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com

Do knee abnormalities visualised on MRI

explain knee pain in knee osteoarthritis? A
systematic review
Erlangga Yusuf, Marion C Kortekaas, Iain Watt, et al.
Ann Rheum Dis 2011 70: 60-67 originally published online September 9,
2010

doi: 10.1136/ard.2010.131904

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Extended report

Do knee abnormalities visualised on MRI explain knee

pain in knee osteoarthritis? A systematic review
Erlangga Yusuf,1 Marion C Kortekaas,1 Iain Watt,2 Tom W J Huizinga,1
Margreet Kloppenburg1

Supplementary tables are

published online only. To view
these files please visit the
journal online (http://ard.bmj.
com).

1Department

of Rheumatology,
Leiden University Medical
Center, Leiden, The Netherlands
2Department of Radiology,
Leiden University Medical
Center, Leiden, The Netherlands
Correspondence to
Erlangga Yusuf, Department of
Rheumatology, Leiden University
Medical Center, C1-46, Postbus
9600, 2300 RC Leiden, The
Netherlands;
[email protected]
EY and MCK contributed equally
to this work.
Accepted 11 July 2010
Published Online First
12 October 2010

ABSTRACT
Objective To systematically evaluate the association
between MRI findings (cartilage defects, bone marrow
lesions (BML), osteophytes, meniscal lesion, effusion/
synovitis, ligamentous abnormalities, subchondral
cysts and bone attrition) and pain in patients with knee
osteoarthritis (OA) in order to establish the relevance of
such findings when assessing an individual patient.
Methods The Medline, Web of Science, Embase and
Cumulative Index to Nursing & Allied Health Literature
(CINAHL) databases up to March 2010 were searched
without language restriction to find publications with
data on the association between MRI findings of knee
OA (exposure of interest) and knee pain (outcome). The
quality of included papers was scored using a predefined
criteria set. The levels of evidence were determined
qualitatively using best evidence synthesis (based on
guidelines on systematic review from the Cochrane
Collaboration Back Review Group). Five levels of evidence
were used: strong, moderate, limited, conflicting and no
evidence.
Results A total of 22 papers were included; 5 had
longitudinal and 17 cross-sectional data. In all, 13
reported a single MRI finding and 9 multiple MRI findings.
Moderate levels of evidence were found for BML and
effusion/synovitis. The OR for BML ranged from 2.0 (no
CI was given) to 5.0 (2.4 to 10.5). The OR of having pain
when effusion/synovitis was present ranged between 3.2
(1.04 to 5.3) and 10.0 (1.1 to 149). The level of evidences
between other MRI findings and pain were limited or
conflicting.
Conclusions Knee pain in OA is associated with BML
and effusion/synovitis suggesting that these features may
indicate the origin of pain in knee OA. However, due to
the moderate level of evidence these features need to be
explored further.
INTRODUCTION
Knee is the major site of osteoarthritis (OA), the
most common rheumatic disorder which is characterised by pain that leads to signicant restriction
in patients daily activity.1 2 Despite its importance, the source of pain remains unclear.3 To treat
OA optimally, knowledge of the source of pain is
important since new therapies can be specically
targeted.
An important element in understanding pain
is to know which structures produce it inside the
knee since the pathology of knee OA involves the
whole knee joint.3 To assess knee structures in vivo
imaging modalities are needed. On radiographs,
hallmarks of knee OA such as bony outgrowth
and cartilage loss, which are visualised as osteophytes and joint space narrowing, respectively, do

60

not show a consistent association with knee pain.4

Other potential sources include abnormalities in
subchondral bone, ligamentous damage, meniscal injury and synovitis.5 However, these potential
sources cannot be assessed on conventional radiographs. More advanced imaging techniques are
needed currently best exemplied by MRI.
Several studies have investigated MRI ndings
related to pain but to our knowledge, no summarisation of data has been performed in a systematic
manner. Such a review requires a focused research
question, an explicit research strategy and a system
to evaluate the quality of evidence.6 Therefore, we
sought to evaluate the relationship between MRI
ndings in knee OA and knee pain. We summarised
eight commonly reported MRI ndings: cartilage
defects, bone marrow lesions (BML), osteophytes,
meniscal lesion, effusion/synovitis, ligamentous
abnormalities, subchondral cysts and bone attrition
(see supplementary material).

