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https://doi.org/10.1177/1759720X231165558
https://doi.org/10.1177/1759720X231165558
Ther Adv Musculoskelet Dis
2023, Vol. 15: 1–14
DOI: 10.1177/
1759720X231165558
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THERAPEUTIC ADVANCES in
Musculoskeletal Disease
Introduction
Imaging plays an important role not only in oste-
oarthritis (OA) research in general1 but specifi-
cally also in disease-modifying OA drugs
(DMOAD) clinical trials.2 Although the OA
research community has been aware of the limita-
tions of conventional radiography as an imaging
tool,3 magnetic resonance imaging (MRI) and
other more advanced modalities have not resulted
in regulatory approval of a DMOAD to date.
MRI enables detailed structural assessment of
OA-affected joints that is not possible using radi-
ography.4,5 Despite decades of research efforts
and multiple clinical trials to try to develop
efficacious DMOADs, we still do not have a drug
that has been approved by regulatory agencies.
It has been discussed that the radiography-based
definition of structural eligibility is one of the rea-
sons for failure of DMOAD trials.6–10 Several
plausible explanations exist to elaborate on this
statement. First, the definition of OA disease
severity based on radiography is limited due to
lack of reproducibility of radiographic joint space
measurements.3 Second, there are only weak
associations between radiography-depicted struc-
tural changes and pain.11 Third, radiography can-
not depict potentially detrimental findings, which
Strategic application of imaging in DMOAD
clinical trials: focus on eligibility, drug
delivery, and semiquantitative assessment
of structural progression
Ali Guermazi , Frank W. Roemer , Michel D. Crema, Mohamed Jarraya,
Ali Mobasheri and Daichi Hayashi
Abstract: Despite decades of research efforts and multiple clinical trials aimed at
discovering efficacious disease-modifying osteoarthritis (OA) drugs (DMOAD), we still do
not have a drug that shows convincing scientific evidence to be approved as an effective
DMOAD. It has been suggested these DMOAD clinical trials were in part unsuccessful since
eligibility criteria and imaging-based outcome evaluation were solely based on conventional
radiography. The OA research community has been aware of the limitations of conventional
radiography being used as a primary imaging modality for eligibility and efficacy assessment
in DMOAD trials. An imaging modality for DMOAD trials should be able to depict soft
tissue and osseous pathologies that are relevant to OA disease progression and clinical
manifestations of OA. Magnetic resonance imaging (MRI) fulfills these criteria and advances
in technology and increasing knowledge regarding imaging outcomes likely should play a
more prominent role in DMOAD clinical trials. In this perspective article, we will describe
MRI-based tools and analytic methods that can be applied to DMOAD clinical trials with a
particular emphasis on knee OA. MRI should be the modality of choice for eligibility screening
and outcome assessment. Optimal MRI pulse sequences must be chosen to visualize specific
features of OA.
Keywords: clinical trial, disease-modifying osteoarthritis drugs, imaging, knee osteoarthritis,
MRI
Received: 13 September 2022; revised manuscript accepted: 2 March 2023.
Correspondence to:
Ali Guermazi
Department of Radiology,
School of Medicine, Boston
University, Boston, MA
02132, USA
VA Boston Healthcare
System, 1400 VFW
Parkway, West Roxbury,
MA, USA.
guermazi@bu.edu
Frank W. Roemer
Department of Radiology,
Universitätsklinikum
Erlangen & Friedrich-
Alexander Universität
(FAU) Erlangen-Nürnberg,
Erlangen, Germany
Department of Radiology,
School of Medicine, Boston
University, Boston, MA,
USA
Michel D. Crema
Institute of Sports
Imaging, Sports Medicine
Department, French
National Institute of Sports
(INSEP), Paris, France
Department of Radiology,
School of Medicine, Boston
University, Boston, MA,
USA
Mohamed Jarraya
Department of Radiology,
Massachusetts General
Hospital, Harvard Medical
School, Boston, MA, USA
Ali Mobasheri
Research Unit of Health
Sciences and Technology,
Faculty of Medicine,
University of Oulu, Oulu,
Finland
Department of
Regenerative Medicine,
State Research Institute
Centre for Innovative
Medicine, Vilnius,
Lithuania
Department of Joint
Surgery, First Affiliated
Hospital of Sun Yat-sen
University, Guangzhou,
China
1165558TAB0010.1177/1759720X231165558Therapeutic Advances in Musculoskeletal DiseaseA Guermazi, FW Roemer
review-article20232023
Review
THERAPEUTIC ADVANCES in
Musculoskeletal Disease
Volume 15
2 journals.sagepub.com/home/tab
indicate an increased risk of articular collapse or
rapid disease progression.2 Last, radiography can-
not depict most of the articular and periarticular
tissues [such as menisci, cartilage, bone marrow
lesions (BMLs), ligaments, and synovitis].3
In this perspective article, we will describe how
we can wisely utilize available imaging modalities
and techniques for DMOAD trials, with an
emphasis on MRI and knee OA. We will explain
available MRI-based semiquantitative (SQ) scor-
ing systems that can be applied to DMOAD tri-
als, how to select appropriate MRI pulse
sequences depending on the specific target tissue
of the trial, how radiography can still be utilized
in DMOAD trials in combination with MRI, and
the need to consider different phenotypes of OA
when designing DMOAD trials.
