Association of pain in knee osteoarthritis with distinct patterns of synovitis

Pain in knee osteoarthritis patients associates with distinct pattern of synovitis.

de Lange-Brokaar BJE1, Ioan-Facsinay A

1, Yusuf E

1, Visser AW

1, Kroon HM

5, van Osch

GJVM2, Zuurmond A-M

3, Stojanovic-Susulic V

4, Bloem JL

5, Nelissen RGHH

6, Huizinga

TW1, Kloppenburg M

1,7

From:

1: Department of Rheumatology, Leiden University Medical Centre, Leiden, the

Netherlands

2: Department of Orthopaedics and Department of Otorhinolaryngology, Erasmus MC,

University Medical Center, Rotterdam, the Netherlands ; 3: TNO, Leiden, the

Netherlands

4: Janssen, Pharmaceutical companies Johnson & Johnson, Pennsylvania, USA ;

5: Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands

6: Department Orthopaedics, Leiden University Medical Center, Leiden, the Netherlands

7: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the

Netherlands

Corresponding Author:

Margreet Kloppenburg, MD, PhD

Department of Rheumatology, Leiden University Medical Centre

C1-42, Postbus 9600

2300 RC Leiden, The Netherlands

Fax: +31 71 5266752; Phone: +31 71 5263598. E-mail: [email protected]

Full Length Arthritis & RheumatologyDOI 10.1002/art.38965

This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as an‘Accepted Article’, doi: 10.1002/art.38965© 2014 American College of RheumatologyReceived: Jan 21, 2014; Revised: Sep 26, 2014; Accepted: Nov 13, 2014

This article is protected by copyright. All rights reserved.

2

Key words: knee osteoarthritis; synovitis; pain; MRI; radiographic severity

Word count: 3082 Abstract: 250

Running head: Pain in knee OA patients associates with distinct pattern of synovitis.

Competing interests: None declared

Funding: This work was financially supported by TI-Pharma, however this institution

did not contribute to design, interpretation of data, drafting and final approval of the

manuscript.

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ABSTRACT

Objective: To determine patterns of synovitis on contrast-enhanced magnetic resonance

images and its relation to pain and severity of radiographic OA. Methods: 86 patients

(mean age 62 years, 66% woman, median BMI 29 kg/mm2 and Kellgren-Lawrence score

3 ) with symptomatic knee OA were included. T1-weighted Gd-chelate-enhanced MRI

with fat-suppression (3T) were used to semi-quantitatively score synovitis at 11 sites

(range 0-22). Self-reported pain was assessed by standardized questionnaires. With

principal component analysis (PCA) patterns of synovitis as assessed by location and

severity were investigated. Subsequently, patterns were associated with pain measures

and radiographic severity in adjusted logistic regression models.

Results: Synovitis was observed in 85 patients and generally mild (median(range) 7.0

(0-16)). Median (range) VAS pain was 53.0 (0-96), KOOS pain 51.4 (2.8-97.2), ICOAP

constant pain 35.0 (0-75) and ICOAP intermittent pain 40.6 (0-87.5). PCA resulted in

extraction of 3 components, explaining 53.4% of variance. Component 1 was

characterized by synovitis at 7 sites (mainly medial parapatellar involvement) and was

associated with KOOS pain and ICOAP constant pain. Component 2 was characterized

by synovitis at 4 sites (mainly site adjacent to the anterior cruciate ligament), but did not

associate with pain measures nor with radiographic severity. Component 3, characterized

by synovitis at 3 sites (mainly by loose bodies), was associated with radiographic

severity.

Conclusion: Different patterns of synovitis in knee OA were observed. The pattern

including several patellar sites was associated with pain, whereas other patterns were not,

suggesting a localized response in pain perception in knee OA patients.

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INTRODUCTION

Although one of the major results of knee osteoarthritis (OA) is pain, the

pathophysiological and pain causing mechanisms in OA remain largely unknown. (1)

Studies in the past years have elucidated that synovitis is one of the key players in pain

perception, as it has been associated with pain in knee OA (2,3).

For a long time, OA was considered a non-inflammatory condition. However, recently it

became evident that synovial inflammation is prevalent in OA (4) and could play an

important role in the pathophysiology of OA (5). Although, histological assessment of

synovitis in synovial biopsies is currently the gold standard for defining synovial

inflammation, contrast enhanced (CE) MRI has proven to be a good surrogate in

evaluating synovitis in knee OA patients (6-11). As the anatomical distribution of

synovitis on CE-MRI is patchy and heterogeneous (12), an MRI scoring method should

encompass a sufficient number of compartments. A recently developed method by

Guermazi et al. is a semi-quantitative method that scores synovitis on CE-MRI at 11

different sites throughout the knee (13) and constitutes a comprehensible and practical

method for assessing synovitis in the whole joint. Synovitis on CE-MRI as assessed by

this scorings method compares well with synovial inflammation in tissue biopsies of knee

OA patients(9).