MATERIALS AND METHODS

The present review is systematic review of observational studies. Therefore, we adhered to a protocol
developed from a widely recommended method
for systematic review/meta-analysis of observational studies (MOOSE).7 We included studies
with data on the association between MRI features
of knee OA (exposure of interest) and knee pain
(outcome). The following studies were excluded:
reviews, abstracts, letters to the editor, case reports,
case series and studies concerning study population
with other underlying musculoskeletal diseases.

Data sources, searches and extraction

Using the following key words: knee, knee pain,
MRI, osteoarthritis in combination with all
possible key words concerning MRI features we
wanted to investigate, we searched the following medical databases up to March 2010: Medline
(from 1966), Science Citation Index through Web
of Science (from 1945), Embase (from 1980) and,
Cumulative Index to Nursing & Allied Health
Literature (CINAHL) (from 1982). No language
restriction was applied and no search of unpublished studies was performed. Additionally, the
reference lists of all relevant identied articles were
screened and Google Scholar was searched to nd
additional papers. Complete search strategies can
be obtained from the authors on request.
Two reviewers, EY (a PhD student) and MCK (a
rheumatologist) independently screened the titles
of retrieved references for obvious exclusion and
read the remaining abstract to determine eligible
Ann Rheum Dis 2011;70:6067. doi:10.1136/ard.2010.131904

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Extended report
studies. Differences were solved by discussion or by consulting
a third reviewer (MK, a senior rheumatologist).
From eligible papers, information was collected on the following categories: (i) type of study, performed by looking at the
method of data analysis (when a study provided data on the
association between MRI features change in time with change
in pain level in time, the study was considered to be a prospective cohort study; if this analysis was not available, such as in
a case-control study, the study was regarded to be of a crosssectional design); (ii) study population (patient characteristics,
size, gender and age); (iii) denition of knee OA; (iv) assessment
of MRI ndings; (v) assessment of pain; (vi) potential confounders; and (vii) results of the association between MRI features and
pain.

Assessment of study quality

Independently, the same two reviewers assessed the methodological quality of included studies using a predened criteria
set which was previously used in systematic reviews in the area
of musculoskeletal disorders (see supplementary material).8 9
Several domains were assessed: population, selection bias,
assessment of determinants on MRI, assessment of the outcome, follow-up analysis and data presentation.
For each criterion met in the article, a 1 was given; otherwise, a 0 was given. We dened rules on how to assess specic
situations. A study could describe multiple MRI features but not
all were assessed reproducibly (criterion 5) or using standardised
criteria (criterion 6). For such a study, the criteria are scored as
a proportion of MRI features which were assessed reproducibly or using standardised criteria from the total MRI features
investigated.
Differences in scoring were resolved by discussion or by consulting the third reviewer. Maximum scores possible were 11 for
prospective cohort and 9 for cross-sectional study design. The
total score for a study (in %) is the total score given for a study
divided by the maximum possible score. The mean of the quality scores of all studies, which was 62%, was used to classify
studies as high or low quality.

Rating the body of evidence

The summary of evidence for each MRI feature was given by
using best evidence synthesis based on the guidelines on systematic review of the Cochrane Collaboration Back Review
Group.10 This is an alternative to pooling of association sizes
when the included studies were heterogenous.8 The synthesis
has ve levels of evidence: (1) strong, when general consistent
ndings were reported in multiple high-quality cohort studies;
(2) moderate, when one high-quality cohort study and at least
two high-quality cross-sectional studies show general consistent
ndings or when at least three high quality cross-sectional studies who general consistent ndings; (3) limited, when general
consistent ndings were found in a single cohort study, or in
maximum two cross-sectional studies; (4) conicting, when no
consistent ndings were reported; and (5) no evidence, when
no study could be found. This synthesis puts more weight on a
prospective cohort design which is appropriate for our review
question since it takes into account the change in determinant
(MRI feature) and change in outcome (pain).
Sensitivity analyses by dening other cut-offs (median score
of all studies instead of mean) of high quality studies were performed. We also present the number of positive studies without
quality assessment to give readers the opportunity to compare
this with the best evidence synthesis results.
Ann Rheum Dis 2011;70:6067. doi:10.1136/ard.2010.131904

A study that investigated multiple features was counted

as a single study for each MRI feature investigated. A study
was regarded as positive if it showed a signicant association
between an MRI feature and knee pain. When a study included
subfeatures of an MRI nding, that is, tear and subluxation for
meniscal lesion, the study was regarded as positive when at
least one of these showed positive association. Since effusion
and synovitis cannot be readily differentiated on non-enhanced
MRI,9 11 we analysed these features together.

