Best Practice & Research Clinical Rheumatology

Vol. 22, No. 6, pp. 1019–1044, 2008

doi:10.1016/j.berh.2008.09.014
available online at http://www.sciencedirect.com

Imaging in rheumatoid arthritis – status and

recent advances for magnetic resonance
imaging, ultrasonography, computed
tomography and conventional radiography

Mikkel Østergaard * MD, PhD, DMSc

Professor in Rheumatology/Arthritis
Department of Rheumatology, Copenhagen University Hospitals at Herlev and Hvidovre, Copenhagen, Denmark

Susanne Juhl Pedersen MD

Research Fellow
Department of Rheumatology, Copenhagen University Hospital at Herlev, Copenhagen, Denmark
Department of Radiology, Copenhagen University Hospital at Herlev, Copenhagen, Denmark

Uffe Møller Døhn MD

Research Fellow
Department of Rheumatology, Copenhagen University Hospital at Hvidovre, Copenhagen, Denmark

Sensitive and reproducible tools for diagnosis, monitoring of disease activity and damage, and
prognostication are essential in the management of patients with rheumatoid arthritis (RA).
Conventional radiography (X-ray), the traditional gold standard for imaging in RA, is not
able to detect early disease manifestations such as inflammatory changes in the soft tissues
(synovitis, tensynovitis, enthesitis etc.) and the earliest stages of bone erosion. In contrast,
magnetic resonance imaging (MRI) and ultrasonography (US) allow direct visualization of early
inflammatory and destructive joint changes, and have several documented and potential appli-
cations in RA patients. This chapter will review key aspects of the current status and recent
important advances in imaging in RA, briefly discussing X-ray and computed tomography, and
particularly focusing on MRI and US. Suggestions for use in clinical trials and practice are
provided.

* Corresponding author. Department of Rheumatology, Copenhagen University Hospital at Hvidovre,

Kettegaard Alle 30, DK-2650 Hvidovre, Denmark. Tel.: þ45 21603865/36322839; Fax: þ45 36471410.
E-mail address: mo@dadlnet.dk (M. Østergaard).
1521-6942/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.
1020 M. Østergaard et al

Key words: rheumatoid arthritis; imaging; magnetic resonance imaging; ultrasonography;

computed tomography; conventional radiography.

The optimal imaging method in rheumatoid arthritis (RA) would be a sensitive and re-
producible tool for diagnosis, monitoring of disease activity and damage, and prognos-
tication. Conventional radiography (X-ray), the traditional gold standard for imaging in
RA, is not able to detect early disease manifestations such as soft tissue changes and
the earliest stages of bone erosion.1–3 In contrast, ultrasonography (US) and magnetic
resonance imaging (MRI) allow direct visualization of early inflammatory and destruc-
tive joint changes in RA2–6, and these imaging techniques have therefore attracted sub-
stantial interest. This chapter will review key aspects of the current status and recent
important advances in imaging in RA, briefly discussing X-ray and computed tomogra-
phy (CT), and particularly focusing on US and MRI.

CONVENTIONAL RADIOGRAPHY

Which abnormalities?

X-ray can visualize bone erosions, joint space narrowing as an indirect sign of cartilage
thinning, juxta-articular osteoporosis, cysts and, in severe cases, joint subluxations,
malalignment and/or ankylosis (Figure 1).1,7
X-ray depicts the time-integrated cumulative record of joint damage. The clinical
relevance of a measure of structural joint damage as X-ray depends on its relationship
with a patient-focused outcome, i.e. how the patient feels, functions or survives. For
practical purposes, these outcomes are in RA pain and disability. In early disease, X-ray
status is not related to functional outcome measures such as the Health Assessment
Questionnaire (HAQ) score, whereas in established disease (disease duration >5
years), the radiographic damage visualized by X-ray are significantly correlated with
functional status and explain approximately 25% of the disability.8 More advanced im-
aging modalities, such as MRI, may be able to capture disease manifestations respon-
sible for >25% of patient disability provided by X-ray, by visualizing all structures
involved in the RA disease process.
The advantages of X-ray include low cost, high availability, possibility of standardi-
zation and blinded centralized reading, reasonable reproducibility, and existence of val-
idated assessment methods.9 The disadvantages of X-ray include projectional
superimposition due to the two-dimensional representation of three-dimensional pa-
thology, use of ionizing radiation, relative insensitivity to early bone damage, and total
insufficiency for assessment of soft tissue changes including synovitis.10–12

Diagnosis and prognostication

Characteristic X-ray findings are part of the American College of Rheumatology

(ACR) classification criteria for RA.13 X-ray can be helpful in the differentiation of
RA from other joint conditions including osteoarthritis, psoriatic arthritis and
neoplasms.7
Early bone erosions are correlated with poor long-term radiographic and functional
outcome14, and early progression in X-ray erosions is related to future impairment in
physical function.15 In early undifferentiated arthritis, presence of X-ray erosions in-
creases the risk of developing persistent arthritis.16 However, radiographic erosions
 Imaging in rheumatoid arthritis 1021

