The Relationship Between Synovial Pathobiology and ... · PhD, Centre for Experimental Medicine and...

1311Humby, et al: MRI, synovitis, pathobiology

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The Relationship Between Synovial Pathobiology andMagnetic Resonance Imaging Abnormalities inRheumatoid Arthritis: A Systematic ReviewFrances Humby, Arti Mahto, Muaaze Ahmed, Andrew Barr, Stephen Kelly, Maya Buch,Costantino Pitzalis, and Philip G. Conaghan

ABSTRACT. Objective. Magnetic resonance imaging (MRI) has been increasingly recognized as a critical tool forthe assessment of patients with rheumatoid arthritis (RA) and is able to reliably identify synovitis,bone marrow edema, bone erosion, and joint space narrowing (JSN)/cartilage loss. Understandingthe exact relationship between each MRI feature and local synovial pathobiology is critical to dissectdisease pathogenesis as well as develop future predictive models.Methods. A systematic review was performed of the current published literature examining therelationship between MRI abnormalities and synovial pathobiology in patients with RA.Results. Eighteen studies were identified; most focused on validation of MRI as a tool to detect andquantify synovitis, with a significant relationship demonstrated. Additionally, from the limited dataavailable, a critical role seems likely for synovial pathways, at least in driving joint damage. However,there was a lack of data examining the relationship between synovial pathobiology and bone marrowabnormalities and JSN.Conclusion. Although understanding the interrelationship of these disease biomarkers offers thepotential to enhance the predictive validity of modern imaging with concomitant synovial pathobio-logical analysis, further studies integrating MRI with synovial tissue analysis in well-controlledcohorts at distinct disease stages before and after therapeutic intervention are required to achieve this.(First Release July 15 2017; J Rheumatol 2017;44:1311–24; doi:10.3899/jrheum.161314)

Key Indexing Terms:MAGNETIC RESONANCE IMAGING SYNOVITIS PATHOBIOLOGYRHEUMATOID ARTHRITIS BONE MARROW EDEMA

From the Centre for Experimental Medicine and Rheumatology, WilliamHarvey Research Institute, Barts and The London School of Medicine andDentistry, Queen Mary, University of London; Department of Radiology,Barts Health UK National Health Service (NHS) Trust; Department ofRheumatology, Barts Health NHS Trust, London; Leeds Institute ofRheumatic and Musculoskeletal Medicine, University of Leeds and UKNational Institute for Health Research (NIHR) Leeds MusculoskeletalBiomedical Research Centre, Leeds, UK.AB, MB, and PGC are supported in part by the NIHR LeedsMusculoskeletal Biomedical Research Centre.F. Humby, MRCP, PhD, Centre for Experimental Medicine andRheumatology, William Harvey Research Institute, Barts and The LondonSchool of Medicine and Dentistry, Queen Mary, University of London; A. Mahto, MRCP, Centre for Experimental Medicine and Rheumatology,William Harvey Research Institute, Barts and The London School ofMedicine and Dentistry, Queen Mary, University of London; M. Ahmed,FRCR, Department of Radiology, Barts Health NHS Trust; A. Barr, MRCP,

PhD, Leeds Institute of Rheumatic and Musculoskeletal Medicine,University of Leeds and NIHR Leeds Musculoskeletal BiomedicalResearch Centre; S. Kelly, MRCP, PhD, Department of Rheumatology,Barts Health NHS Trust; M. Buch, FRCP, PhD, Leeds Institute ofRheumatic and Musculoskeletal Medicine, University of Leeds and NIHRLeeds Musculoskeletal Biomedical Research Centre; C. Pitzalis, MD,PhD, Centre for Experimental Medicine and Rheumatology, WilliamHarvey Research Institute, Barts and The London School of Medicine andDentistry, Queen Mary, University of London; P.G. Conaghan, MD, PhD,Leeds Institute of Rheumatic and Musculoskeletal Medicine, University ofLeeds and NIHR Leeds Musculoskeletal Biomedical Research Centre.Address correspondence to Dr. F. Humby, Centre for ExperimentalMedicine and Rheumatology, William Harvey Research Centre, John VaneScience Centre, Charterhouse Square, London EC1M 6BQ, UK. E-mail: [email protected] for publication May 11, 2017.