RESULTS
Literature flow
After screening their title, 2144 of 2629 identied references
were excluded (gure 1). From the 485 remaining references,
19 papers were included. We selected the most recent publication12 of two publications with overlapping results.12 13
Four publications1417 came from the same authors and used
the same patient population. We therefore selected two of
them.14 16 These two selected studies dened cartilage loss
as determinant and pain as outcomes, contradictory to the
two others which dened the determinant and outcomes conversely. After additional searching, another three papers were
found.16 18 19 In total, 22 papers were selected. In all, 5 studies
reported longitudinal data12 14 16 20 21 and 1718 19 2236 were
cross-sectional studies.

Characteristics of included studies

Of the 22 analysed papers, 8 published associations of multiple
MRI features (table 1),19 25 26 29 30 32 34 36 the others investigated
only a single MRI feature.
Of these papers (table 1), 10 were results from 3 studies:
the Boston Osteoarthritis Knee Study (BOKS),12 18 22 24 28 33
the Southeast Michigan OA (SEM) cohort26 34 and the Genetic
Arthrosis Progression Study (GARP).20 29 Most studies used a
General Electric MRI system (in 14 publications.12 13 16 18 19 2224
26 28 30 3234 A Siemens MRI system was used in six publications14 25 27 31 and a Philips MRI system was used in two publications.20 29 Two studies35 36 used a 3 T magnetic eld system,
all others used a 1.5 T system. Only one study35used MRI contrast agent.
Patients investigated in the included studies were of both
sexes and older than 50 years, except for one which studied
women alone with mean age of 47 years (table 1).26 Almost all
studies dened knee OA by using clinical and radiographic criteria of American College of Rheumatology, which requires at
least knee pain and osteophyte on radiograph. Only ve studies
dened knee OA purely radiographically.19 23 26 27 31

Study quality assessment

We agreed on 212 of 227 (93%) quality assessment items scored
(see supplementary material). Most disagreement focused on
the clarity of description of the study population (criterion 2)
and participation rate (criterion 3).
In general, many publications either did not assess MRI ndings using standardised and validated criteria or they did not
inform the reader about this (criterion 5). In many prospective
cohort studies the researchers were not blinded for the time
order of MRI scans (criterion 7) and differences between withdrawal and completed groups were not described (criterion 10).
In cross-sectional studies, the most common limitations were
participation rate (criterion 3) and lack of adjustment of possible
confounders such as age and sex (criterion 11).
61

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Extended report
Identified references,
titles and abstracts reviewed
2629
Obvious exclusions
2144
Possibly relevant references,
full text articles obtained
485
Not relevant
466
Additional full text fullfilled
in and exclusion criteria
3

Full text articles fullfiled inand exclusion criteria

19

Total included
articles(studies)
22

Cohort studies
5

Cross-sectional
studies
17

Figure 1 Results of literature research

Association between MRI features and pain (best-evidence

synthesis)
Cartilage defect
Six studies19 26 2932 investigated cartilage defects using semiquantitative scores, ve14 16 23 25 34 used quantitative methods and
one used quantitative method on contrast-enhanced MRI.35The
level of evidence on the association between cartilage defects
and pain was conicting: three16 19 34 of ve high-quality studies showed a positive association with pain. When all 12 studies
which investigated cartilage defects14 16 19 23 25 27 2932 34 35 were
summarised, 50% showed a positive association independent of
study quality.

Bone marrow lesions

The evidence about the association between BML and pain was
moderate. Four19 24 34 36 of ve high-quality studies showed an
association between BML and pain. One high-quality cohort
study showed no association.20 Three of the four high-quality
cross-sectional studies that demonstrated a positive association
presenting an OR as quantitative measure of association. The
OR ranged from 2.0 (adjusted for effusion and synovitis)36 to
5.0 (unadjusted, 95% CI 2.4 to 10.5).34 One study reported a
coefcient of 3.72 (95% CI 1.76 to 5.68).19 When all eight studies investigating BML19 20 24 26 30 32 34 36were taken into account
63% reported a positive association between BML and pain.

When all studies were taken into account; 33% showed a positive association.