X-ray-based patient selection/screening for
DMOAD trials
Radiographic SQ assessment of knee radiographs
is typically performed to select/screen participants
for DMOAD trials. Structural disease severity of
OA is defined by the Kellgren and Lawrence
(KL)12 grading system, which assigns a score
based on the presence or absence of osteophytes
and joint space narrowing. Investigators can strat-
ify patients into those who are eligible (the pres-
ence of definite OA but not end-stage OA) and
those who are ineligible (the absence of definite
OA or the presence of end-stage OA). Subjects
who have mild OA (KL grade 2) and moderate
OA (KL grade 3) are usually enrolled in DMOAD
trials. Because the radiographic appearance of
joint space width (JSW) can vary significantly
depending on the knee positioning or angulation
of the X-ray beam, it is important to acquire
standardized weight-bearing anteroposterior
bilateral knee X-rays at the time of eligibility
screening.13 For this purpose, positioning devices
such as Synaflexer™ should be used, or fluoros-
copy-guided X-ray acquisition should be per-
formed.3,14 Despite using positioning devices,
false-positive or false-negative longitudinal
change in JSW may be observed as shown in
Figure 1 in an exemplary fashion.
At baseline, JSW should be measured as a surro-
gate for the integrity of cartilage and menisci. There
are pros and cons for selecting low or high JSW
thresholds for enrolling patients, and there is mixed
literature evidence to support either choice. On one
hand, investigators may wish to include knees with
sufficiently preserved cartilage, especially for study-
ing potential anti-catabolic drug effects on articular
cartilage. For example, prior DMOAD trials have
used a threshold value of the remaining medial JSW
to be ⩾2 mm or 2.5 mm.15–17 Using ⩾2 mm minimal
JSW (mJSW) will lead to inclusion of a higher pro-
portion of knees because a larger number of KL
grade 2/3 patients (including those with diffuse full-
thickness chondral loss) would fulfill that crite-
rion.16,17 On the other hand, a recent clinical trial of
Sprifermin showed that selection of patients with
low minimum JSW and moderate to high knee pain
at baseline resulted in more rapid progression of
OA and knees with advanced OA showed symptom
modification by the drug.18 Furthermore, KL grade
3 knee OA was shown to progress more rapidly
than KL grade 2 knee OA.19
Figure 1. Reproducibility limitations of radiography and superiority of magnetic resonance imaging (MRI) in
depicting osteoarthritis as a whole-joint disease. (a) Baseline anterior–posterior (a.p.) radiograph shows a
normal medial tibiofemoral joint space width (arrows). (b) At 2 years follow-up, there is apparent definitive
joint space narrowing (arrowheads). Soft tissues are not assessable on the radiograph. (c) Baseline MRI of the
same knee shows discrete superficial cartilage thinning of the medial tibia (arrowhead) while the cartilage of
the medial femur is apparently normal. There is minimal medial meniscal extrusion of 2 mm still considered
physiologic. (d) Two years later, no definite cartilage loss is observed (arrowheads) and meniscal extrusion has
not progressed (arrow). Apparent progression on the a.p. radiograph is due to positioning errors with minimal
change in beam angulation leading to false-positive joint space narrowing.
World Health
Organization
Collaborating
Centre for Public
Health Aspects of
Musculoskeletal Health
and Aging, Liege,
Belgium
Daichi Hayashi
Department of
Radiology, Tufts
Medical Center, Tufts
Medicine, Boston, MA,
USA
Department of
Radiology, School
of Medicine, Boston
University, Boston,
MA, USA
A Guermazi, FW Roemer et al.
