scoring were not limited to joints with
clinically detectable swelling; they were also observed in 18 syno-
vial hyperplasia (Fig. 3). This finding would have been missed
without US monitoring. Despite improvement of synovial hyper-
plasia in a significant number of joints after RTX, a substantial
proportion of joints with different degrees of synovial hyperplasia
at baseline did not respond. This observation might be due to
location-dependent primary resistance to RTX and corticosteroid
tapering. Moreover, we occasionally observed worsening of
normal joints from grey-scale score 0 to 18 in therapeutic B-cell
depletion, which may also indicate spontaneous fluctuation
between these two states (Fig. 3). Nevertheless, notable agreement
of grey-scale US results with joint swelling status in four separate
cross-sectional analyses from two visits and in MCP and PIP
joints by different blinded investigators document the validity
of the data. In addition, significant improvement in grey-scale
scoring, along with change of joint swelling status, indicates the
sensitivity of this method to change.
FIG. 3. Change of grey-scale scores in (A) joints that were clinically swollen
at baseline but improved upon treatment (middle), in contrast to joints that were
clinically assessed as not swollen at baseline and in B-cell depletion (left) or joints
that were swollen at baseline and in B-cell depletion (right). (B) Average grey-scale
scoring is significantly improved upon RTX in 28 and 38 synovial hyperplasia, but
can change between normal and 18 synovial hyperplasia in both directions. Circles
represent median change in grey-scale scores over time and error bars depict
the 95% CI.
Rituximab reduces synovial hyperplasia941
by guest on November 14, 2015
There are some critical issues from the present study that
warrant further discussion. Correlation of grey-scale US with
DAS28 is, at best, moderate. This divergence may be explained
by differences in the number of joints assessed. Furthermore,
DAS28 is affected more by the number of tender joints and
ESR than the SJC, due to its mathematical formula. As expected,
grey-scale mode US correlated better with joint swelling than
with DAS28. Therefore, grey-scale US provides information in
addition to the DAS28. It is currently speculative whether
DAS28 or one of the novel imaging methods will be more
accurate and suitable for diagnostic or prognostic purposes in
As with grey scale, we decided to limit PD assessment in
the present study to the palmar side, according to a publication
available at the initiation of our study . In the meantime, other
investigators reported that PD signals could be detected from
a dorsal view, that they were modifiable by anti-TNF treatment
and that destruction was more likely to progress in PD positive
joints [26, 27]. It was also reported that the palmar view of finger
joints was rather insensitive to PD ultrasound signals [12, 28].
Positive PD results appear more prevalent in wrist joint synovitis
than finger joint synovitis . Although there is surprisingly
little change after clinically effective treatments, including local
corticosteroids and anti-TNF, in wrist joints , there is notable
reported sensitivity of PD signals to change in finger joints .
The validation process of PD US for arthritis is presently not
completed . Nevertheless, it is necessary to comment on the
missing impact of RTX on PD signals in our patient cohort
despite potentially method-dependent implications, rather low
clinical disease activity and low number of PD-positive joints
Due to well-established changes in B-cell aggregates in the
synovium [23–25, 30], we primarily examined synovial hyperplasia
and hyperperfusion, pathologies detectable by US and MRI
[12, 27, 31, 32]. However, with our methods, intraosseous
processes such as bone oedema, the best predictive parameter
for erosions in MRI studies [27, 33, 34], could not be addressed.
In summary, high-resolution US provided evidence of signifi-
cant reductions in synovial hyperplasia after RTX treatment.
Yet, we also noted persistence of synovial hyperplasia in several
joints for currently unknown reasons. Use of a validated
novel imaging tool, such as US, could further substantiate
improvement in RA by B-cell depletion. This method displays
response, but also resistance, to RTX and provides an objective
and clinically applicable link between B-cell-directed immune
modulation and arthritis symptoms. Based on these characteris-
tics, grey-scale US is recommended for monitoring synovial
hyperplasia after RTX therapy. It remains speculative whether
more relevant information might be obtained by optimizing
the PD method.
Rheumatology key messages
? Grey-scale US provides evidence of reduced synovial hyperplasia
and improved RA disease activity after RTX treatment.