Synovitis/joint effusion
A moderate association was found for effusion/synovitis, since
all four12 19 29 36 high-quality studies showed a positive association. One of which was a high-quality cohort study.12 19 29 This
study performed separate analyses for effusion and synovitis:
the analysis between effusion and pain showed no association
whereas the association between synovitis and pain was positive. We regarded this study as positive, because we deemed a
study was as a positive study when at least one of the subfeatures showed a positive association. Four high-quality studies
reported quantitative measures of association. Three reported
the OR of having pain when effusion/synovitis was present,
ranging between 2.6 (adjusted for synovitis and BML)36 and 10.0
(adjusted for age, sex BMI and intrafamily effects, 99% CI 1.13
to 149).29 One other study reported regression of 9.82 (95%
CI 0.38 to 19.27).19 When no quality assessment was performed,
86% of included studies12 19 21 25 26 29 30 36 showed a positive
association with pain.

Ligament disease

Neither of the two high-quality studies showed a positive association between osteophytes with pain.29 33 According to best
evidence synthesis this gives limited level of evidence on the no
association between osteophytes and knee pain.

Two studies28 30 classied ligament abnormalities as presence

or absence of tears, and three studies19 22 26 used semiquantitative scores. Since only two high-quality studies19 22 were
available, which showed positive association, this resulted in
a limited level of evidence for a positive association between
ligament abnormalities and pain. When all ve studies19
22 26 30 were taken in account, only 40% showed a positive
association.

Meniscal lesions

Subchondral cyst

Only one19 of three high-quality cross-sectional studies showed

a positive association resulting in a conicting level of evidence
for the association between meniscal lesions and pain.18 19 29

Subchondral cysts were not associated with pain. Two highquality studies showed no association and this resulted in a limited level of evidence.19 29

Osteophytes

62

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Extended report
Table 1

Characteristics of included studies (listed alphabetically by first author surname)

Studies
Cohort studies
Hill et al12
Kornaat et al20

Pelletier et al21

Raynauld et al14
Wluka et al16

Cross-sectional studies
Anandacoomarasamy
et al35
Amin et al22
Bhattacharyya et al18

Dunn et al23
Felson et al24

Fernandez-Madrid et al25

Hayes et al26

Hernndez-Molina et al27

Hill et al28

Kornaat et al29

Link et al30
Lo et al36

Pelletier et al31

Phan et al32

Sengupta et al33
Sowers et al34

Torres et al19

Patients with knee OA (ACR criteria). n=270 (42%

women); mean age 679 years. BOKS, USA.
Generalised patients with OA. n=182 (86%
women); median age 60 years (range: 4377).
GARP study, The Netherlands.
Patients with knee OA (ACR criteria) from
outpatient rheumatology clinic, n=27 (52%
women), mean age 649.6 years. Canada.
Patients with knee OA (ACR criteria). n=40
(88% women); mean age 628 years. Canada.
Patients with knee OA (ACR criteria). n=132
(54% women); mean age 63 years (range 4186)
Australia.
Obese patients with knee OA from general
population (ACR criteria), n=77 (68% women),
mean age: 5112.7 years, Sydney, Australia.
BOKS, USA. See above. n=265 (43% women);
mean age 679 years.
Cases: BOKS, USA. See above. n=154, mean age:
65 years. Controls: no knee pain, n=49 mean age:
67 years.
Patients suspected for clinical OA. n=55
(55% women); mean age 633 years. USA.
BOKS, USA. See above. n=401 (33% women in
knee pain group, 48% in no pain group); mean age:
62 years (range: 2291).
Case: patients with knee OA (ACR criteria). n=52
(67% women); mean age 5514 years. Control:
general population. n=40 (62% women), 4915
years. Detroit, USA.
Four groups (each n=30, 100% women): no pain,
no radiographic knee OA, mean age 451 years;
no pain, radiographic knee OA, 461 years; pain,
no radiographic knee OA, 471 years; pain,
radiographic knee OA, 471 years. Southeast
Michigan Osteoarthritis cohort, USA.
Patients with knee OA (K&L 2). n=1273 (48%
women); mean age: 659 years. Framingham OA
study cohort, Massachusetts, USA.
Cases: BOKS, USA. See above. n=360, 33%
women, mean age: 68 years. Controls: no knee
pain. n=73, 65% with K&L 2 and JSN1, 57%
men, 66 years.
GARP. See above. n=205 (80% women); median
age 60 years (range: 4377).
Patients with knee OA (ACR criteria). n=50
(60% women); mean age 6411 years.
Patients with knee OA (Knee pain or stiffness and
osteophytes OARSI atlas score 13), n=160
(50% women), mean age 619.9. OA initiative.
Knee OA (radiographic) from general population.
Subset from clinical trial on Risendronate in North
America. n=110 (64% women); mean age 627
years.
Patients with knee OA (ACR criteria), n=34 and
general population, n=6, 60% women, mean age:
5816 years.
BOKS. See above. n=217 (30% women); mean
age 67 9 years.
Southeast Michigan Osteoarthritis cohort, USA.
See above.
Patients with knee OA (K&L 2 and a little
difficulty in one or two WOMAC physical function
scale). n=143 (88% women); mean age 7010
years.