journals.sagepub.com/home/tab 3
Trained and experienced musculoskeletal radiol-
ogists play a key role in X-ray-based screening for
DMOAD trials. First, they should perform the
X-ray-based eligibility reading in a centralized
fashion14 based on KL grading to exclude sub-
jects without radiographic OA (KL grade 0 or 1)
or end-stage OA (KL grade 4). Second, they
should perform the assessment of the minimum
JSW, although the same task may also be per-
formed in a semi-automated fashion using vali-
dated tools being quality checked by expert
readers after the initial assessment. Third, they
should exclude additional subjects at eligibility
who meet predefined radiographic exclusionary
findings described below. These exclusionary
findings include advanced osteonecrosis, sub-
chondral insufficiency fractures, severe varus or
valgus malalignment, large subchondral cysts
which may have a high risk of collapse during a
trial, femoral or tibial fracture, and radiographi-
cally appreciable rheumatic/neoplastic/metabolic
disease.2
MRI-based eligibility screening and
phenotypic stratification of subjects
Following successful radiography-based screen-
ing and consideration of relevant exclusionary/
inclusionary criteria, MRI should be utilized as an
additional eligibility screening tool. ROAMES20
is a relatively new scoring system (published in
January 2020) and data from clinical trials using
ROAMES are yet to be published. In ROAMES,
SQ assessment of cartilage, menisci, BMLs, oste-
ophytes, synovitis (‘Hoffa-synovitis’), and joint
effusion (‘effusion-synovitis’) is performed.
Moreover, diagnoses of exclusion including sub-
chondral insufficiency fractures and meniscal
root tears are recorded as ‘present’ or ‘absent’
(Figure 2). An important aim of ROAMES is to
perform phenotypic stratification (Table 1) of
potentially eligible participants and to detect
exclusionary findings which cannot be depicted
by radiography.20,21 A recent study showed that it
is uncommon to find high-risk exclusionary MRI
findings that potentially precludes safe participa-
tion in a DMOAD trial.22 However, such exclu-
sionary findings are found in about 3% of KL
grade 2 knees and about 12% of KL grade 3
knees. This study highlights the value of using
MRI screening.22
Based on the aim of DMOAD trials and types of
agents being tested, several factors should be con-
sidered when deciding patients belonging to
which phenotype will be most suitable for inclu-
sion in a trial. Of note, in this article, we focus our
discussions to structural phenotypes that are rel-
evant to imaging-based outcome criteria.
However, there are clinical phenotypes (intra-
articular/extra-articular/secondary/age-related
and systemic) and molecular endotypes (bone
and cartilage/inflammatory/low repair/metabolic)
of OA that are of interest to the broader OA
Figure 2. Diagnoses of exclusion using MRI as an instrument to define patient eligibility. (a) Axial T2-
weighted MRI shows a complete posterior root tear of the medial meniscus (arrows). (b) Corresponding
coronal intermediate-weighted fat-suppressed image shows corresponding medial meniscal extrusion due
to mechanical instability of the medial meniscus (arrow). Root tears are considered high-risk findings for
rapid progression of cartilage loss and subsequent articular collapse. For this reason, patients exhibiting root
tears should not be included in clinical DMOAD trials as joints exhibiting root tears are likely not amenable to
any pharmacologic DMOAD effects. (c) Coronal intermediate-weighted fat-suppressed image shows articular
collapse due to subchondral insufficiency fracture of the medial femoral condyle. There is an osteochondral
depression at the fracture site (arrow) and corresponding large bone marrow edema (asterisk). In addition,
there is a large nonspecific subchondral cyst (arrowhead). Bone cysts that potentially increase the risk for
fracture are considered exclusionary at screening.
THERAPEUTIC ADVANCES in
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research community, and those are described in
other dedicated publications.23,24 If one is testing
a compound that is aimed to regenerate cartilage,
there should be enough cartilage remaining in the
knee joint so the drug’s efficacy in cartilage regen-
eration at the site of cartilage damage can be
demonstrated. Inclusion of knees with the ‘carti-
lage-meniscus’ phenotype is likely to be most rel-
evant for such a study. However, in a recent
FNIH study, only 5% of 485 subjects (after
excluding KL grade 1 knees and those having
meniscal root tears) fulfilled the cartilage/menis-
cus phenotype based on the original ROAMES
definition.21 These knees had diffuse full-thick-
ness chondral damage and meniscal tears/macer-
ation in medial and lateral tibiofemoral
compartments. Application of a less stringent
definition with a single compartment needing to
demonstrate meniscal tear, the number of partici-
pants classified as cartilage-meniscus phenotype
rose to 21%. A recent analysis based on the FNIH
cohort showed phenotypic stratification of the
cartilage-meniscus phenotype in various subtypes
can be done, and may help to define trial cohorts
at the time of screening.25 In that analysis, KL
grade 2 knees and all definitions demonstrated
raised odds of progression, while KL grade 3
knees demonstrated an apparent protective effect.