Figure 1. X-rays of hands, wrist and forefeet. X-rays in posterior–anterior (hands and wrists, top) and an-
terior–posterior (feet, bottom) projection, as used for scoring by the Sharp/van der Heijde method. Images
illustrate various degrees of erosions and joint space narrowing. Scores of erosions (E) and joint space nar-
rowing (N) of selected metacarpophalangeal joints and proximal interphalangeal (PIP) joints of the hands, and
metatarsophalangeal joints and PIP1 joints of the feet are noted proximal to the scored joint.

are only present in a minority of patients with early RA, with a prevalence of 8–40% at
6 months2,17–20, and X-ray is not effective for identifying future ‘non-progressors’, i.e.
patients that will not show increasing structural joint damage (see MRI section
below).21

Monitoring disease progression

In routine clinical management of RA and clinical trials, X-ray evaluation focuses on

joint space narrowing and bone erosions in hands, wrists and forefeet as measures
of structural joint damage (Figure 1).22–24 Validated scoring methods of radiological
damage (the Larsen method, the Sharp method and their modifications) are available
1022 M. Østergaard et al

and are used extensively in clinical trials.9,23,24 The van der Heijde and Genant mod-
ifications of the Sharp score are generally considered to be the methods most sensi-
tive to change, but are also the most time-consuming.25 A recent paper reported that
the Sharp/van der Heijde method may register change in erosive damage within as little
as 3 months.26
For clinical practice, the less time-consuming ‘Simple Erosion Narrowing Score’,
based on counting joints with bone erosions and joints with joint space narrowing,
is available.27,28

COMPUTED TOMOGRAPHY

Which abnormalities?

CT is a tomographic radiographic imaging method that visualizes calcified tissue with

high resolution. It can be considered a standard reference for detecting destructions of
calcified tissue, such as bone erosions in RA. By using multidetector CT with multipla-
nar reconstruction, three-dimensional visualization of joints is possible (Figures 2
and 3), whereas X-ray is a projection technique that only offers two-dimensional
visualization of the three-dimensional anatomy. However, in comparison with MRI
and US, CT visualizes soft tissue changes inadequately.29,30
Recent studies have explored the relationship between MRI and US findings with
CT as the reference method.30–34 Good agreement was found between MRI and
CT erosion detection (see MRI section for more details).30,31,33,34 Erosion volumes
have been quantified and high intra-observer agreements have been reported.33,34
CT is very rarely used in clinical practice. However, CT appears to be even more
sensitive for bone erosions than MRI30–34, and as the radiation dose of high-resolution
CT of hand/wrist is at the same level as conventional X-ray, i.e. limited, and the exam-
ination is very short (approximately 1 min for hand and wrist), CT may have an as yet
unexplored potential as an assessment method for RA joint damage.

Monitoring disease progression

A recent study introduced CT as a primary outcome measure in an RA trial of 52 pa-

tients, evaluating the occurrence and frequency of erosion repair in RA patients
treated with anti-tumour necrosis factor (anti-TNF). Repair was rare (1.6% of bones)
but did occur.35 No other longitudinal studies exist.

Diagnosis and prognostication

No data are available regarding CT for diagnosis or prognostication of RA.

MAGNETIC RESONANCE IMAGING

Which abnormalities?

MRI provides multiplanar tomographic imaging with unprecedented soft tissue con-
trast, without the use of ionizing radiation, and allows assessment of all the structures
involved in arthritic disease, i.e. synovial membrane, intra- and extra-articular fluid col-
lections, cartilage, bone, ligaments, tendons and tendon sheaths. It has been shown to
 Imaging in rheumatoid arthritis 1023

Figure 2. Erosive progression documented on computed tomography (CT) and magnetic resonance imaging
(MRI) but not on X-ray. CT and MRI images of the fifth metacarpal head at 0 (a,b,g,h), 6 (c,d,i,j) and 12 (e,f,k,l)
months show the development of new bone erosion (arrows), whereas the corresponding X-ray from 12
months (m) does not reveal any erosions at the metacarpal head. Notice that the CT images from baseline
and 6 months reveal progressive destruction within the bone, even though no cortical breach was identified
at these examinations.

be more sensitive than clinical examination and X-ray for the detection of inflamma-
tory (Figures 4 and 5) and destructive (Figures 2 and 3) joint changes in early RA. MRI
and histopathological signs of synovial inflammation are closely correlated36–38, and in
a study of metacarpophalangeal (MCP) joints in early and established RA patients, mini-
arthroscopy confirmed the presence of bone pathology in all joints with MRI bone
erosions, and histological and macroscopic synovitis in all joints with MRI synovitis.39
MRI bone marrow oedema (Figure 4) has recently, in comparison with histological
 1024 M. Østergaard et al
Figure 3. Assessment of bone erosions in the second metacarpophalangeal joint by computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US) and
X-ray. An erosion on the radial aspect of the second phalangeal basis (short white arrow) is seen on all modalities, whereas an erosion on the radial aspect of the second
metacarpal head (long white arrow) was only registered on CT (a,b: coronal and axial slice), MRI (c,d: coronal and axial slice) and US (e,f: longitudinal and transversal view),
but not on X-ray (g). Other erosions, at the ulnar aspects of the phalangeal basis and metacarpal head (black arrows), were seen by CT and MRI, but not by US (access with
US probe impossible) or X-ray. US images are presented with the radial surface to the right, with proximal at the bottom in (e) and palmar at the bottom in (f).
 Imaging in rheumatoid arthritis 1025