Magnetic resonance imaging (MRI) is an excellent tool todelineate pathology in rheumatoid arthritis (RA) becauseit can define bone, cartilage, fluid, and soft tissues. Thisis possible because MRI can delineate structures with highwater content on T2-weighted fat-suppressed or short-tauinversion recovery sequences, and following injection ofgadolinium-DTPA (Gd-DTPA), regions of high vascu-larity. Thus, feasibly MRI can quantify both synovialvolume and inflammation and act as a surrogate nonin-

vasive marker of histological inflammation. Specific MRIfeatures of RA synovial joints have been demonstrated tobe of particular prognostic value: synovitis, bone marrowedema (BME), bone erosions, and cartilage thinning. MRIhas the capacity to detect bone erosions 2 years earlier1than plain radiographs and sensitivity to detect changeeven in small cohorts2, an effect that is of criticalrelevance given the capacity of improved treatmentalgorithms to halt joint damage3. Consequently, MRI is

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now well recognized as a robust outcome measure in clinicaltrials. Historically, the pathological events leading to jointdamage in RA have been suggested to be a sequence ofprimary synovitis leading to BME, cartilage thinning, andfinally erosions. There is increasing data to challenge thismodel. First, although a significant relationship betweenBME and synovitis4 and between synovitis and the devel-opment of bone erosions has been demonstrated5, debateregarding the exact contribution of synovitis/BME in initi-ating and/or sustaining bone erosion continues6 with someevidence suggesting that BME per semay be an independentpredictor of erosive progression4,7,8,9,10,11,12,13. Further, thereis evidence primarily from MRI studies to support a bio-mechanical effect on erosive progression14. Second, MRIstudies have noted BME and erosions as early events, withcartilage thinning occurring later15. Third, a number ofradiographic studies have reported an incongruent relation-ship between cartilage thinning and erosions15,16. Finally,recent data have demonstrated an association between MRI-documented BME, synovitis, baseline cartilage damage, andsubsequent cartilage loss17. These observations raise anumber of fundamental questions regarding mechanisms ofjoint damage and in particular whether synovial pathobio-logical pathways initiate and/or sustain a local environmentthat drives BME, erosions, and/or cartilage thinning. It was within this context that a systematic literaturereview was conducted to assess published data investigatingthe relationship between RA synovial pathobiology and MRIBME, synovitis, erosions, and cartilage thinning.

MATERIALS AND METHODSThe study methodology was conducted in line with the PRISMA (PreferredReporting Items for Systematic reviews and Meta-Analyses) guidelines18 andwas registered with PROSPERO (www.crd.york.ac.uk/NIHR_PROSPERO,registration CRD42016033875). Because this was a systematic review, noethics approval was sought, in accordance with the policy of Barts HealthNHS Trust.Search strategy. Relevant articles, reviews, and abstracts were identifiedthrough an initial search of EMBASE, MEDLINE, and the Cochrane Libraryfor articles published up to March 2016. The MEDLINE MeSH keywordsearch terms (rheumatoid arthritis, rheumatoid and arthritis, RA, rheumatoid,inflammatory arthritis, nuclear magnetic resonance imaging, magnetic ANDresonance AND imaging, synovitis, synovi, pathology, histopathology,immunohistochemistry, pathol, histo, immune, joint surgery, arthroscopy,biopsy, joints, surgery) and adopted Boolean operators are presented in Table1. These were modified to accommodate each search database. EMBASEand Cochrane search terms are presented as Supplementary Tables 1 and 2,respectively, available from the authors on request.Eligibility criteria. Studies including patients with RA undergoing an MRIscan of a peripheral synovial joint along with sampling of synovial tissuewere eligible. Outcome measures for MRI scanning included BME, jointerosion, synovitis, and cartilage thickness. Outcome measures for synovialtissue included macro/microscopic histological assessment and immunohis-tochemical and gene expression analysis. To be included within the review,studies had to directly compare 1 MRI RA feature with 1 or more synovialoutcome measures. All types of study designs were included and analysiswas restricted to humans. Articles not in English, with no translation