This latter finding was likely because KL grade 3
knees stratified by the suggested definitions had
relatively mild chondral defects at the time of
screening.25
ROAMES is a tool that can be used to perform
for phenotyping of knees that exhibit severe
BMLs (=predominant subchondral bone
changes), (severe BMLs), severe effusion/synovi-
tis (=predominant inflammatory changes), or
mixture of structural phenotypes in different
combinations (e.g. mixed cartilage-meniscus/sub-
chondral bone and mixed subchondral bone/
inflammatory). Depending on the exact type of
DMOAD under investigation, one must deter-
mine whether severe synovitis or BMLs are con-
traindicated for therapy, or they may interfere
with the desired effects of the compound. Figure 3
shows examples of subchondral BMLs in the con-
text of phenotypic stratification. Using ROAMES
one can stratify phenotypes to determine whether
the efficacy of the drug differs in various
phenotypes.
Choice of MRI sequences suitable for
screening and evaluation of different
outcome measures
There are two ways of performing MRI screening
at the time of eligibility assessment of trial partici-
pants. One may choose to obtain a complete
series of MRI sequences for a comprehensive
whole joint assessment at the time of eligibility
screening. In this case, the investigators must
accept the risk of incurring extra cost of imaging
for those who are excluded after screening pro-
cess. A benefit of this approach is simplified
Table 1. Phenotypes of knee OA based on ROAMES.
Inflammatory The maximum grade of 3 of either Hoffa-synovitis or effusion-synovitis and at
least grade 2 in the respective other feature based on MOAKS
Cartilage-meniscus Presence of a meniscus score of at least grade 3 (i.e. any type of meniscal
substance loss/maceration) in the medial or lateral compartment and at least
grade 1 (any type of tear) in the other compartment, respectively, and presence
of cartilage damage grades 2.1, 2.2, 3.2, or 3.3 according to MOAKS
Subchondral bone Subregional bone marrow lesion size of grade 3 in at least one of three knee
compartments
Atrophic Osteophytes ⩽1 in all locations of the TFJ and cartilage damage of grade 3 in at
least one MOAKS subregion of one or both compartments of the TFJ
Hypertrophic At least one osteophyte grade 3 in the medial TFJ or lateral TFJ and PFJ;
cartilage damage not more than grade 1 in any subregion of the same
compartment of the TFJ
MOAKS, Magnetic resonance Osteoarthritis Knee Score; OA, osteoarthritis; PFJ, patellofemoral joint; ROAMES, Rapid
OsteoArthritis MRI Eligibility Score; TFJ, tibiofemoral joint.
A Guermazi, FW Roemer et al.
journals.sagepub.com/home/tab 5
logistics and patient convenience. Alternatively,
an abbreviated protocol with two quick sequences
[i.e. a sagittal and coronal PDW FS or IW FS,22
or a 3 min three-dimensional (3D) FSE sequence,
e.g. SPACE and VISTA] can be used at the time
of eligibility screening, and if a patient is indeed
eligible for inclusion, the patient will then return
to complete a full set of sequences of comprehen-
sive whole joint MRI assessment. This option is
logistically more challenging because there is a
need for two visits for included subjects in a rela-
tively short period. Some patients might decline
to return for the second full exam. So long as
there is sufficient budget, the first option would
be a preferable option for both the participants
and the researchers.
For the full MRI protocol, appropriate technical
considerations should be given. A dedicated knee
coil should be used to ascertain the best image
quality. Optimization of all MRI acquisition
parameters should be performed, including, but
not limited to, patient positioning, signal homo-
geneity, image orientation, and spatial resolution
and signal-to-noise ratio. This is an important
step to optimize quality of imaging and minimize
image degradation secondary to artifacts.26
Additional factors to consider are minimization of
patient discomfort during the MRI scan without
sacrificing image quality, and imaging cost within
the budgetary constraint. From the radiological
point of view, the most important issue is the
choice of most appropriate pulse sequences for
each specific pathological feature to be evaluated.
The use of an incorrect pulse sequence will pre-
clude the meaningful interpretation of acquired
images. Table 2 presents the summary of sug-
gested MR pulse sequences for optimum SQ
analysis of each knee OA feature, based on the
available literature evidence and authors’ own
expertise.26–28 Suggested protocols are optimally
performed on a 3T scanner, using multichannel
phased-array extremity coils for an optimal sig-
nal-to-noise ratio.29 However, 1.5T scanners will
also provide images with sufficient quality to per-
form reproducible SQ analyses.26
Fluid-sensitive fast spin echo (FSE) or turbo spin
echo (TSE) sequences [which include, for exam-
ple, T2-weighted, intermediate-weighted, or
Figure 3. Subchondral bone phenotype of knee osteoarthritis. Phenotypic stratification may help in
selecting patients most likely to benefit from a specific candidate DMOAD molecule. Compounds targeting
the subchondral bone may have an impact on bone marrow lesions. For this reason, knees with large bone
marrow lesions or those with multiple lesions are included in such trials. (a) Sagittal intermediate-weighted
fat-suppressed image shows a large bone marrow lesion in the medial femoral condyle fulfilling the definition
of the subchondral bone phenotype (arrows). In addition, there is a minor subchondral cyst and widespread
full-thickness cartilage damage. Note that knees with extensive widespread full-thickness cartilage loss are
likely not responsive to any anti-catabolic mode of action as there is not sufficient cartilage to preserve and
measure structural DMOAD effects. Phenotypes may overlap and one knee may exhibit more than one specific
phenotype. This knee also exhibits large effusion-synovitis and thus fulfills the inflammatory phenotype, in
addition. (b) Sagittal intermediate-weighted fat-suppressed MRI of another patient shows several tibial and
femoral bone marrow lesions (arrows). In comparison with the bone marrow lesion in (a), these are smaller in
size or volume but numerous and thus defining this knee as exhibiting the subchondral bone phenotype. Note
that bone marrow lesions are nonspecific findings and multiple differential diagnoses apply. In this case, there
is an identical-appearing signal change at the femoral metaphysis consistent with red marrow conversion in
the typical location. In contrast, subchondral OA-related bone marrow lesions are localized directly adjacent to
the subchondral plate.