samples obtained during surgery in patients with established RA, been shown to rep-
resent inflammatory infiltrates in the bone marrow, i.e. osteitis.40,41 In contrast to ra-
diographic erosions, which reflect bone damage that has already occurred, bone
marrow oedema appears to represent the link between joint inflammation and
bone destruction.
A high level of agreement for detection of bone erosions in RA wrists and MCP
joints (concordance at 77–90% of sites) between MRI and CT (Figure 3), the gold stan-
dard reference for detection of bony destruction, shows that MRI erosions represent
true bone damage.30,31,34

Which joints to assess and how to acquire images

The majority of MRI studies in RA have investigated knee, wrist or finger joints. Re-
ports on other peripheral joints are few and not essentially different. The few studies
available on MRI of feet have not supported an advantage of imaging feet compared
with wrists and hands.42 Although only one formal comparison with follow-up of other
joints exists, MRI of unilateral MCP and wrist joints is most commonly recommended
for MRI follow-up of RA patients, whereas MRI of other joints should only be obtained
if there is a specific clinical indication.
Compared with X-ray, MRI offers clear advantages, but also disadvantages as in-
creased cost and lower availability. However, the costs of MRI only represent a fraction
of the total expense incurred in the management of RA patients, when the costs of
biological RA treatment or the indirect costs of sick leave/early retirement are consid-
ered. Nevertheless, reducing the cost of MRI would be advantageous and would en-
courage clinicians to use MRI more often. Dedicated extremity MRI (E-MRI) units
are being used increasingly because they offer improved patient comfort at lower
cost than conventional MRI units.5,43–51 The better of dedicated low-field MRI units
provide similar information on erosions and synovitis as conventional high-field MRI
units.46,47 However, performance characteristics of different machines differ widely,
as illustrated by a recent study in which Duer-Jensen et al found that the sensitivity
for bone erosions varied from 0.50 to 0.23 between E-MRI units, when CT was con-
sidered as the standard reference method.52 This stresses the need for careful testing
of individual machines.
Optimal MRI assessment of synovitis requires the use of intravenous gadolinium
contrast, whereas assessment of bone oedema and erosion does not.53 Thus, for
assessment of synovitis, bone oedema and erosions, a pre- and post-contrast T1-
weighted sequence in two planes plus a T2-weighted fat-saturated or short tau
inversion recovery sequence is recommended.54

Monitoring disease activity and damage

To be valuable for monitoring joint inflammation and destruction in clinical trials, an

applied MRI measure must be reproducible but also sensitive to change.55 MRI allows
quantitative [early contrast uptake (‘enhancement’) rate after intravenous injection
(only synovitis) or volume] as well as less detailed (qualitative: presence/absence; semi-
quantitative: scoring) evaluation of synovitis and bone erosions. In observational and
randomized clinical trials, semiquantitative scoring has been the most frequently
used approach. The OMERACT (Outcome Measures in Rheumatology) RA MRI scor-
ing system (RAMRIS) involves semiquantitative assessment of synovitis (Figure 4), bone
erosions (Figures 2 and 3) and bone oedema (Figures 4 and 6) in RA hands and
 1026 M. Østergaard et al
Figure 4. Assessment of inflammation by magnetic resonance imaging (MRI) and ultrasonography (US). (a,b) T1-weighted fat-suppressed MRI of the second to fifth meta-
carpophalangeal (MCP) joints before (a) and after (b) gadolinium contrast injection. Signs of severe synovitis are seen in the second and third MCP joints. (c) Coronal short
tau inversion recovery (STIR) MRI showing osteitis (bone marrow oedema) in the second and third metacarpal heads and phalangeal bases. The image also shows synovitis
in these joints. (d,e) Longitudinal dorsal US scans confirm synovitis on grey-scale US (d) and power Doppler US (e).
 Imaging in rheumatoid arthritis 1027
Figure 5. Ultrasonography (US) and magnetic resonance imaging (MRI) of tenosynovitis. (a,b) Palmar longitudinal (a) and transversal (b) US scans of the third metacar-
pophalangeal joint show tenosynovitis with presence of effusion (long arrows) and power Doppler signal (short arrows) around the flexor tendon. (c,d) Two consecutive
coronal short tau inversion recovery MRI images showing bright signal (arrows) around the same flexor tendon, confirming tenosynovitis.
1028 M. Østergaard et al

Figure 6. Magnetic resonance imaging for assessment of change in osteitis (bone marrow oedema). Coronal
short tau inversion recovery images before (a) and after 6 months (b) of anti-tumour necrosis factor therapy,
showing massive bone oedema in many wrist bones at baseline, whereas no bone oedema was seen at
6 months.