Only a small number of studies have investigated synovitis on CE-MRI and even less

studies used a scoring system that encompasses sufficient number of sites throughout the

whole knee (12,13). These studies have found that some sites displayed more synovitis

than others. Whether synovitis at different sites within the knee joint occurs

independently or whether synovitis forms patterns, is currently unknown, since patterns

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of synovitis have not been investigated in an unbiased manner. Moreover, investigation

of potential patterns of synovitis could contribute to the understanding of disease

mechanisms in OA as it might help to unravel both underlying mechanisms of synovitis

and pain mechanisms in OA.

In the present study, we aimed to investigate whether different patterns of synovitis as

assessed by location and severity on Gd-chelate-enhanced MRI exist in patients with

knee OA and if these patterns exist, whether they would associate with pain and severity

of radiographic knee OA.

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MATERIALS AND METHODS

Study design

This study is part of the ongoing geMstoan study (GEneration of Models, Mechanism &

Markers for STratification of OsteoArthritis patieNts), an observational study in

established and end-stage knee OA patients to find new biomarkers for OA progression.

This study has been approved by the ethics committee of the Leiden University Medical

Center (LUMC). All patients provided written informed consent.

Patients

Between 2008 and 2013, patients with symptomatic radiographic primary knee OA,

according to ACR criteria, (14) attending the rheumatology or orthopaedic department of

the LUMC or orthopaedic department of the Diaconessenhuis, Leiden, were included.

The geMstoan study comprises two groups of patients based on a clinical end point; one

with end-stage disease who received a total knee arthroplasty and the other group with a

mild to established OA, with no indication for an arthroplasty. Patients with other

rheumatic diseases, using immunosuppressive drugs or having knee injections (i.e.

corticosteroids) in the past 3 months were excluded. Patients with renal insufficiency

(Cockroft-Gault < 60 mL/min) did not undergo Gd-chelate enhanced MRI.

MRI acquisition

MR scanning was performed on a 3T Philips Achieva MR system (Philips Healthcare,

Best, The Netherlands) using an 8-channel dedicated knee coil. Gd-DOTA, (Dotarem,

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Guerbet, 0.2 ml/kg at a rate of 2 ml/s followed by a saline flush 40 ml at a rate of 2 ml/s)

was injected in the cubital vein for visualizing synovitis. Both axial and sagittal CE, T1-

weighted, turbo spin echo (TSE), spectral presaturation with inversion recovery (SPIR)

sequences and fat- suppression were used for scoring synovitis. Scan parameters were

(for axial and sagittal): multi-slice, spin echo, echo train length 6, TR 655 ms, TE 20 ms,

FOV 160x160 mm, pixel size 0.75x0.75 mm, slice thickness 2.5 mm, slice gap 0.8 mm,

24 slices. Sequences were obtained between 8 and 10 minutes after contrast agent

injection.

MRI scoring

Sagittal and axial T1-weighted Gd-chelate-enhanced MRI (3T) were used to semi-

quantitatively score synovitis at 11 different sites according to Guermazi et al. (13)

Synovial thickness was measured and scored as followed: 0, when synovial thickness was

less than 2 mm, 1 when thickness was between 2-4 mm and 2 when synovial thickness

was above 4 mm. (Figure 1) The total sum score of 11 sites was calculated (range 0-22).

A total score of 0-4 was considered normal (no synovitis); 5-8 represents a mild, 9-12 a

moderate and above 13 a severe synovitis.(13)

Bone marrow lesions (BML) and effusion were scored using axial and coronal proton

density weighted images according the Knee Osteoarthritis Scoring System (KOSS) score

in 9 compartments, as described elsewhere.(15) BML were defined as an ill-defined area

in the subchondral bone extending from the articular surface and also graded from 0-3 (0

= absent, 1= minimal < 5 mm, 2 = moderate 5-20mm, 3 severe ≥ 20mm). For analysis

BML was recoded into a binary variable (0 = not present, 1 = present). Effusion was

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scored from 0-3 (0 = no joint effusion , with only a small, physiological sliver of synovial

fluid was observed, 1= small effusion, one or two distended joint recesses (suprapatellar

pouch, medial or lateral patellar recess, dorsal femorotibial joint space, popliteal tendon

sheath, recesses surrounding the cruciate ligaments, meniscosynovial recesses), 2 =

moderate effusion, more than two joint recesses were partially distended, 3 = massive

effusion when there was full, marked distention of all the joint recesses). For analysis

effusion was recoded into a binary variable (0 = not present, 1 = present).