Features assessed

Pain assessment

Statistical analysis

Quality
score (%)

Effusion/synovitis

VAS

Linear regression

68

BML

WOMAC pain

Linear mixed model

64

Synovitis

WOMAC and VAS pain

Spearman correlation

36

Cartilage

WOMAC and VAS pain

Spearman correlation

64

Cartilage

WOMAC pain

Spearman correlation

64

Cartilage

WOMAC pain

Spearman correlation

67

ACL tear

VAS

Student t test

67

Meniscal tear

VAS

Student t test

67

Cartilage

WOMAC pain

Spearman correlation

22

BML

Presence/absence
of pain

Logistic regression

75

Cartilage, osteophytes,
subchondral lesions, effusion/
synovitis, meniscal tears

Presence/absence
of pain

2 test

72

Cartilage, osteophytes,
subchondral cysts, BML,
effusion/synovitis, meniscal
tear, ACL tear

Presence/absence
of pain

Fisher exact test of

general association

56

Bone attrition

Presence/absence
of pain

2 test

78

ACL tear

Presence/absence
of pain

2 test

50

Cartilage, osteophytes,
subchondral cysts, BML,
effusion, meniscal defects
Cartilage, BML, meniscal tear,
ACL tear
BML, effusion/synovitis

Presence/absence
of pain

Logistic regression

78

WOMAC pain

Wilcoxon rank sum test 47

WOMAC pain

Logistic regression

78

Cartilage

WOMAC pain

Spearman correlation

39

Cartilage, BML

WOMAC pain

Correlation not specified 67

Osteophytes

10-point pain scale

Logistic regression

Cartilage, BML

VAS pain

Cartilage, osteophytes, bone

cysts, bone attrition, BML,
synovitis, meniscal tears,
ligament abnormalities (MCL,
LCL and ACL)

VAS pain

Wilcoxon or Maentel 78
Haenszel test of general
association
Median quantile
78
regression

78

ACR clinical and radiographic criteria requires knee pain and osteophytes on radiograph.50
ACL, anterior cruciate ligament; ACR, American College of Rheumatology; BMI, body mass index; BML, bone marrow lesion; BOKS, Boston OA of the knee study; GARP, Genetic
Arthrosis Progression Study; JSN, joint space narrowing; K&L, Kellgren and Lawrence Osteoarthritis Scoring System for knee radiographs; LCL, lateral cruciate ligament; MCL, medial
cruciate ligament; n, number of study population; OA, osteoarthritis; VAS, visual analogue scale; WOMAC, Western Ontario and McMaster University.

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Extended report
Table 2 Best evidence synthesis (MRI features arranged from top to bottom according to the number of studies included)
Number of studies:
positive/total (%)

Association (sizes)
Studies

Study design

Cartilage defects (level of evidence: conflicting)

Scored using semiquantitative scores
Pelletier et al31
CS
Phan et al32
CS
Torres et al19
CS
Hayes et al26
CS
Kornaat et al29
CS
Link et al30
Scored quantitatively
Raynauld et al14

CS

Crude

Adjusted

Adjusted confounders

All

High quality

r=0.09, p=0.38
r Not mentioned, NS
=1.03 (95% CI 0.6 to 1.5)
Positive, p=0.001

0.53 (0.08 to 0.98)

OR 1.12 (99% CI 0.4 to 3.2)

6/12 (50%)

3 (1 C, 2 CS)/6
(2 C, 3 CS) (50%)

positive, p<0.05

NA
NA
Age and BMI
NA
Age, sex, BMI, intrafamily
effects
NA

NA

NA
NA
NA
NA

NA

Mean difference (increasing

BML)=2 (95% CI 8 to 11)

OR=3.31 (95% CI 1.5 to 7.4)

5/8 (63%)

4 (CS)/5
(1 C, 4 CS) (80%)

2/6 (33%)

0/2 (CS) (0%)

2/6 (33%)

1/3 (CS) (33%)

6/8 (80 %)
Age, sex, BMI, cartilage
score at baseline, effusion
score, BML score, change
in effusion and BML score.
NA