wrists.54 This method was developed and validated through iterative multicentre stud-
ies under OMERACT and European League against Rheumatism (EULAR) ban-
ners.53,54,56–58 Consensus MRI definitions of important joint pathologies and a core
set of basic MRI sequences were also suggested.54
The OMERACT erosion scores are closely correlated with erosion volumes esti-
mated by MRI and CT.30,34 Very good intrareader reliability, good inter-reader reliabil-
ity, and a high level of sensitivity to change have been reported for the RAMRIS,
demonstrating that, after proper training and calibration of readers, this system is suit-
able for monitoring joint inflammation and destruction in RA.59,60 A EULAR–OMER-
ACT RA MRI reference image atlas has been developed, providing an easy-to-use tool
for standardized RAMRIS scoring of MR images for RA activity and damage in compar-
ison with standard reference images.61
Haavardsholm et al have recently published a scoring system for tenosynovitis (Fig-
ure 5), which has shown high intra- and inter-reader agreement, and which can be used
as an addendum to the OMERACT scoring system.62
The OMERACT synovitis score is sensitive to change over weeks as well as
months.63–65 MRI is being used increasingly in trials of biological agents to measure
changes in synovitis. Studies have demonstrated efficacy of anti-TNF agents64–68 and
rituximab69, but not anakinra.70 Recently, Haavardsholm et al reported that a combined
score of synovitis, tenosynovitis and bone oedema was more sensitive to change than
conventional biomarkers and clinical measures, as well as the individual MRI parame-
ters separately.71
Quantitative methods of synovitis (synovial membrane volumes and postcontrast
enhancement rates), which have been shown to be closely related to histopathological
synovitis36–38 and sensitive to change in knee joints37,72, have only been used sparsely
in clinical trials, probably because they are laborious (particularly volumes) and/or have
 Imaging in rheumatoid arthritis 1029

limited reproducibility with multicentre use (particularly early enhancement rates/dy-

namic MRI). However, recent software improvements, providing more automated
methods, potentially increase assessment speed and reproducibility.73–77 As such,
the virtues of such quantitative methods should be revisited.
Several studies have shown that MRI is more sensitive than X-ray for monitoring
erosive progression in the individual joint regions (Figure 2).4,10–12 Ejbjerg et al showed
that, in established RA, RAMRIS scoring of unilateral wrist and MCP joints is more sen-
sitive to change than Sharp/van der Heijde X-ray scoring of bilateral hands, wrist and
forefeet.42 Similar results have been found in early RA.78
The superior sensitivity to change and discriminatory ability of MRI compared with
X-ray has been demonstrated in randomized controlled clinical trials.66,79,80 Quinn et al
demonstrated a significantly lower erosion progression rate by MRI, but not by the
Sharp/van der Heijde X-ray method, in 12 early RA patients treated with methotrexate
plus infliximab compared with 12 patients receiving methotrexate alone.66 This was the
first study to verify that the use of MRI in randomized controlled trials allows shorter
duration and/or fewer patients to discriminate between different therapies concerning
reduction of structural joint damage. Subsequently, a 26-week randomized controlled
trial of 39 RA patients demonstrated a significantly lower MRI erosion progression
rate in patients treated with the bisphosphonate zoledronic acid plus methotrexate
compared with patients treated with placebo plus methotrexate, whereas the radio-
graphic progression rate was numerically, but not significantly, lower.79 In a study of
the receptor activator of nuclear factor kappa B ligand (RANKL) inhibitor denosumab,
both MRI and X-ray showed 6 months of structural damage inhibition compared with
placebo in the 180-mg group but not in the 60-mg group81, but MRI was closer to
showing a significant difference (P ¼ 0.12 vs P ¼ 0.28), indicating a somewhat higher
discriminatory ability than X-ray. Finally, Durez et al demonstrated a significantly lower
MRI erosion progression rate during 18 weeks of treatment with infliximab plus
methotrexate compared with intravenous methylprednisolone plus methotrexate ther-
apy (15 patients per group).80 X-rays were not included in this study.
The data above show that MRI demonstrates superior sensitivity to change in ero-
sive damage compared with X-ray. It is still awaited that the US Food and Drug Admin-
istration and the European Medicines Agency accept MRI as a method that can form
the basis for regulatory approval of a drug being capable of structural joint damage
inhibition.