available, and abstracts with no corresponding full-text article wereexcluded. Two reviewers (FH and AM) independently reviewed the titles andabstracts from potentially relevant articles identified through the searchstrategy. Both reviewers assessed the full texts of all potentially eligiblearticles.Data extraction. Data were entered onto a predefined data extraction table.For each study, the following data were recorded regarding study design:type of study, disease stage (e.g., early vs established disease), procedure forsynovial sampling, time interval between synovial sampling and MRI scan,whether concomitant disease-modifying antirheumatic drugs (DMARD)and/or steroid therapy were controlled for, joint imaged, and joint biopsied.The following MRI variables were also recorded: MRI feature scored, acqui-sition strength, and method of assessment of MRI features. Additionally, thefollowing variables regarding synovial tissue analysis were recorded:number of synovial samples taken, procedure for synovial tissue preparation,macroscopic assessment of synovium, histological assessment of H&Estained samples, immunohistochemical assessment, synovial geneexpression analysis, and main conclusions. Data extraction was performedby 1 reviewer (FH) and was verified by a second (AM). Any disagreementsregarding data extraction were resolved following discussion among thereviewers.Quality assessment. The quality of each study was independently assessedby 2 reviewers (FH and AM) using an adapted standardized quality scoringtool (Supplementary Table 3, available from the authors on request)19,20 toassess the following components: (1) study population, (2) MRI assessmentand scoring, (3) histological assessment, and (4) study design and analysisand data presentation. A score of “1” or “0” was allocated for each questionaccording to whether the study fulfilled the criteria or not, respectively. Astudy was considered to be high quality if it exceeded or equaled the meanscore (% of total) in its class [cross-sectional vs randomized controlled trial(RCT) vs cohort study].

RESULTSSearch strategy. A summary of the results of the searchstrategy is presented in the PRISMA flow chart shown inFigure 1. This indicates that a total of 505 articles wereidentified. Following the exclusion of duplicates (n = 117)and review articles (n = 103), 273 articles were screened. Ofthese, 237 were excluded (134 because they did not includepatients with RA, 91 because they did not include histopatho-logical analysis of synovial tissue, 10 because they wereexaminations of tissue in vitro or in animal models, and 2because no MRI scans were included). Of the remaining 36articles, 18 were then excluded: 2 because no English trans-lation was available, 5 because of no synovial histopatho-biological examination (3 had no synovial histology and 2had synovial explants in vitro only), 1 because there was nocomparison of MRI and synovial pathobiology (not relevantto task), 4 because they did not include patients with RA, and6 because they were abstracts only with no full text (Supple-mentary Table 5, available from the authors on request).Eighteen articles were then identified that satisfied the eligi-bility criteria and were therefore included in the review.Characteristics of included studies. A summary of the charac-teristics of the 18 studies is presented in Table 2 (MRI characteristics) and Table 3 (histopathobiological charac-teristics)21–30,31,32,33,34,35,36,37,38,39. A total of 442 participantswere included in the analyses from the 18 studies. Of these,

1312 The Journal of Rheumatology 2017; 44:9; doi:10.3899/jrheum.161314






Table 1. The MEDLINE MeSH keyword search terms and Boolean operators from 1946 to present.