THERAPEUTIC ADVANCES in
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proton density (PD)-weighted fat-suppressed
sequences] obtained in three orthogonal planes are
time-efficient to deploy and particularly important
for evaluation of BMLs.30 Use of GRE sequences
for BML assessment31 is less suitable for SQ assess-
ment than fluid-sensitive fat-suppressed FSE/TSE
sequences because GRE sequences are relatively
insensitive to BMLs and can lead to underestima-
tion of the lesion size.32,33 A direct comparison of
BML visualization using GRE and FSE/TSE
sequences is shown in Figure 4.
GRE sequences are ideally deployed for 3D quan-
titative cartilage analysis (e.g. thickness and volu-
metric measurements), but not for focal cartilage
defects which should be evaluated using fluid-
sensitive FSE/TSE or short-tau inversion recov-
ery sequences.34,35 Another thing to consider is
that GRE sequences are prone to magnetic
susceptibility artifacts. One should be aware that
intra-articular vacuum phenomenon is depicted
as linear or punctate hypointensity within the
joint space, and misinterpreting such artifact as
meniscal damage or a chondral defect must be
avoided.36
Addition of a T1-weighted FSE/TSE or Dixon
sequence allows evaluation of subchondral sclero-
sis or intra-articular loose bodies with high sensi-
tivity. Angulating the imaging plane specifically
for certain structures to be assessed may be help-
ful, for example, paracoronal T2-weighted
sequence is helpful for differentiating anterior
cruciate ligament partial tears versus complete
tears. Fat-suppressed 3D FSE/TSE sequences
can be used as an alternative triplanar two-dimen-
sional (2D) TSE sequences. Both these tech-
niques can provide comparable results for SQ
Table 2. List of MRI pulse sequences that are suitable for evaluating various OA features using
semiquantitative scoring.
OA feature Imaging planes Pulse sequences (without intravenous
contrast unless otherwise stated)
Bone marrow lesions Axial/sagittal/coronal
(at least two orthogonal
planes)
T2-weighted FS TSE/FSE or STIR
Intermediate-weighted FS TSE/FSE or STIR
PD-weighted FS TSE/FSE or STIR
Osteophytes Axial/sagittal/coronal 3D high-resolution GRE (e.g. FLASH, DESS,
SPGR) and non-FS short TE-weighted (T1 is
preferred over PD)
Cartilage Variable 3D high-resolution GRE (e.g. FLASH, DESS,
SPGR) and T2-weighted* TSE, Intermediate-
weighted* TSE, or
PD-weighted* TSE (*FS or non-FS depending
on the specific research question)
Meniscus Sagittal/coronal T1-weighted FS, T2-weighted FS, PD-weighted
FS
Ligaments Axial/sagittal/coronal Intermediate-weighted FS TSE, PD-weighted
FS TSE
Popliteal cyst Axial T2-weighted, PD-weighted
Synovitis on contrast
enhanced MRI
Axial/sagittal/coronal Pre- and post-contrast T1-weighted FS
Hoffa-synovitis on
noncontrast MRI
Mid-slices of the
sagittal plane
T2-weighted FS TSE, intermediate-weighted
FS, TSE, or PD-weighted FS TSE
Effusion synovitis on
noncontrast MRI
Axial T2-weighted* TSE, Intermediate-weighted*
TSE, or PD-weighted* TSE (*FS or non-FS
depending on the specific research question)
DESS, dual echo steady state; FLASH, fast low-angle shot; FS, fat-suppressed; GRE, gradient echo; MRI, magnetic
resonance imaging; OA, osteoarthritis; PD, proton density; SPGR, spoiled gradient echo; STIR, short-tau inversion
recovery; TE, time of echo; TSE/FSE, turbo spin echo/fast spin echo.