Diagnosis

A number of relatively small studies (50 patients per study) have investigated the dif-
ferential diagnostic value of MRI82–86, with ambiguous results.
Sugimoto et al investigated MRI criteria (bilateral MRI synovitis in hands/wrists) as
an adjunct to the 1987 ACR criteria for establishing a diagnosis of RA. With the ad-
dition of MRI criteria, some improvement in diagnostic accuracy (94% vs 83%) was
found in early undifferentiated arthritis patients.82 This has not been tested in other
studies.
In a study by Boutry et al of patients with RA, systemic lupus erythaematosus and
primary Sjogren’s syndrome with polyarthralgia involving the hand, MCP joint bone oe-
dema was much more common in RA patients (71%) than non-RA patients (5%).83
However, no features of bone oedema that were unique to RA were identified. Tamai
et al performed MRI of wrists and hands in 80 patients with early (<2 years) RA and
33 non-RA patients, and reported symmetrical synovitis, bone oedema and erosion
1030 M. Østergaard et al

related to the diagnosis of RA.85 However, MRI was not performed before diagnosis,
and therefore these two studies did not truly investigate the differential diagnostic
value of MRI.
Solau-Gervais et al studied 30 patients with anti-cyclic citrullinated peptide (anti-
CCP)-negative polyarthralgia and morning stiffness with or without clinical synovitis,
and without X-ray erosions.84 Except for a significantly higher OMERACT MCP ero-
sion score, no significant differences were found at 1-year follow-up of MRI of wrists/
hands between patients judged by a rheumatologist to be RA or non-RA.
Duer et al reported that among 41 polyarthritis patients, who were unclassified de-
spite conventional clinical, biochemical and radiographic examinations, application of
MRI (of unilateral wrist and MCP joints) and scintigraphy allowed correct classification
as RA or non-RA in 39 of 41 patients, when fulfillment of ACR 1987 criteria for RA 2
years later was considered as the standard reference.86
With fulfillment of ACR RA criteria at 1–3.5 years follow-up as the gold standard,
Narvaez et al recently reported sensitivity of 100% and specificity of 78% when apply-
ing a selected MRI criterion [synovitis and bone erosions/bone oedema on MRI of uni-
lateral wrist, MCP and proximal interphalangeal (PIP) joints] in 40 undifferentiated RA
patients (age >18 years, symmetrical involvement of three or more joint areas, disease
duration >6 weeks and 12 months, rheumatoid factor negative, no X-ray erosions),
whereas the sensitivity and specificity of anti-CCP antibodies were 23% and 100%,
respectively.87
Overall, the above studies suggest that MRI may have a value in diagnosing specific
forms of inflammatory arthritis, including RA, but further, larger studies are needed to
reach definite conclusions.

Prognostication

Several imaging studies have demonstrated that MRI pathology (synovitis, bone ero-
sions or, most often, bone marrow oedema) of the wrist and MCP joints at disease
onset in early RA is predictive of radiographic erosions.10,88–94 Some studies looked
at the short-term predictive value of MRI after 1 year10,88,90,92,93, whereas other stud-
ies had 290,94, 689 or 1091 years of follow-up. All studies found MRI to be a highly sig-
nificant predictor of radiographic erosions. A high combined score of wrist joint MRI
erosions and synovitis at baseline was the best predictor of radiographic erosive pro-
gression in the hand, wrists and feet after 10 years in 114 patients with early RA.91 In
this study, however, bone marrow oedema was not assessed, and the separate predic-
tive values of MRI bone erosions and MRI synovitis were not reported. In two small
studies of early RA88,90, bone marrow oedema at baseline was the strongest individual
predictor of MRI bone erosions at 1 and 2 years follow-up, but conventional X-rays
were not obtained. A study of dedicated E-MRI in 25 patients with early RA found a rel-
ative risk of 4.0 for X-ray erosions after 1 year if erosions or oedema were present at
baseline.92
All studies, except two very recent studies93,94, were imaging studies that did not
include anti-CCP or take other potential prognostic markers, such as smoking or
shared epitope carriage, into account. Haavardsholm et al93 reported that bone mar-
row oedema and male gender (but not anti-CCP) were independent predictors of
radiographic progression after 1 year in a single-centre cohort of 84 patients treated
according to standard clinical practice. A study by Hetland et al was the first clinical
trial with a standardized treatment protocol to investigate the predictive value of
a variety of potential prognostic markers including both imaging (MRI and conventional
 Imaging in rheumatoid arthritis 1031

X-ray), immunological markers (anti-CCP, immunoglobulin M rheumatoid factor, im-

munoglobulin A rheumatoid factor), environmental markers (smoking, educational
level), genetic markers (shared epitope) and disease activity markers.94 The main find-
ing was that in this comprehensive model, MRI bone marrow oedema at presentation
(by multiple regression as well as logistic regression analyses) was the strongest pre-
dictor of radiographic progression 2 years later in early RA patients.
A relationship between baseline MRI findings and long-term functional disability has
only been documented in one study.95 Data from the same cohort revealed that ex-
tensive MRI bone oedema and erosions at the wrist in early RA predicted tendon dys-
function and impaired hand function.96 Furthermore, a high baseline MRI tendinopathy
score was predictive of tendon rupture at 6 years [odds ratio (OR) 1.52].97 Further
studies are required to determine the clinical importance of these findings.
Another issue of high clinical importance is whether MRI is useful in patients in clin-
ical remission to predict the disease course. MRI synovitis is common in patients in
clinical remission.98,99 The impact of subclinical imaging findings has been studied by
Brown et al.100 Seventeen controls and 102 RA patients on conventional treatment
judged to be in remission by their treating rheumatologist underwent clinical, labora-
tory, functional and quality-of-life assessments during a 12-month period. X-rays of
hands and feet, and MRI and US of unilateral hand and wrist were performed at base-
line and 12 months. Despite clinical remission, 19% of patients experienced progres-
sion in radiographic joint damage during the study period. Baseline US synovial
hypertrophy, US power Doppler signal and MRI synovitis scores in individual joints
were significantly related to progressive radiographic damage.
Thus, the progression in structural joint damage in RA patients in clinical remission
on conventional therapy reflected subclinical joint inflammation.101 The study empha-
sized the usefulness of imaging for predicting the disease course and for evaluating dis-
ease status, including defining remission.