All MRI were analyzed by means of consensus between two readers (BdL and WV).

Both BDL and WV (over 1000 MRI’s scored) have more than 3 years of experience in

scoring knee MRI. Scoring was done after extensive learning sessions and under

supervision of experienced musculoskeletal radiologist JB. During the assessment, the

readers were blinded to radiographic results and patient data. Intra-class correlation (ICC,

with 95% confidence interval(CI)) was based on random sample of 14 Gd-chelate

enhanced MR images and was 0.84 (0.58 to 0.95).

Scoring knee radiographs:

Radiographs (posterior anterior (PA) fixed flexion) were obtained of all patients.

Radiographs were scored, blinded for patient characteristics, by an experienced

musculoskeletal radiologist (HK), with 30 years of experience in scoring musculoskeletal

radiographs, according to the Kellgren- Lawrence (KL) scale.(16) The intraclass

correlation coefficient (ICC, (95% CI)) was based on a randomly selected sample of 36

radiographs (18 right and 18 left knees) and was 0.99 (0.98-0.99). The knees with KL < 2

were rescored in consensus between HK and an experienced rheumatologic reader (MK).

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Clinical data

In the geMstoan patients demographics and disease characteristic were collected via

standard questionnaires.

Measurement of pain was achieved by using different questionnaires that each

investigates different dimensions of pain. All questionnaires were filled in for the imaged

knee. Three questionnaires were used. First, general assessment of self-reported pain was

assessed by the visual analogue scale (VAS, 0-100). The VAS is a one-dimensional

measure of pain intensity. Participants were asked to place an X at a 10 cm line that

represented their general pain intensity for that knee. A score of 100 represents worst

possible pain intensity. Second, the measure of Intermittent and Constant OsteoArthritis

Pain (ICOAP) (17), subscale constant pain and subscale intermittent pain were used.

Higher scores indicate worse pain experience. Thirdly, the Knee injury and Osteoarthritis

Outcome Score (KOOS subscale pain, 0-100) (18) was used. In contrast to all other

scales a score of 0 represents worst possible pain. Patients were asked to fill in both

KOOS and ICOAP questionnaire for pain experienced in the last 7 days.

Statistics

For comparison between groups, Independent t-test was used for age, Mann-Whitney-U

test was used for BMI, KL-grade, MRI total score and all pain scales and Chi-squared

test was used for gender and right knee.

Principal component analysis (PCA) was used to investigate possible patterns of

synovitis. All 11 items of the synovitis score of Guermazi et al. (13) were subjected to

PCA. Prior to performing PCA, suitability of data was assessed. For this purpose the

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correlation matrix was inspected and revealed the presence of correlation coefficients of

0.3 and above. Furthermore, the Kaiser-Meyer-Oklin value was 0.738, which exceeded

the recommended value of 0.6 (19,20). Finally, the Barlett’s Test of Sphericity (21) was

calculated, which turned out to be significant (p < 0.001), supporting the factorability of

the correlation matrix. Using Eigen values >1, the number of components was

determined. A Varimax rotation with Kaiser normalization was done to help with the

interpretation of the results. In the present study a synovitis site was said to load

significantly on a component if the factor loading was at least 0.4 (22).

To investigate the association between components and pain and radiographic severity in

knee OA patients, regression factor scores that represented location on a factor for each

patient, were calculated for all components (23). Spearman’s rank correlations (r) were

used to investigate the unadjusted correlations between regression factor scores and the

MRI total score and clinical data. Subsequently, regression factor scores were

transformed into binary variables with 0 representing negative location on a component

and 1 representing positive location on a component. A logistic regression adjusted for

age, gender and BMI, and additionally for BMLs and effusion, was used to investigate

the association between components with pain and radiographic severity. Statistics were

calculated by SPSS 20.0.

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RESULTS

Patient characteristics

Of 101 patients (mean (SD) age 62 (7.5) years, 68% woman, BMI median (range) 29 (21-

49) kg/mm2, median (range) KL score 3 (1-4)) included in the geMstoan study, 87

patients had undergone Gd-chelate-enhanced MRI. One patient developed after one year

a CCP positive, rheumatoid factor positive oligoarthritis and was excluded, resulting in

86 patients (Table 1). These 86 patients did not significantly differ from original 101

patients in age, gender, BMI or KL grade (data not shown). Gd-chelate administration

was well tolerated by all patients.