4 (1 C, 3 CS)/4
(1 C, 3 CS)
(100%)

r=0.25, NS (WOMAC),
r=0.12, NS (VAS)
C
r=0.28, positive, p=0.002
Wluka et al16
Fernandez-Madrid et al25
CS
NS
Sowers et al34
CS
Positive, p<0.0001
Dunn et al23
CS
Positive, p<0.05
Scored using other methods (ie, quantitatively after giving contrast agent)
Anandacoomarasamy et al35 CS
r=0.21, p=0.07
Bone marrow lesion (level of evidence: moderate)
Kornaat et al20
C

Hayes et al26
Felson et al24

CS
CS

Positive, p=0.001

Link et al30
Lo et al36

CS
CS

p>0.05
Positive, RR BML scores
versus no BML:
1:1.3
2:2.1
3:2.3
p For trend=0.0009
r Not mentioned, NS
OR=5.0 (95% CI 2.4 to 10.5)
=5.0 (95% CI 3.0 to 7.0)

Positive:

Age, sex, BMI, intrafamily

effects
NA
Age, sex, radiological and
effusion score
NA
Effusion and synovitis

1:1.2
2:1.9
3:2.0
p For trend 0.006

3.72 (1.8 to 5.7)

NA
NA
Age and BMI

NS
Positive, p<0.001

OR=1.05 (99% CI 0.4 to 2.9)

p>0.05
=1.2 (95% CI 0.6 to 1.7)

=0.5 (0.07 to 0.94)

NA
NA
Age, sex, BMI, intrafamily
effects
NA
Age and BMI

PR=0.94 (0.8 to 1.1)

Age, sex, BMI

NS
Positive, p=0.001

p=0.7

Tears: OR=1.26 (99% CI 0.6

to 2.7), subluxation: OR=1.03
(99% CI 0.5 to 2.2)

Tears: 2.0 (0.6 to 3.4)

Age
NA
NA
Age, sex, BMI, intrafamily
effects

Phan et al32
CS
Sowers et al34
CS+
Torres et al19
CS+
Osteophytes (level of evidence: limited)
Presence
Fernandez-Madrid et al25
CS
Hayes et al26
CS
Kornaat et al29
CS
Link et al30
CS
Torres et al19)
CS
Signal strength
Sengupta et al33
CS
Meniscal lesion (level of evidence: conflicting)
Bhattacharyya et al18
CS
Fernandez-Madrid et al25
CS
Hayes et al26
CS
Kornaat et al29
CS

Link et al30
Torres et al19

CS
CS

Effusion and synovitis (level of evidence: moderate)

C
Hill et al12

Fernandez-Madrid et al25

CS

Hayes et al26

CS

p>0.05
Tears: =3.3
(95% CI 0.9 to 5.8)
Subluxation: =15.0
(95% CI 0.3 to 30.3)

Effusion: positive, p<0.001

Synovitis: NS
Effusion: positive, p<0.001
Synovitis: positive, p<0.001

NA
Age and BMI

Subluxation: 2.22 (6.9 to 11.3)

Effusion: OR=1.2
(95% CI 8.1 to 10.5),
synovitis: OR=3.2
(95% CI 1.04 to 5.3)

NA
Continued

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Extended report
Table 2 continued
Number of studies:
positive/total (%)

Association (sizes)
Studies

Study design

Crude

Adjusted

Adjusted confounders

Kornaat et al29

CS

Link et al27
Lo et al*36

CS
CS+

Effusion: p>0.05
Effusion: RR BML scores
versus no BML:
1:1.8
2:2.4
3:3.1
p For trend<0.0001
Synovitis:
1:1.9
2:1.9
3:2.3
p For trend 0.20
=15.0
(95% CI 8.2 to 38.2)
Effusion: r=0.07, positive,
p=0.71 (WOMAC);
r=0.01,positive,
p=0.93 (VAS)

Effusion: OR=10.0
(99% CI 1.1 to 149)

Age, sex, BMI, intrafamily

effects
NA
Synovitis and BML

Torres et al19

CS

Pelletier et al21

Knee ligament abnormalities

(level of evidence: limited)
Amin et al22

1:1.7
2:2.0
3:2.6
p For trend=0.0004
Synovitis:
1:1.4
2:1.5
3:1.9
p For trend=0.22
9.8 (0.4 to 19.3)