A Guermazi, FW Roemer et al.
journals.sagepub.com/home/tab 7
assessment of knee OA, although 3D TSE
sequences exhibit different image characteristics
(e.g. increased blurriness).37
Thanks to modern advanced MRI techniques,
highly accelerated acquisition of imaging became
possible and scan time can be decreased to a frac-
tion of conventional scanning method. Examples
of such techniques include parallel imaging and
improvements in 3D FSE imaging, which enables
the acquisition of triplanar MRI of the knee in
less than 5 min.38–40 Artificial intelligence shows
additional promise regarding image accelera-
tion41,42 (Figure 5).
Imaging-guided intra-articular injection of
investigational drugs
Some investigational drugs and emerging biologic
treatment need to be administered through an
intra-articular injection.43–46 Such drugs include,
but not limited to, nerve growth factor agents,
fibroblast growth factors, platelet-rich plasma,
mesenchymal stem cells, etc.47 Intra-articular
injections of the knee should ideally be performed
under imaging guidance.48,49 A systematic review
revealed the superolateral approach was investi-
gated most and had the highest pooled accuracy
rate of correct injection of 91% [95% confidence
interval (CI) of 84–99%].50 An investigational
compound is unlikely to work if the injection is
extra-articular. Therefore, if an extra-articular
injection is documented, affected subjects should
be excluded from any outcome analysis to pre-
vent artificial reduction of demonstrated clinical
efficacy of the DMOAD being evaluated. Also,
the drug may cause an adverse event if it is extra-
articularly injected (e.g. development of hetero-
topic ossification or other structural side effects)
at follow-up.51 Examples of extra-articular admin-
istration with X-ray documentation are shown in
Figure 6.
To confirm correct intra-articular needle place-
ment, a lateral projection X-ray should be obtained
after injection of a small amount of intra-articular
air prior to the injection of the investigational
compound or placebo itself.52 Audible squishing
sounds after intra-articular injection of air can be
used as an additional proof of successful injec-
tion.53 Alternatively, ultrasound-guided intra-
articular drug delivery can be performed.54 This
technique is advantageous over X-ray guidance in
that real-time visualization of the needle tip posi-
tion is possible during the procedure. The pres-
ence of joint fluid in the medial or lateral gutters
can be helpful, providing an additional target for
needle placement. However, one may note that a
recent study showed that neither ultrasound-
guided nor palpation-guided intra-articular knee
injections provide a 100% success rate, using
intra-articular air visualization on lateral projec-
tion X-ray as a reference.55 Although ultrasound-
guided injection demonstrated somewhat higher
Figure 4. Relevance of sequence selection of feature-specific assessment. (a) Coronal intermediate-weighted
fat-suppressed sequence shows the medial tibiofemoral compartment. There are large bone marrow lesions
at the medial femur (arrows) and tibia (asterisk) reflected as areas of high signal intensity contrasting the
normal fatty marrow that is depicted with low signal. In addition, there are other signs of advanced structural
knee OA including widespread cartilage damage, marginal osteophytes, and meniscal extrusion. (b) Coronal
fast low-angle shot (FLASH) with water excitation (WE) MRI, a 3D high-resolution sequence, is commonly
used for cartilage quantification. This type of sequence, a gradient echo sequence, is prone to magnetic
susceptibility and thus relatively insensitive to BMLs and will lead to underestimation of the lesion size as
shown by the arrows. The tibial lesion is hardly depicted at all.
THERAPEUTIC ADVANCES in
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success rates than palpation-guided injection,
documenting the presence of intra-articular air
seems important to avoid subsequent extra-articu-
lar injection of DMOAD and to help minimize
artificial reduction of efficacy of such drugs.
SQ MRI scoring systems applicable
to DMOAD trials
There are several published SQ scoring systems
for the assessment of the articular and
periarticular tissues in knee OA. To overcome the
limitation of radiography-based evaluation, MRI
enables scoring of the whole joint including carti-
lage, menisci, BMLs, osteophytes, joint effusion,
synovitis, subchondral cysts, ligaments, and intra-
articular bodies. Some scoring systems such as
MRI Osteoarthritis Knee Score (MOAKS)56 can
score the OA features of the whole joint, whereas
others may target only select features, e.g. BMLs,
synovitis, menisci, and osteophytes.20,27,57 Of
these, Rapid OsteoArthritis MRI Eligibility Score
Figure 5. Artificial intelligence applied to accelerate image acquisition. Trained convolutional neural
networks (CNNs) are used for post hoc image reconstruction. The original MRI data set is undersampled and
the missing structural information is re-created by the CNN resulting in almost equivalent image quality.