The patients with mild to established OA had a median (range) KL score of 2 (1-4) and

patients with end-stage disease requiring arthroplasty of 4 (1-4); the difference was

significant between the groups (P-value < 0.001). The percentage of female subjects was

significantly lower in the end-stage group than in the mild to established group (P-

value=0.007).

As expected all pain scales were significantly higher in the patients with end-stage knee

OA. Patient characteristics are displayed in table 1 (Table 1).

Synovitis on Gd-chelate-enhanced MRI

The synovitis scores of patients are shown in figure 2. The median (range) of the MRI

total synovitis score was 7 (0-16) and was significantly different between the groups: the

median (range) was 6 (0-14) in the mild-established group versus 8 (1-16) in the end-

stage group (P-value=0.005). Synovitis was most frequently present at the medial

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parapatellar site (n=77), adjacent to the posterior cruciate ligament (PCL) (n=74), the

suprapatellar (n=65) and the lateral parameniscal sites (n=70). The site adjacent to the

PCL was most frequently scored the maximal score of 2 (n=31). Loose body synovitis

was found in only six patients. Overall the synovitis pattern in the mild to established OA

group resembled the pattern in the end-stage OA group, although synovitis was more

extensive and severe in end-stage disease (Figure 2).

BMLs were seen in 76 (88%) patients, whereas effusion was seen in 80 (93%) patients.

Synovial patterns based on principal component analysis

PCA resulted in extraction of three components, together explaining 53.4% of variance.

After rotation loading factors for each synovitis site for all three components were

calculated (see loading table in table 2).

Component 1 was characterized by synovitis at seven sites with mainly medial

parapatellar involvement. Component 2 was characterized by synovitis at the site

adjacent to the anterior cruciate ligament (ACL), and medial parameniscal, intercondylar

and suprapatellar sites and component 3 was characterized by synovitis at three sites

(mainly characterized by synovitis at the loose body site).

Correlation of synovitis sites with clinical outcomes

To investigate the association of synovitis components with pain measures and

radiographic damage, regression factor scores were calculated for all three components.

Statistically significant correlations were seen between regression factor score for

component 1 and KOOS subscale pain (r = -0.24 (P-value=0.030) and ICOAP constant

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pain (r=0.22 (P-value=0.05)), but not with the other pain questionnaires. The regression

factor scores of the two other components and the MRI total score did not correlate with

any of the pain measures. Moreover, MRI total score did not correlate with any of the

pain measures. Furthermore, statistically significant correlations were observed between

radiographic severity and regression factor scores for component 1 (r=0.267 (P-

value=0.013)) and for component 3 (r=0.312 (P-value=0.004)), and MRI total score

(r=0.411 (p<0.001)). No significant correlations were found between BMI and regression

factors.

Subsequently, the association between synovitis components and pain and radiographic

severity was investigated in a logistic regression model with regression factor scores

transformed into binary variables. Logistic regression adjusted for age, gender and BMI

revealed a statistically significant association between component 1 and KOOS subscale

pain; a trend between component 1 and ICOAP constant pain was shown (P-value=0.07).

Further adjustment for BMLs and effusion did not change the associations with pain

(association with KOOS subscale pain 0.8 (0.6-0.998) and with ICOAP constant pain 1.3

(1.001-1.6). Component 2 and 3 did not associate with any of the pain questionnaires.

Furthermore, radiographic severity was significantly associated with component 3 and

component 1 showed a trend with radiographic severity (P-value=0.05) (table 3).

Sensitivity analyses in knees with at least a KL score of 2, decreased the association of

component 1 with radiographic severity (2.5 (0.8-7.5), after adjustment for BMLs and

effusion 1.8 (0.6-5.8)), but increased the association between component 3 and

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radiographic severity (3.8 (1.1-12.4), after adjustment for BMLs and effusion 3.4 (1.0-

11.5)).

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DISCUSSION

In the present study we found distinct patterns of synovitis as assessed on Gd-chelate-

enhanced MRI in patients with knee OA. Furthermore, these different patterns of

synovitis seem to be of clinical relevance as only one pattern associated with pain.

Moreover, we have shown that patterns at different stages of the disease are roughly the

same, although synovitis in end-stage disease is more severe.

To our knowledge this is the first study that investigates synovial patterns on Gd-chelate-

enhanced MRI by using PCA. While synovitis in OA is known to be patchy and

heterogeneous, it is not known whether the distribution of synovitis is similar in all

patients or whether it differs per patient. Synovitis could differ between patients as result

of a localized response to triggers such as micro trauma, cartilage breakdown products or

mechanical loading. Therefore, we chose to study the 11 synovitis sites by PCA without

the inclusion of patient characteristics and without assumptions based on anatomical

location.