1 Exp *RHEUMATOID ARTHRITIS/ 19 Exp*IMMUNOHISTOCHEMISTRY2 (Rheumatoid AND arthritis).ti,ab 20 Pathol*. ti,ab3 RA.ti,ab 21 Histo*.ti,ab4 Rheumatoid.ti,ab 22 Immuno*.ti,ab5 “inflammatory arthritis”.ti,ab 23 17 OR 18 OR 19 OR 20 OR 21 OR 22 OR 236 1 OR 2 OR 3 OR 4 OR 5 24 Exp *JOINT SURGERY/7 Exp *NUCLEAR MAGNETIC 25 Exp *ARTHROSCOPY RESONANCE IMAGING/8 (magnetic AND resonance AND imaging).ti,ab 26 Exp*BIOPSY/9 MRI.ti,ab 27 Exp*JOINT/10 DCE.ti, ab 28 Surgery.ti,ab11 (magnetic AND resonance AND imag*).ti,ab 29 Arthroscopy.ti,ab12 7 OR 8 OR 9 OR 10 OR 11 30 Joint.ti,ab13 6 AND 12 31 Biopsy.ti,ab14 Exp *SYNOVITIS/ 32 24 OR 25 OR 26 OR 27 OR 28 OR 29 OR 3015 Synovi*, ti.ab 33 16 AND 23 AND 3216 14 OR 15 34 13 AND 3317 Exp *PATHOLOGY/ 34 [Limit to: Human and English Language]18 Exp *HISTOPATHOLOGY/

RA: rheumatoid arthritis; MRI: magnetic resonance imaging; DCE: dynamic contrast-enhanced.

Figure 1. PRISMA flow chart presenting the results of the search strategy. PRISMA: PreferredReporting Items for Systematic reviews and Meta-Analyses; RA: rheumatoid arthritis; MRI:magnetic resonance imaging.





Table 2.

Summ

ary of

studie

s dire

ctly co

rrelati

ng MR

I featu

res wi

th syn

ovial p

athobi

ology:

MRI

chara

cteris

tics.

Study

D

escrip

tion

E

arly v

s S

ynovia

l Sam

pling

Time f

rom M

RI

Conc

omitan

t

Jo

int As

sessed

MRI

E

st RA

T

echniq

ue/joi

nt

to Sy

novial

D

MARD

/steroi

d

by M

RI/bi

opsy

F

eature

Score

d

Acqu

isition

As

sessm

ent

S

ample

d

S

ampli

ng

Ther

apy Co

ntroll

ed? S

ite Pre

determ

ined

by

MRI

Image

?

Konig

, et al

30

Case-

contro

l cross

-sectio

nal

E

st

Ar

throsc

opic a

nd

3 we

eks

No

/no

Knee

yes

Syn

ovial

memb

rane,

1.5T

+ con

trast

DCE w

ith

st

udyof

20 RA

and 2

contr

ols (O

A).

a

rthrop

lastic/

knee

joint

capsul

e, hyal

ine

RO

I anal

ysis

8

pts w

ith pa

ired M

RI and

synov

ial

cartil

age, su

bchon

dral b

one

t

issue

data. M

ain aim

of stu

dy wa

s to

m

arrow

, juxta

articu

lar

c

ompar

e T1 a

nd con

trast-e

nhance

d T2-w

eighte

d

m

uscle t

issue,

pann

us

MRI im

ages w

ith hi

stolog

ical ev

idence

of sy

novit

is.

Tamai, et al2

1

Cross-

sectio

nal stu

dy of

Est

Arthr

oplast

ic/knee

1–

15 day

s No

/intra

articu

lar ste

roid

K

nee/ye

s

Syno

vitis

1.5T

+ con

trast

DCE

9 RA

. To c

larify

wheth

er sig

nal

f

or 3 m

os pri

or to

study

enhan

cement

in dy

namic M

RI is

i

nclusi

on or

during

inter

val

depend

ent on

the s

everity

of pa

tholog

ic

betw

een M

RI an

d arth

roplas

ty

findi

ngs in

the r

heuma

toid s

ynoviu

m.

w

as not

perm

itted.