(a) Example shows coronal intermediate weighed fat-suppressed images acquired with a 7T ultrahigh-
field system. A super high-resolution matrix of 720 × 720 pixels is used with an in-plane resolution of 0.15
mm × 0.15 mm, 3 mm thickness, acquired in 9 min 30 s. (b) Fourfold undersampling with post-acquisition AI
reconstruction results in a decrease in imaging acquisition time down to 2 min 22 s. The image overall exhibits
a smoother image impression but the overall quality seems comparable. As CNNs always need extensive
training data, the future will need to show if rare findings are depicted with confidence and determination of
the ideal acceleration factor without losing relevant structural information needs to be shown in the future.
Figure 6. Example of documentation of extra-articular injection. The documentation of an intra-articular route
of administration is paramount and most easily achieved using air administered at the time of injection. (a)
Lateral radiograph shows air within Hoffa’s fat pad but not intra-articularly (arrows). (b) Another lateral X-ray
shows air in the prefemoral fat pad (arrow) but not within the joint cavity. (c) Another example shows an air
collection in the subcutaneous tissue but not in the joint (arrows).
A Guermazi, FW Roemer et al.
journals.sagepub.com/home/tab 9
(ROAMES)20 was created so that it can be used
to evaluate the eligibility of subjects in DMOAD
trials. Investigators can use MRI SQ scoring tools
to assess multi-tissue changes between the base-
line and follow-up time points for the determina-
tion of DMOAD efficacy and safety.2,26,58 For
instance, for the evaluation of anabolic com-
pounds, SQ assessment enables investigators to
capture safety concerns such as increased ossifi-
cation and osteophyte growth. Other concerning
imaging findings that can be detected include the
occurrence of subchondral insufficiency fracture,
osteonecrosis, and others.20 When compared with
quantitative volumetric cartilage assessment
(which evaluates quantitative changes invisible to
the human eye over a period by addressing an
entire knee joint compartment or plate),59 SQ
assessment is suited to evaluate superficial, par-
tial-thickness, and full-thickness focal chondral
defects. For a more global assessment of articular
cartilage across the entire compartment or a plate,
SQ evaluation may also depict chondral loss over
time (in periods as short as 6 months)60 but has
limited ability to capture anabolic effects like car-
tilage growth.
Importance of within-grade scoring
To increase the sensitivity to detect small changes
between time points, ‘within-grade’ SQ MRI
scoring is typically performed.61 Using this meth-
odology, even a small morphologic change that
does not fulfill the criteria for a full-grade change
(i.e. score change of 1) is still recorded as a longi-
tudinal change.62 Recently, it could also be shown
that within-grade assessment is associated with
longitudinal quantitative cartilage thickness loss
supporting the assumption that within-grade
change reflects real cartilage damage progres-
sion.63 Within-grade changes are also applied for
BML assessment and have been shown to be clin-
ically valid, which is illustrated in Figure 7.61
MRI interpretations without blinding
to time points
MRI evaluation is performed at multiple time
points in a DMOAD trial to observe the struc-
tural change between the baseline and the follow-
up time points. It is a routine practice within the
OA research community to perform MRI SQ
scoring at follow-up time points without readers
being blinded to the time points.64 Scoring of
MRIs in chronological order is known to increase
sensitivity in the detection of clinically relevant
longitudinal changes. If SQ scoring is done in a
random order and a blinded manner, readers may
not be able to capture a meaningful longitudinal
score changes for each imaging feature.64
Utility of the delta-sum and
delta-subregion approaches
SQ scoring of MRI data requires careful consid-
eration so that investigators can best deploy it to
record score changes at different timepoints in
DMOAD clinical trials. To begin with, adding
together all subregional scores from the knee
joint is not an ideal way of assessing longitudinal
score changes for the joint. As an example,
BMLs can show changes in size in a short time
period, and worsening and improvement of
BMLs in different subregions can occur at the
same time in the whole joint. In this case, there
may be no apparent change in an overall score
calculated by addition of all subregional scores.
Thus, the use of a ‘summation score’ can mask
what is truly happening in the joint.65,66 Another
important consideration is the use of ‘delta-sum
and delta-subregion’ method.67 In this method,
all subregional scores are summed up to calcu-
late the overall deterioration (>0), unchanged
(0), or improvement (<0). For example, the
knee joint is divided into 14 subregions in
MOAKS. For cartilage evaluation, no change in
two subregions, worsening in seven subregions,
and improvement in four subregions yield a
delta-subregion change of +3 for the whole
knee. One can use alternative methodology for
assessment of longitudinal changes, such as the
use of maximum grades and a latent class
analysis.68
Conclusions and future prospects
The use of MRI from screening to outcome
assessment, likely in combination with X-ray-
based KL grading, particularly to define eligibil-
ity, is encouraged in DMOAD trials, rather than
relying solely on radiography-based imaging cri-
teria. It is important to recognize various struc-
tural phenotypes of OA to perform more targeted
clinical trials. SQ analysis tools such as ROAMES
are available to facilitate longitudinal evaluation
of OA features and to assess the efficacy of
DMOADs. The choice of appropriate MR pulse
sequences and protocols are the key to a mean-
ingful evaluation of imaging features of OA. A
tailored abbreviated protocol of two sequences
usually takes less than 7 min depending on the
THERAPEUTIC ADVANCES in
Musculoskeletal Disease
Volume 15
10 journals.sagepub.com/home/tab
MRI parameters, which is notably shorter than a
standard MRI protocol that takes around 15 min.