Investigation by PCA resulted in extraction of three components. Component 1 explained

the largest portion of total variance and consisted of seven sites with mainly medial

parapatellar involvement. In the present study the results of logistic regression revealed

that only component 1 was associated with pain. Several mechanisms could underlie this

observation.

Four of the seven sites of component 1 were in the vicinity of the patella. Earlier studies

on the innervation and pain sensation of the knee showed that the patellar region is richly

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innervated and that anterior synovial tissues in the vicinity of patella are very sensitive to

pain stimulation, which could explain the association between component 1 and pain

(24,25). The association between synovitis in the parapatellar subregion and pain is in

accordance with earlier observations, showing an association between this region and

WOMAC pain (13,26).

Although component 1 explained the largest portion of the variance and included sites

that displayed most severe synovitis (medial parapatellar site, suprapatellar site, lateral

meniscal site and site at PCL), we do not believe that the association found could be a

reflection of synovitis in the whole knee with pain. The MRI total score was not

correlated to pain as assessed with the different questionnaires, which implicates a

different mechanism underlying the association of component 1 with pain.

In conclusion, our data suggest that each synovitis location has its location specific

properties and further investigation is needed to unravel underlying mechanism.

In our study component 2 was characterized by synovial inflammation at the ACL, the

medial parameniscal, suprapatellar and intercondylar sites; we didn’t find an association

of this component with pain. At the intercondylar site the infrapatellar fat pad is located.

Previous studies that investigated the association of synovitis at the infrapatellar fat pad

on non Gd-chelate-enhanced MRI and pain did not find a significant association with

pain, which is in accordance with the present finding (26,27).

We found that synovitis was most frequently present at four sites throughout the whole

knee: the site adjacent to the PCL, the medial parapatellar site, the suprapatellar site and

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the lateral parameniscal site. Of these the site adjacent to the PCL , the medial

parapatellar site and the suprapatellar site were also reported by Roemer et al. in their top

four of most frequent sites with synovitis in a population with American knee OA

patients, supporting the robustness of the present findings (12). Remarkably, the most

frequent synovitis sites were not localized at one specific subregion, but were found

throughout the whole knee, emphasizing that using a whole knee scoring system instead

of predefined subregions, is the best way to study synovitis in knee OA patients. This

also stresses the importance of an inflammatory component of the knee joint as a whole

and pure mechanical, one compartment origin of OA.

Loose bodies were seen in seven patients. Although not frequently observed, they usually

display synovitis when present, which is in accordance with other studies (12,13). In the

present study, investigation of the raw data revealed different synovitis distributions in

these seven patients and therefore we chose to include the loose body site in our PCA.

This resulted in a separate component underscoring the fact that patients who have

synovial inflammation at the loose body site are indeed different from other OA patients.

These results, however, should be interpreted with caution and should be replicated in

larger cohorts.

In the present study we aimed to investigate different stages of OA in symptomatic

patients. Therefore we chose to divide our patients based on a hard clinical end point:

those who did and those who did not received an arthroplasty. Remarkably, a

radiographic KL score of 4 was observed in the mild to established OA group had,

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whereas a KL score of 1 was observed in the arthroplasty group. These findings

underscore the discrepancy between radiographic features of OA and clinical symptoms

and emphasize the fact that radiographs do not accurately define clinical severity of OA

Sensitivity analysis in knees with KL ≥2 revealed no effect on the associations with

component 1, however the association of radiographic severity with component 3 became

stronger.

The present study also has some limits. Firstly, only 86 patients were included in the

present study, which might explain why some of the pain measures failed to reach

significance in their association with component 1. Nevertheless, because effect sizes and

direction (e.g. more severe pain) were quite similar for different pain scales, we do think

our conclusions are valid. The effect sizes, however, are small reflecting the

multidimensionality of pain, which is also influenced by genetic predisposition and

psychosocial factors (28-30). Only KOOS subscale pain and ICOAP constant pain

showed a statistically significant association with component 1, which confirms that

different pain scales measure different pain dimensions.

Furthermore the time from Gd injection to acquisition of T1-W images was 8-10 minutes

due to the fact that our protocol included several dynamic sequences (that are not part of

the current analysis). Although, some controversy exist concerning the optimal time after

Gd injection (12,31,32) we feel this could have potentially have led to washout of the

contrast into the cavity and might have led to increased measurements of synovial

thickness. However, because the aim of present study was to compare findings between

patients and in all patients the time after injection was comparable, the actual

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measurements of synovial membrane were of lesser importance and this is less of a

problem.