Age and BMI

NA

ACL: positive, p<0.05

Age, sex, BMI and cartilage 2/5 (40%)

scores
NA
NA

CS

Hill et al28
Link et al30

CS
CS

Torres et al19

CS

Hayes et al26

CS

ACL: positive, p=0.0004

ACL: p>0.05, MCL and

LCL: p>0.05
(95% CI)
ACL: 5.0 (13.0 to 23.0)
ACL: 6.8 (5.4 to 19.0)
MCL: 0 (11.9 to 11.9)
MCL: 6.10 (14.0 to 1.7)
LCL:15.0 (95% CI 8.2 to 38.2)LCL: 29.5 (17.8 to 41.1)
ACL and PCL: p=0.23,

MCL and LCL, p=0.86

Subchondral cysts (level of evidence: limited)

Hayes et al26
CS
Kornaat et al29
CS
CS
Link et al27
Fernandez-Madrid et al22
CS
Torres et al19
CS
Bone attrition (level of evidence: conflicting)
Hernndez-Molina et al27
CS

Torres et al19

CS

Positive, p<0.001

All

OR=1.71 (99% CI 0.8 to 3.6)

p>0.05

NS

=2.50 (95% CI 0.4 to 5.4) 0.82 (0.5 to 2.1)

OR=2.1 (95% CI 1.4 to 3.4)

1.2 (0.7 to 2.0)

=3.3 (95% CI 1.8 to 4.9)

1.9 (0.7 to 3.1)

High quality

2/2 (CS) (100%)

Age and BMI

NA

NA
Age, sex, BMI, intrafamily
effects
NA
NA
Age and BMI

1/5 (20%)

Age, sex, BMI, K&L grade, 1/2 (50%)

presence of BML and
effusion
Age and BMI

0/2 (CS) (0%)

1/2 (CS) (50%)

Authors name in bold indicates high-quality studies; positive in front of p values indicates significant positive association sizes.
r: (Spearmans or Pearsons) correlation coefficient between MR feature of interest and pain in continuous scale (WOMAC pain subscale or VAS); in a cohort study the correlation
coefficient showed the association between changes of the MRI features with the changes in pain during the follow-up. OR, odds of having pain (in cross-sectional studies) or
increasing pain (in cohort studies) when a MRI feature is present or increasing comparing to the odds when MRI feature is absent. is regression coefficient representing the increase
in knee pain severity associated with increase in lesion score, PR, prevalence (odds) ratio.
ACL, anterior cruciate ligament; BMI, body mass index; BML, bone marrow lesion; C, cohort, CS, cross-sectional studies; K&L, Kellgren and Lawrence; LCL, lateral cruciate ligament;
MCL, medial cruciate ligament; NA, not applicable; NS, not significant; PCL, posterior cruciate ligament; VAS, Visual analogue scale; WOMAC, Western Ontario and McMaster Scoring.

Bone attrition

DISCUSSION

Conicting evidence was found on the association between

bone attrition and pain. One19 of two high-quality cross-sectional studies,19 27 showed a positive association.

Pain is the most disabling symptom of OA. Knowledge about the

structures that cause pain is crucial, because in the future it may
be possible to specically target interventions. For a long time,
research on the structural cause of pain has been focused on cartilage defects, even though cartilage does not have pain bres.3
Further, research on structures that produce pain in the knee was
hampered by the limited ability of radiographs to visualise knee
structures extensively. MRI has been shown to be superior to
plain lms. It demonstrates the whole joint organ. Since several
initial reports seemed positive about the association between
MRI ndings and pain, we therefore investigated the evidence

Sensitivity analysis
When we used median score of all studies instead of mean score
as the cut-off of high quality studies, the level of evidence of the
association of all MRI nding investigated remained the same.
The number of positive studies without quality assessment is
shown in table 2.