? This finding further substantiates the known beneficial effects of
therapeutic B-cell depletion in RA.
We are grateful to Marianne Rotzetter for her excellent technical
assistance. We also acknowledge manuscript editing assistance
provided by San Francisco Edit.
Funding: We are grateful to Roche Pharma, Switzerland for
supporting our data collection with a research grant of 10000
Disclosure statement: B.M. has received honorary fees of less
than 10000 Swiss Francs from Roche Pharma, Switzerland for
attending advisory board meetings. All other authors have
declared no conflicts of interest.
1 Edwards JC, Szczepanski L, Szechinski J et al. Efficacy of B-cell-targeted therapy
with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572–81.
2 Emery P, Fleischmann R, Filipowicz-Sosnowska A et al. The efficacy and safety of
rituximab in patients with active rheumatoid arthritis despite methotrexate treatment:
results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging
trial. Arthritis Rheum 2006;54:1390–400.
3 Cohen SB, Emery P, Greenwald MW et al. Rituximab for rheumatoid arthritis
refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized,
double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety
at twenty-four weeks. Arthritis Rheum 2006;54:2793–806.
4 Takemura S, Klimiuk PA, Braun A, Goronzy JJ, Weyand CM. T cell activation in
rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710–8.
5 Taylor RP, Lindorfer MA. Drug insight: the mechanism of action of rituximab
in autoimmune disease–the immune complex decoy hypothesis. Nat Clin Pract
6 Keystone EC, Emery P, Peterfy CG et al. Rituximab inhibits structural joint damage in
rheumatoid arthritis patients with an inadequate response to tumour necrosis factor
inhibitor therapies. Ann Rheum Dis 2009;68:216–21.
7 Zikou AK, Argyropoulou MI, Voulgari PV et al. Magnetic resonance imaging
quantification of hand synovitis in patients with rheumatoid arthritis treated with
adalimumab. J Rheumatol 2006;33:219–23.
8 Iagnocco A, Filippucci E, Perella C et al. Clinical and ultrasonographic monitoring
of response to adalimumab treatment in rheumatoid arthritis. J Rheumatol 2008;
9 Quinn MA, Conaghan PG, O’Connor PJ et al. Very early treatment with infliximab
in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces
magnetic resonance imaging evidence of synovitis and damage, with sustained
benefit after infliximab withdrawal: results from a twelve-month randomized,
double-blind, placebo-controlled trial. Arthritis Rheum 2005;52:27–35.
10 Albrecht K, Grob K, Lange U, Muller-Ladner U, Strunk J. Reliability of different
Doppler ultrasound quantification methods and devices in the assessment of
therapeutic response in arthritis. Rheumatology 2008;47:1521–6.
11 Hau M, Kneitz C, Tony HP, Keberle M, Jahns R, Jenett M. High resolution ultrasound
detects a decrease in pannus vascularisation of small finger joints in patients with
rheumatoid arthritis receiving treatment with soluble tumour necrosis factor alpha
receptor (etanercept). Ann Rheum Dis 2002;61:55–8.
12 Naredo E, Collado P, Cruz A et al. Longitudinal power Doppler ultrasonographic
assessment of joint inflammatory activity in early rheumatoid arthritis: predictive
value in disease activity and radiologic progression. Arthritis Rheum 2007;
13 Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association
1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum
14 Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van
Riel PL. Modified disease activity scores that include twenty-eight-joint counts.
Development and validation in a prospective longitudinal study of patients with
rheumatoid arthritis. Arthritis Rheum 1995;38:44–8.
15 van Gestel AM, Prevoo ML, van’t Hof MA, van Rijswijk MH, van de Putte LB, van
Riel PL. Development and validation of the European League Against Rheumatism
response criteria for rheumatoid arthritis. Comparison with the preliminary American
College of Rheumatology and the World Health Organization/International League
Against Rheumatism criteria. Arthritis Rheum 1996;39:34–40.
16 Scheel AK, Hermann KG, Kahler E et al. A novel ultrasonographic synovitis scoring
system suitable for analyzing finger joint inflammation in rheumatoid arthritis. Arthritis
17 Torp-Pedersen ST, Terslev L. Settings and artefacts relevant in colour/power
Doppler ultrasound in rheumatology. Ann Rheum Dis 2008;67:143–9.