Finally, we adjusted our logistic regression model for age, gender and BMI and

additionally for BMLs and effusion. Although, BMI was significantly correlated with all

the pain measures, it was not correlated with the components and therefore is by

definition not a confounder. When adjusted for age and gender both KOOS subscale pain

and ICOAP constant pain were significantly associated with component 1 (data not

shown), adjusting for BMI, BMLs and effusion did not change effect sizes.

In conclusion the present study confirms that the distribution of synovitis on Gd-chelate-

enhanced MRI is patchy in knee OA patients. This distribution is not random as distinct

synovitis patterns on Gd-chelate-enhanced MRI exist. Furthermore, these patterns are of

clinical relevance as different patterns associate differentially with pain. The next

research step is to understand what the underlying mechanisms are for these synovitis

patterns.

ACKNOWLEDGEMENTS

This work was performed within the framework of Dutch Top Institute Pharma, project

"Generation of models, mechanisms and markers for stratification of osteoarthritis

patients" (project nr. T1-213). The authors would like to acknowledge support of the

cooperating hospital Diaconessenhuis, Leiden (Nurse practitioner C.E. Jonxis and

orthopaedic surgeons Dr. R. Krips, J.B. Mullers and Dr. H.M. Schuller) and referring

rheumatologists, orthopaedic surgeons and nurse practitioner.

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COMPETING INTERESTS

None declared

FUNDING

This work was financially supported by TI-Pharma, however this institution did not

contribute to design, interpretation of data, drafting and final approval of the manuscript.

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Table 1: patient characteristics

Variables Patients

N = 86

Age, yrs, mean (SD) 62.3 (7.4)

Female sex, no. (%) 57 (66)

BMI, kg/m2 ,median (range) 28.6 (22.0-47.8)

Right knee, no. (%) 45 (52)

KL grade, median (range) 3 (1-4)

MRI total score, median (range) 7 (0-16)

ICOAP constant pain, median(range) 35.0 (0.0-75.0)

ICOAP intermittent pain, median (range) 40.6 (0.0-87.5)

KOOS pain, median (range) 51.4 (2.8-97.2)

VAS pain knee, mm, median (range) 53 (0-96)

Abbreviations: VAS= visual analogue scale pain, KOOS= knee injury and osteoarthritis

outcome score, subscale pain, ICOAP measure of intermittent and constant osteoarthritis

pain, KL = Kellgren and Lawrence

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Table 2: Principal component analysis with Varimax rotation of 3 component

solution for 11 different sites on contrast enhanced (CE) MRI in 86 patients with

knee OA, loading table

Only loadings > 0.4 are displayed

Anatomical sites of synovitis on Gd-chelate

enhanced MRI

COMPONENTS

1 2 3

Medial parapatellar site 0.808

Lateral parapatellar site 0.693

Adjacent to posterior cruciate ligament site 0.538 0.506

Lateral parameniscal site 0.534

Baker Cyst 0.530

Infra patellar site 0.488

Adjacent to the anterior cruciate ligament 0.854

Medial parameniscal site 0.622

Intercondylar site (at surface of Hoffa’s fat pad) 0.533

Loose Body 0.840

Suprapatellar site 0.421 0.404 0.598

% variance explained 24.4% 15.6% 13.4%

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Table 3: The association of the three components with pain and radiographic

severity adjusted for age, gender and BMI.

Regression factor scores were calculated for each component and transformed into binary

variables, with 0 representing negative location and 1 representing positive location

* OR shown per 10 units on pain scale

Abbreviations: CI = confidence interval, VAS= visual analogue scale pain, KOOSp =

knee injury and osteoarthritis outcome score, subscale pain), ICOAP measure of

intermittent and constant osteoarthritis pain, KL = Kellgren and Lawrence. Components

are displayed in table 2.

Component 1 Component 2 Component 3

Adj. OR (95%CI)

Adj. OR (95%CI)

Adj. OR (95%CI)

VAS pain * 1.2 (1.0-1.4) 1.1 (0.9-1.3) 1.0 (0.9-1.3)

KOOSp * 0.8 (0.6-0.954) 1.0 (0.8-1.2) 0.9 (0.7-1.1)

ICOAP intermittent* 1.2 (1.0-1.5) 1.0 (0.8-1.2) 1.0 (0.8-1.2)

ICOAP constant* 1.2 (1.0-1.5) 0.9 (0.8-1.2) 1.0 (0.8-1.2)

KL 3&4 2.7 (1.0-7.4) 0.9 (0.3-2.2) 3.2 (1.1-9.0)