Artificial intelligence approaches will help speed
up image acquisition by a factor of around 2 in
the near future.69 Technically successful imaging-
guided intra-articular injection of investigational
drugs is important to prevent unwanted reduction
in efficacy of such drugs. We anticipate that
DMOAD research and development will focus
more on early knee OA (i.e. knees with KL grade
0 and 1), painful and symptomatic knee OA, and
knees with imaging features fulfilling the MRI
diagnosis of OA. At present, however, an MRI
definition of early OA is yet to be fully deter-
mined, and regulatory agencies are unlikely to
approve a drug that is targeting a disease status
without a validated definition (i.e. ‘early’ MRI-
defined OA). Therefore, it is likely that candidate
DMOADs will have to show efficacy in sympto-
matic patients with established structural OA
first. If we can identify patients in the earliest pos-
sible stage of OA and treat them with available
efficacious DMOADs, we may be able to prevent
patients with early knee OA from progressing into
more advanced OA with irreversible damage for
which total knee arthroplasty will be the only cur-
rent treatment option. Of note, the US Food and
Drug Administration recently proposed that
DMOADs should help patients feel and function
better.70 Our research efforts and journey toward
the discovery and clinical development of an effi-
cacious DMOAD must continue to accomplish
these aims.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Author contributions
Ali Guermazi: Conceptualization; Investigation;
Methodology; Writing – original draft; Writing –
review & editing.
Frank W. Roemer: Data curation; Visualization;
Writing – original draft; Writing – review &
editing.
Michel D. Crema: Methodology; Visualization;
Writing – original draft; Writing – review &
editing.
Mohamed Jarraya: Methodology; Visualization;
Writing – original draft; Writing – review &
editing.
Ali Mobasheri: Methodology; Visualization;
Writing – original draft; Writing – review &
editing.
Daichi Hayashi: Conceptualization; Data cura-
tion; Formal analysis; Investigation; Writing –
original draft; Writing – review & editing.
Acknowledgements
None.
Figure 7. Within-grade assessment. Semiquantitative MRI assessment is based on expert evaluation of MRIs
applying validated scoring systems. While definitive visual change may be apparent, often lesions (particularly
bone marrow lesions and cartilage alterations) do not fulfill the definition of a so-called full-grade change.
For this reason, and particularly to increase sensitivity to change, so-called within-grade changes have been
introduced that are able to document definite change despite not fulfilling a full-grade change. Within-grade
changes have been shown to be clinically valid and to correspond to quantitative cartilage loss. (a) Coronal
short tau inversion recovery (STIR) image shows a small bone marrow lesion at the central medial femur
(arrow). (b) Follow-up MRI 1 year later shows a definite increase in size that does not fulfill the criteria for a
full-grade change (arrowhead). This is a typical example of a within-grade increase of a subchondral bone
marrow lesion.
A Guermazi, FW Roemer et al.
journals.sagepub.com/home/tab 11
Funding
The authors received no financial support for the
research, authorship, and/or publication of this
article.
Competing interests
The authors declared the following potential con-
flicts of interest with respect to the research,
authorship, and/or publication of this article: AG:
received consultancy fees from Pfizer, Novartis,
MerckSerono, TissueGene, AstraZeneca, and
Regeneron. He is a shareholder of Boston Imaging
Core Lab., LLC.
FWR: Consultant to Calibr and Grünenthal. He
is a shareholder to of Boston Imaging Core Lab.,
LLC.
MDC: He is a shareholder to of Boston Imaging
Core Lab., LLC.
AM: received consultancy fees from Pfizer,
Novartis AG, Kolon TissueGene, Sanofi, GSK,
Haleon, Laboratoires Expanscience, CSC
Pharma, Orion Corporation, Pacira Biosciences,
and Aptissen SA. He serves on the Scientific
Advisory Board of Kolon TissueGene,
ResearchSquare and Aptissen SA.
DH: received publication royalties from Wolters
Kluwer.
All other authors have no competing interests.
Availability of data and materials
Not applicable.
ORCID iDs
Ali Guermazi https://orcid.org/0000-0002-
9374-8266
Frank W. Roemer https://orcid.org/0000-
0001-9238-7350
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