18 Voskuyl AE, Dijkmans BA. Remission and radiographic progression in rheumatoid
arthritis. Clin Exp Rheumatol 2006;24:S37–40.
19 Cohen G, Gossec L, Dougados M et al. Radiological damage in patients with
rheumatoid arthritis on sustained remission. Ann Rheum Dis 2007;66:358–63.
20 Smolen JS, Han C, Bala M et al. Evidence of radiographic benefit of treatment with
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
21 Smolen JS, Keystone EC, Emery P et al. Consensus statement on the use of
rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2007;66:143–50.
22 Finckh A, Ciurea A, Brulhart L et al. B cell depletion may be more effective than
switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis
patients with inadequate response to anti-tumor necrosis factor agents. Arthritis
23 Kavanaugh A, Rosengren S, Lee SJ et al. Assessment of rituximab’s immuno-
modulatory synovial effects (arise trial). 1: Clinical and synovial biomarker results.
Ann Rheum Dis 2008;67:402–8.
942Hans-Rudolf Ziswiler et al.
by guest on November 14, 2015
24 Teng YK, Levarht EW, Hashemi M et al. Immunohistochemical analysis as a means
to predict responsiveness to rituximab treatment. Arthritis Rheum 2007;56:3909–18.
25 Thurlings RM, Vos K, Wijbrandts CA, Zwinderman AH, Gerlag DM, Tak PP. Synovial
tissue response to rituximab: mechanism of action and identification of biomarkers of
response. Ann Rheum Dis 2008;67:917–25.
26 Taylor PC, Steuer A, Gruber J et al. Ultrasonographic and radiographic results from a
two-year controlled trial of immediate or one-year-delayed addition of infliximab to
ongoing methotrexate therapy in patients with erosive early rheumatoid arthritis.
Arthritis Rheum 2006;54:47–53.
27 Brown AK, Conaghan PG, Karim Z et al. An explanation for the apparent dissociation
between clinical remission and continued structural deterioration in rheumatoid
arthritis. Arthritis Rheum 2008;58:2958–67.
28 Naredo E, Rodriguez M, Campos C et al. Validity, reproducibility, and responsive-
ness of a twelve-joint simplified power doppler ultrasonographic assessment of joint
inflammation in rheumatoid arthritis. Arthritis Rheum 2008;59:515–22.
29 Boesen M, Boesen L, Jensen KE et al. Clinical outcome and imaging changes after
intraarticular (IA) application of etanercept or methylprednisolone in rheumatoid
arthritis: magnetic resonance imaging and ultrasound-Doppler show no effect of IA
injections in the wrist after 4 weeks. J Rheumatol 2008;35:584–91.
30 Vos K, Thurlings RM, Wijbrandts CA, van Schaardenburg D, Gerlag DM, Tak PP.
Early effects of rituximab on the synovial cell infiltrate in patients with rheumatoid
arthritis. Arthritis Rheum 2007;56:772–8.
31 Conaghan PG, O’Connor P, McGonagle D et al. Elucidation of the relationship
between synovitis and bone damage: a randomized magnetic resonance imaging
study of individual joints in patients with early rheumatoid arthritis. Arthritis Rheum
32 Ostergaard M, Hansen M, Stoltenberg M et al. Magnetic resonance imaging-
determined synovial membrane volume as a marker of disease activity and a
predictor of progressive joint destruction in the wrists of patients with rheumatoid
arthritis. Arthritis Rheum 1999;42:918–29.
33 Hetland ML, Ejbjerg BJ, Horslev-Petersen K et al. MRI bone oedema is the strongest
predictor of subsequent radiographic progression in early rheumatoid arthritis.
Results from a 2 year randomized controlled trial (CIMESTRA). Ann Rheum Dis
34 McQueen FM, Benton N, Perry D et al. Bone edema scored on magnetic resonance
imaging scans of the dominant carpus at presentation predicts radiographic joint
damage of the hands and feet six years later in patients with rheumatoid arthritis.
Arthritis Rheum 2003;48:1814–27.
Rituximab reduces synovial hyperplasia943
by guest on November 14, 2015