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Extended report
between the MRI ndings and knee pain in patients with knee
OA. Our ndings will be relevant to researchers, clinician and
radiologists reporting MRI studies.
We identied a moderate level of evidence for a positive association for BML and effusion/synovitis with pain in knee OA.
The level of evidence was limited for a positive association for
knee ligamentous abnormalities. We found limited levels of evidence for no association for osteophytes and subchondral cysts.
Conicting levels of evidence were found for cartilage defects,
meniscal lesions and bone attrition. We did not investigate studies found during the literature search which investigated features
beyond the scope of this review: patella alignment,37 peripatelar
and other periarticular lesions,38 popliteal or synovial (Bakers
cyst).13 26 29
In our review, we used a priori dened qualitative levels of
evidence to reach a summary. We consider this as a strength
because we provide an alternative to quantitative statistics,
which could not be calculated as the topic of our review included
several aspects of studies that were heterogenic. However,
simply counting positive studies also has several drawbacks.
It does not take into account the size of the studies, and the
decision on positive or negative studies was based only on
statistical signicance. In meta-analysis, it is theoretically possible that individual studies are negative but the pooled effect
is positive.39 Another technical limitation of our review is the
use of quality scores to asses the methodological quality of the
studies. It could be that when different quality score sets were
used, the interpretation of the results could be inuenced.40
Other limitations of this review mostly reect the limitations
of the studies investigated. First, no publication bias could be
assessed using a funnel plot due to the limited number of studies that reported their results in RR or OR.41 Therefore, we do
not know whether preferentially positive ndings were published. Second, the quality of included studies was not excellent. There are several obvious examples of limitations of the
studies. MRI scan interpretation is by nature subjective, as
few, if any, quantitative methods exist. Attempts at standardisation may not be generally used. Also, most scans were read
unblinded to order. It is possible that MRI readers dene the
later ndings as more severe than the rst ndings. This could
lead to misclassication.
The moderate associations found in the review have the consequence that more research is needed.42 Epidemiological studies about BML and effusion/synovitis could strengthen the levels
of association. An ideal epidemiological study design would be a
case-crossover study where individual MRI ndings in the presence of knee pain at one time point are compared with MRI
ndings in the same patient without knee pain at another time
point. The ideal data analysis would give an association size
and permit adjustment for confounders, including age and sex,
and also for other MRI features when multiple MRI ndings are
studied simultaneously.
The causal relationship between BML and effusion/synovitis
and pain in knee OA needs further study. Our knowledge is now
limited to the fact that BML, dened as ill-dened hyperintensities on T2-weighted MRI,43 comprises normal tissue, oedema,
necrosis and brosis in histological slices.44 Further, although
knee OA is not considered as an inammatory arthritis per se,
research on the role of inammation in knee OA and the potential use of anti-inammatory treatments in knee OA should also
be pursued in the light of the possible association between effusion/synovitis with knee pain in knee OA. Evaluation of effusion
and synovitis can be improved by using contrast enhancement,

66

since it can highlight inammation and improve the distinction

between synovitis and effusion.12 19 Gadolinium contrast diffusion is affected in synovitis tissue, where the blood ow and
permeability are changed.45 In the present review, no included
papers performed contrast-enhanced MRI.
Beyond the knee itself further research needs to be focused on
the origin of pain in OA and representation in the central nervous
system. Some observations have shown that pain in arthritis is
also characterised by abnormal pain response (hyperalgaesia)46
and functional MRI has the potential to study hyperalgaesia and
other pain response.
Knowing which structures in the knee are associated with
knee OA will add to our understanding of OA and, in the long
term, will lead to rational therapeutic targets for OA. This will
mean improvement in patient care, since at this moment the
therapeutic options against OA are limited.47 At present, the
clinical implication of BML is not clear, despite being a common
nding in knee OA, being present in 78% of patients with knee
OA with pain and in 30% of patients with knee OA without
pain.24 BML is plainly not pathognomonic of knee OA as it is
also found in a range of conditions such as trauma, osteoporosis and rheumatoid arthritis.48 Moreover, BML is also not a
static nding. Almost every BML in knee changes in size over
a period of 3 months.49 The clinical implications of effusion/
synovitis may be clearer, since they might permit the potential
use of anti-inammatory drugs in treatment of OA. Effusion/
synovitis is common in knee OA. Moderate effusion being seen
in 36% of patients with knee OA and synovitis present in (84%)
of knees.26
The nding that ligamentous abnormalities may associate
with pain is of special interest. While the exact aetiology and
management of these nding remains unclear it may be that
surgical intervention could in theory be aimed at repair of these
structures to alleviate pain. However, based on present knowledge, surgical intervention for symptomatic treatment is not
currently indicated.
In summary, this systematic review has shown that BML
and effusion/synovitis were associated with knee OA pain.
However, the level of evidence is moderate and these features
need to be explored further.
Acknowledgements We thank Dr J W Schoones, medical librarian of Leiden
University Medical Center for his assistance in performing literature search.
Competing interests All authors have completed the Unified Competing Interest
form at http://www.icmje.org/coi_disclosure.pdf (available on request from the
corresponding author).
Contributors EY, MCK, IW, TH and MK contributed to conception and design of
this review. EY, MCK and MK drafted the article. IW and TH revised the article for
important intellectual content. All authors gave final approval of the version to be
published.
Provenance and peer review Not commissioned; externally peer reviewed.

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