ULTRASONOGRAPHY

Which abnormalities?

It US has several advantages. It has low running costs, and is patient-friendly, relatively
accessible, and interactive with the patient. The examination involves no ionizing
radiation, is multiplanar and visualizes structures in real-time. Doppler examination
provides haemodynamic information on the examined tissue. US enables quick exam-
ination of several joints in different body regions at one session, and is easy to repeat,
making follow-up examinations convenient and comfortable for the patient. However,
the assessment of joints with US is limited by the fact that US cannot penetrate bone,
by intermachine and inter-reader variability, by lack of consensus on systems for
assessment of activity and damage, and by limited testing of the available systems in
longitudinal follow-up studies.
US can visualize inflammatory as well as destructive RA changes. High-frequency
probes are required for satisfactory examination of the small joints of the hands
and feet. It allows assessment of synovitis by detection of thickening of the synovial
membrane of inflamed joints, bursae or tendon sheaths by grey-scale (B-mode)
US3,102, and by revealing and potentially quantifying increased synovial blood flow using
Doppler techniques.103–110 At knee and hip joints, power Doppler signal has been
found to correlate well with histological assessment of synovial membrane
1032 M. Østergaard et al

microvascular density.112,113 No similar data are available for the small joints. However,
there is strong agreement between US and MRI in terms of detecting synovial inflam-
mation (Figure 4).3,12,104,114–118
US can also detect fluid in joints, bursae and tendon sheaths12,119, and may be used
to evaluate the integrity of tendons and ligaments, as well as imaging entheseal inflam-
mation119–121, and, for instance, in the heel fat pad.122 Wakefield et al recently found
high specificity (0.98) and moderate sensitivity (0.15–0.44) for detection of finger
tenosynovitis, with MRI as the standard reference.123
US has been reported to be more sensitive for visualizing bone erosions in RA
MCP, PIP and metatarsophalangeal (MTP) joints than X-ray3,115,124,125, but inferior
to MRI for detection and follow-up of erosions at the wrists and hands.126 Its sensitiv-
ity for detecting bone erosions is markedly site-dependent (high in easily accessible
joints but low in anatomically complicated joints), due to the fact that US cannot pen-
etrate bone (Figure 3).115,117,124 Where accessibility is optimal, US registration of bone
erosions shows high agreement with assessments by MRI115,117,124 and CT.30

Which joints to assess and how to acquire images/do the examination

No generally accepted US system for assessment of RA activity (e.g. grey scale, Dopp-
ler or a combination) and damage exists, but important advances have been made. In
working groups under OMERACT and EULAR banners, definitions of important joint
pathologies have been reported and a series of reproducibility studies have been per-
formed, aiming at international consensus.127–129 The degree of interscanner variation
remains untested. Although standardization and validation are still incomplete, US is
widely used in clinical practice in several countries for guiding injections and for inves-
tigating joint inflammation.
When considering the reliability required of MRI and US measures, it should be re-
membered that the reproducibility of the clinical assessments used routinely in clinical
practice is not very high. For instance, Naredo et al reported Kappa values for clinical
assessments of joint tenderness and joint swelling of 0.00–0.67, in comparison with
0.59–1.00 for US measures of effusion, synovitis and PD signal.110
The exact number and localization of joints to examine by US in order to best mon-
itor RA has not yet been clarified. Several systems have been suggested, but these
need further testing.116,130–132
Scheel et al described a six-joint approach (second to fifth MCP and PIP joints, bi-
laterally).117 However, this method only examined the palmar aspect of the joints, po-
tentially leading to missing a significant number of inflamed PIP joints and, particularly,
MCP joints.133 Szkudlarek et al investigated a 30-joint US joint count (all MCP, first IP
and PIP joints of the hands, and all MTP), and reported a significant relationship be-
tween clinical joint counts and a sensitivity to change during anti-TNF therapy.130
Hameed et al investigated 10 PIP and 10 distal interphalangeal joints and found that
erythrocyte sedimentation rate and C-reactive protein were more closely correlated
with power Doppler scores than grey-scale scores of synovitis.134
A systematic approach to optimized joint selection was undertaken by Naredo
et al, who assessed the validity, reproducibility and responsiveness of various joint
combinations in 160 patients starting biological therapy. They found a high correla-
tion between a simplified power Doppler US scoring system of 12 joints (elbow,
wrist, second MCP, third MCP, knee and ankle, bilaterally) and a comprehensive
44-joint score, and good reproducibility and sensitivity to change.132 The good
 Imaging in rheumatoid arthritis 1033

performance and feasibility of this simplified scoring system encourages further sys-
tematic testing.