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FIGURE LEGENDS

Figure 1. synovitis scoring on Gd-contrast enhanced (CE) MRI Images: (A) Sagittal

fat-suppressed T1-weigthed CE image at the level of the posterior cruciate ligament

(PCL), showing synovitis and a large loose body (open arrow), (B) Sagittal fat-

suppressed T1-weigthed CE image at the level of the anterior cruciate ligament (ACL)

showing synovitis adjacent to ACL (#) and at suprapatellar (white arrow), infrapatellar

(*), and intercondylar sites (open arrow) (C) Axial T1-weigthed fat-suppressed CE image

showing synovitis at both medial (open arrow) and lateral (white arrow) parapatellar sites

and a large medial Bakers cyst with surrounding white peripheral rim indicating synovitis

(*), (D) Sagittal fat-suppressed T1-weigthed CE image at the level of the tibiofibular joint

showing synovitis at the posterior horn of the lateral meniscus (white arrow), (E) Sagittal

fat-suppressed T1-weigthed CE image showing synovitis at the posterior horn of the

medial meniscus (white arrow) and Bakers cyst, (F-J) Fat-suppressed T1-weigthed CE

images at the same locations as A-B with almost no synovitis. Please note small Bakers

cyst in image H (*).

Figure 2: MRI synovitis score (11 sites) for all patients with knee osteoarthritis,

stratified for mild to established disease and end-stage disease requiring an

arthroplasty.

Each row represents one patient. Column’s represent 11 different sites of the synovitis

score. (Score ranges from 0-2: 0 = white, 1 = light grey, 2 = dark grey)

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Reference List

(1) Felson DT. Clinical practice. Osteoarthritis of the knee. N Engl J Med 2006;

354(8):841-8.

(2) Yusuf E, Kortekaas MC, Watt I, Huizinga TW, Kloppenburg M. Do knee

abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A

systematic review. Ann Rheum Dis 2011; 70(1):60-7.

(3) Baker K, Grainger A, Niu J, Clancy M, Guermazi A, Crema M et al. Relation of

synovitis to knee pain using contrast-enhanced MRIs. Ann Rheum Dis 2010;

69(10):1779-83.

(4) de Lange-Brokaar BJ, Ioan-Facsinay A, van Osch GJ, Zuurmond AM, Schoones

J, Toes RE et al. Synovial inflammation, immune cells and their cytokines in

osteoarthritis: a review. Osteoarthritis Cartilage 2012; 20(12):1484-99.

(5) Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical

symptoms of osteoarthritis. Nat Rev Rheumatol 2010; 6(11):625-35.

(6) Loeuille D, Chary-Valckenaere I, Champigneulle J, Rat AC, Toussaint F,

Pinzano-Watrin A et al. Macroscopic and microscopic features of synovial

membrane inflammation in the osteoarthritic knee: correlating magnetic

resonance imaging findings with disease severity. Arthritis Rheum 2005;

52(11):3492-501.

(7) Loeuille D, Rat AC, Goebel JC, Champigneulle J, Blum A, Netter P et al.

Magnetic resonance imaging in osteoarthritis: which method best reflects synovial

membrane inflammation? Correlations with clinical, macroscopic and

microscopic features. Osteoarthritis Cartilage 2009; 17(9):1186-92.

(8) Loeuille D, Sauliere N, Champigneulle J, Rat AC, Blum A, Chary-Valckenaere I.

Comparing non-enhanced and enhanced sequences in the assessment of effusion

and synovitis in knee OA: associations with clinical, macroscopic and

microscopic features. Osteoarthritis Cartilage 2011; 19(12):1433-9.

(9) de Lange-Brokaar BJ, Ioan-Facsinay A, Yusuf E, Visser AW, Kroon HM,

Andersen SN et al. Degree of synovitis on MRI by comprehensive whole knee

semi-quantitative scoring method correlates with histologic and macroscopic

features of synovial tissue inflammation in knee osteoarthritis. Osteoarthritis

Cartilage 2013 Dec 21. pii: S1063-4584(13)01047-9. doi: 10.1016/j.joca.2013.12.013

[Epub ahead of print]

(10) Roemer FW, Felson DT, Yang T, Niu J, Crema MD, Englund M et al. The

association between meniscal damage of the posterior horns and localized

posterior synovitis detected on T1-weighted contrast-enhanced MRI--the MOST

study. Semin Arthritis Rheum 2013; 42(6):573-81.

of 29

John Wiley & Sons



26

(11) Guermazi A, Hayashi D, Roemer FW, Zhu Y, Niu J, Crema MD et al. Synovitis

in Knee Osteoarthritis Assessed by Contrast-enhanced Magnetic Resonance

Imaging (MRI) is Associated with Radiographic Tibiofemoral Osteoarthritis and

MRI-detected Widespread Cartilage Damage: The MOST Study. J Rheumatol

2014; 41(3):501-8.