Monitoring disease activity and damage

Differences in US techniques, definitions of joint pathology and scoring systems make

comparisons between studies difficult. Follow-up data have revealed that US measures
of synovitis (Doppler signal and B-mode synovial membrane thickness) decrease in
parallel with other markers of disease activity when glucocorticoids103,110,135 or
TNFa antagonists109,136–140 are administered, indicating their potential for monitoring
joint inflammation in RA (Figure 7).133 However, in a recent study, intra-articular meth-
ylprednisolone or etanercept did not change synovitis as assessed by power Doppler
signal or MRI after 4 weeks141, in contrast to Strunk et al who found an reduced sy-
novial perfusion by power Doppler US after approximately 7 days, while effusions and

Figure 7. Ultrasound (US) assessment of changes in synovitis. (a–d) Longitudinal, dorsal US scan of the
fourth metacarpophalangeal (MCP) joint before (a,b) and after 12 months (c,d) of anti-tumour necrosis fac-
tor (anti-TNF) therapy, showing improvement in synovitis as assessed by grey-scale synovial hypertrophy
(a,c) and power Doppler signal (b,d). (e–h) Corresponding longitudinal dorsal US scan of the third MCP joint
of another patient, in which synovitis remained unchanged during 12 months of anti-TNF therapy.
1034 M. Østergaard et al

synovial hypertrophy were often still persistent.142 Recent studies by Iagnocco et al

found that etanercept143 and adalimumab144 reduced the US score of localized inflam-
matory process and/or structural damage. The fact that scoring of inflammation and
damage was not separated in these studies hindered conclusions on the effect of
the drugs. A monitoring system of enthesitis, the Glasgow Ultrasound Enthesitis Scor-
ing System, has been proposed.145 The score has not been found to be sensitive to
change during sulphasalazine treatment.146
The course of US bone erosions has been followed.12,126,147,148 Backhaus et al per-
formed repeated X-ray, MRI and US of fingers, and by 2 years12 and 5 years147 of fol-
low-up, MRI and US signs of synovitis decreased, while the number of bone erosions
detected by both modalities increased. More patients showed erosive progression on
US than on X-ray, suggesting that US has greater sensitivity to change. Hoving et al
found erosive progression in a similar number of patients by X-ray and US in a
6-month follow-up study of RA wrist, MCP and PIP joints.126 MRI detected progression
more frequently. Reproducibility was not evaluated, so it is not known how often
the erosive progression noted exceeded the SDD. Bajaj et al148 followed 21 early RA
patients for 6 months and found markedly more erosive progressors by US than by
X-ray (eight joints: bilateral second and fifth MCP, fifth MTP and the most swollen
PIP). Excellent interobserver agreement (Kappa 0.96–1.0) was found, but only one ob-
server performed US (the two observers read the acquired images independently). Two
separate examiners would almost certainly have increased the interobserver variability
(see below).
Thus, US may be a valid method for monitoring synovitis and, in accessible areas,
erosive progression, but the relative advantage of US over X-ray for showing erosive
progression remains unclear. More data on reproducibility and sensitivity to change,
including SDD calculations when the entire US examination is repeated, are needed.
It should be noted that in the majority of studies reporting inter- and intra-observer
agreement rates, these are calculated based on the same set of selected US images
which have been obtained by the same examiner. This leads to systematic overestima-
tion of the reproducibility of US, as the US examination itself, including probe position-
ing, selection of site for the picture, machine/pressure adjustments etc, constitutes
a very substantial proportion of the inter-reader variability [e.g. concerning power
Doppler, it is very robust to assess whether or not there is flow signal (1 coloured
dot) in a previously acquired image, in contrast to real-life assessments where the en-
tire US examination is repeated. This, to a large extent, explains why reproducibility
can be excellent in some studies, whereas in other studies, agreement is poor to mod-
erate for some parameters.

Diagnosis

The ability of US to visualize intra- as well as extra-articular changes suggests that it

could be used to assist clinicians in reaching a specific diagnosis, e.g. in patients with
early undifferentiated arthritis. However, no data on the differential diagnostic value
of US in undifferentiated arthritis are available to date.