(12) Roemer FW, Kassim JM, Guermazi A, Thomas M, Kiran A, Keen R et al.

Anatomical distribution of synovitis in knee osteoarthritis and its association with

joint effusion assessed on non-enhanced and contrast-enhanced MRI.

Osteoarthritis Cartilage 2010; 18(10):1269-74.

(13) Guermazi A, Roemer FW, Hayashi D, Crema MD, Niu J, Zhang Y et al.

Assessment of synovitis with contrast-enhanced MRI using a whole-joint

semiquantitative scoring system in people with, or at high risk of, knee

osteoarthritis: the MOST study. Ann Rheum Dis 2011; 70(5):805-11.

(14) Altman R, Alarcon G, Appelrouth D, Bloch D, Borenstein D, Brandt K et al. The

American College of Rheumatology criteria for the classification and reporting of

osteoarthritis of the hand. Arthritis Rheum 1990; 33(11):1601-10.

(15) Kornaat PR, Ceulemans RY, Kroon HM, Riyazi N, Kloppenburg M, Carter WO

et al. MRI assessment of knee osteoarthritis: Knee Osteoarthritis Scoring System

(KOSS)--inter-observer and intra-observer reproducibility of a compartment-

based scoring system. Skeletal Radiol 2005; 34(2):95-102.

(16) The Atlas of Standard Radiographs of Arthritis. Rheumatology 2005; 44(suppl

4):iv43-iv72.

(17) Hawker GA, Davis AM, French MR, Cibere J, Jordan JM, March L et al.

Development and preliminary psychometric testing of a new OA pain measure--

an OARSI/OMERACT initiative. Osteoarthritis Cartilage 2008; 16(4):409-14.

(18) Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD. Knee Injury and

Osteoarthritis Outcome Score (KOOS)--development of a self-administered

outcome measure. J Orthop Sports Phys Ther 1998; 28(2):88-96.

(19) Kaiser H. A second generation little jiffy. Psychometrika 1970; 35(4):401-15.

(20) Kaiser H. An index of factorial simplicity. Psychometrika 1974; 39(1):31-6.

(21) Bartlett M. A note on the multiplying factors for various chi-square

approximations. 1989.

(22) Stevens J. Applied multivariate statistics for the social sciences. 1986.

(23) DiStefano C, Zhu M, Mindrila D. Understanding and using factor scores:

Considerations for the applied researcher. Practical Assessment, Research &

Evaluation 2009; 14(20):1-11.

of 29

John Wiley & Sons



27

(24) Dye SF, Vaupel GL, Dye CC. Conscious neurosensory mapping of the internal

structures of the human knee without intraarticular anesthesia. Am J Sports Med

1998; 26(6):773-7.

(25) Buma P. Innervation of the patella. An immunohistochemical study in mice. Acta

Orthop Scand 1994; 65(1):80-6.

(26) Crema MD, Felson DT, Roemer FW, Niu J, Marra MD, Zhang Y et al.

Peripatellar synovitis: comparison between non-contrast-enhanced and contrast-

enhanced MRI and association with pain. The MOST study. Osteoarthritis

Cartilage 2013; 21(3):413-8.

(27) Hill CL, Hunter DJ, Niu J, Clancy M, Guermazi A, Genant H et al. Synovitis

detected on magnetic resonance imaging and its relation to pain and cartilage loss

in knee osteoarthritis. Ann Rheum Dis 2007; 66(12):1599-603.

(28) Mogil JS. The genetic mediation of individual differences in sensitivity to pain

and its inhibition. Proc Natl Acad Sci U S A 1999; 96(14):7744-51.

(29) Colloca L, Benedetti F. How prior experience shapes placebo analgesia. Pain

2006; 124(1-2):126-33.

(30) Wager TD. Expectations and anxiety as mediators of placebo effects in pain. Pain

2005; 115(3):225-6.

(31) Rhodes LA, Grainger AJ, Keenan AM, Thomas C, Emery P, Conaghan PG. The

validation of simple scoring methods for evaluating compartment-specific

synovitis detected by MRI in knee osteoarthritis. Rheumatology (Oxford) 2005;

44(12):1569-73.

(32) Ostergaard M, Klarlund M. Importance of timing of post-contrast MRI in

rheumatoid arthritis: what happens during the first 60 minutes after IV

gadolinium-DTPA? Ann Rheum Dis 2001; 60(11):1050-4.

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Association of pain in knee osteoarthritis with distinct patterns of synovitis

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