Prognostication

The high level of agreement between US and MRI for synovitis and erosions suggests
that US may have value in predicting prognosis in RA, data on this is still limited.
 Imaging in rheumatoid arthritis 1035

In several studies, however, the strongest MRI predictor of future erosive damage was
the presence and extent of bone marrow oedema10,88,89, which cannot be visualized
by US. Consequently, MRI data are not directly transferable to US.
In 24 early RA patients randomized to either anti-TNFa plus methotrexate or
placebo plus methotrexate, Taylor et al found that baseline US-determined syno-
vial thickening and degree of vascularity in the MCP joints correlated with radio-
graphic joint damage at 1 year in the placebo group, but not in the anti-TNF
group.138
Naredo et al followed 42 patients starting disease-modifying antirheumatic drug
therapy.149 There was no significant correlation between the baseline clinical, labora-
tory, functional and US parameters and the 1-year follow-up DAS28, HAQ scores and
radiographic scores. Time-integrated values of power Doppler US parameters demon-
strated a highly significant correlation with DAS28 after 1 year (r ¼ 0.63, P < 0.001),
and a stronger correlation with radiographic progression (r ¼ 0.59–0.66, P < 0.001)
than clinical and laboratory parameters (r < 0.50). Furthermore, a US power Doppler
joint index was the strongest predictive variable of disease activity at the following
visit, whereas pain and HAQ scores were the strongest predictors of functional status
at the following visit.149
The Leeds group98 reported that US (and MRI) signs of joint inflammation are com-
mon in patients in clinical remission (see Prognostication paragraph in MRI section for
more details). Baseline US synovial hypertrophy, US power Doppler and MRI synovitis
scores in individual joints were significantly related to progressive radiographic dam-
age. Furthermore, there was a significant association between power Doppler score
at baseline and structural progression over 12 months in asymptomatic MCP joints,
and 12 times higher odds of structural progression in joints with increased power
Doppler signal (OR 12.2, P < 0.001).
It remains to be verified whether US can predict long-term disease progression,
joint erosions and preservation of function better than traditional clinical or serolog-
ical scores.

USE OF IMAGING IN CLINICAL TRIALS AND PRACTICE

In clinical trials, imaging is mainly used for: assessment of structural joint damage in
phase III/IV RA trials; assessment of the anti-inflammatory effectiveness of a new com-
pound (‘proof of concept’ studies), i.e. as outcome measures; and for pretrial selection
of the patients most likely to progress (‘enrichment’), i.e. as inclusion criterion in trials.
Based on the data above, there is evidence to support the use of X-ray, MRI and US
as indicated in the Practice points (see below), while CT may have as yet unexplored
potential as a method for monitoring RA joint damage. There is a need to obtain more
knowledge through systematic research (see ‘‘Research agenda’’).

SUMMARY

Within the field of imaging in RA, large and exciting advances have been made during
the last decade. Although X-ray is still the most widely used tool for monitoring dis-
ease progression, other methods offer clear advantages through more sensitive depic-
tion of inflammatory and destructive disease manifestations. MRI and US are
increasingly used in RA trials and practice. MRI can visualize all the features involved
in inflammation and damage in RA patients, and have documented independent
1036 M. Østergaard et al

prognostic value and superior sensitivity to change compared with conventional

methods. US offers sensitive assessment of joint damage and, particularly, inflamma-
tion, and can be used by practising rheumatologists as part of the clinical examination.
CT provides high-resolution images of erosion, and may have potential for sensitive
monitoring of erosive progression.
Overall, these new imaging modalities already provide important benefits for
the clinician, including: more sensitive detection of early disease manifestations;
more sensitive monitoring of responses to therapeutic agents, including improved
assessment of whether optimal disease control (remission) has been achieved; and
improved prognostication. Many questions concerning the optimal use of these
new imaging modalities require further research efforts, but as technical advances
are still progressing rapidly, the clinical and research applications of these modern
imaging modalities are also expected to increase markedly during the next decade.

Practice points

Imaging could be useful in practice for the following:

A. In routine clinical practice

 to establish a diagnosis of RA (ACR 1987 criteria): X-ray
 to assist with the diagnostic workout in suspected, but not definite, in-
flammatory joint disease and early, unclassified inflammatory joint dis-
ease (by detection of presence/absence of synovitis, enthesitis, bone
erosions etc.): MRI, US
 to monitor structural joint damage: X-ray, MRI
 to monitor disease activity: MRI, US
 to assist with the prognostic stratification of patients with early RA:
X-ray, MRI
 to help define the presence or absence of true remission: MRI, US
 to guide aspirations and injections in joints, bursae and tendon sheaths:
US
B. In research
 to assess structural joint damage in phase III/IV RA trials: X-ray, MRI
 to assess the anti-inflammatory effectiveness of a new compound (‘proof
of concept’ studies): MRI, US
 for pretrial selection of the patients most likely to progress (‘enrich-
ment’): X-ray, MRI

Research agenda

For the individual imaging modalities, further exploration of:

 clinical value of differential diagnosis in early and in early suspected, but not
certain, inflammatory joint disease: MRI, US
 clinical value of monitoring disease activity by imaging: MRI, US
 defining imaging remission and/or an imaging ‘acceptable state’: MRI, US
 Imaging in rheumatoid arthritis 1037

 clinical value of monitoring joint damage by imaging: MRI, US, CT

 benefit of and optimal methods for using modern imaging in clinical trials:
MRI, US, CT
 development and testing of new technical methods: US (e.g. three-dimen-
sional, new transducers), MRI (e.g. 3 Tesla imaging, whole-body MRI),
X-ray (e.g. software for automated image interpretation)

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