Ga

ffney,

et al2

4

Cross-

sectio

nal stu

dy

Est

Bl

ind ne

edle

J

ust pr

ior*

No

/no

Knee/

no

S

ynov

itis

0.5T +

contr

ast

DCE

of 21

RA to

devel

op a m

ethod

for

bio

psy/kn

ee

quant

ifying

acute

synov

ial

in

flamm

ation i

n RA u

sing M

RI.

Gaffn

ey, et al2

5

Cros

s-sect

ional s

tudy o

f

Es

t

B

lind n

eedle

Just p

rior*

No/no

K

nee/no

Syno

vitis

0.5T

+ con

trast

DC

E

21

RA. T

o deve

lop a q

uantita

tive

biopsy

/knee

techni

que fo

r asse

ssing

synovi

al

va

scular

ity ba

sed up

on con

trast-

enh

anced

MRI.

Os

tergaa

rd, et al2

2 Cros

s-sect

ional s

tudy o

f 17 R

A

Est

Arth

roscop

ic or

1–2

5 days

No/no

Kn

ee/yes

Syn

ovial

volum

e

1.5T +

contr

ast S

tatic (

quant

itative

and 25

OA jo

ints. T

o eval

uate th

e

ar

thropl

astic/k

nee

asse

ssment

)

r

elatio

nship

betwe

en syn

ovial

mem

brane

and jo

int ef

fusion

v

olume

s dete

rmine

d by M

RI

and

macr

oscopi

c and

micro

scopic

s

ynovia

l path

ologic

findin

gs

in p

ts with

RA an

d OA.

Osterg

aard, e

t al23

Cro

ss-sec

tional

study

of 17

RA

Est

Arth

roscop

ic or

1–2

5 days

No/no

Kn

ee/yes

Syno

vitis

1.5T

+ con

trast

Stati

c (qu

antitat

ive

and 25

OA jo

ints. T

o eval

uate d

ynami

c

arthr

oplast

ic/knee

assess

ment)

and D

CE

as we

ll as s

tatic G

d-enha

nced M

RI as

m

easure

s of sy

novia

l infla

mmatio

n

in

arthr

itis, by

comp

arison

with

macro

scopic

and m

icrosc

opic s

ynovia

l path

ology.

Veale

, et al

37

RC

T of 1

3 RA w

ith ac

tive

E

st

Ar

throsc

opic/k

nee

Same

day

Yes/y

es, sta

ble

Knee

/yes

S

ynov

itis

1.5T +

contr

ast

DCE

r

esista

nt kne

e syn

ovitis

random

ized

DMAR

D/ste

roid d

oses

to i

ntraar

ticular

injec

tion o

f

f

or 3 m

os pri

or

placeb

o, 0.4 m

g or 4

0 mg o

f anti

-CD4.

to

study

entry

Under

went

MRI a

nd bas

eline a

nd

D

ay 42

synovi

al biop

sy.





Table 2.

Conti

nued.

Study

D

escrip

tion

Ea

rly vs

Sy

novial

Sampli

ng

Tim

e from

MRI

C

oncom

itant

Joint

Asses

sed

MRI

E

st RA

T

echniq

ue/joi

nt

to Sy

novial

D

MARD

/steroi

d

by M

RI/bi

opsy

F

eature

Score

d

Acqu

isition

Asse

ssment

Sam

pled

Sam

pling

T

herapy

Contr

olled?

Site

Predet

ermine

d

by M

RI Im

age?

Osten

dorf, et al2

6 Cr

oss-se

ctional

study

of 22

RA.

Earl

y

Mini

arthr

oscopy

/

24 h

No

/no

MCP

/no

Sy

novia

l volu

me,

1.5T +

contr

ast

SQ a

ssessm

ent,

Ai

m wa

s to ev

aluate

MRI

findin

gs in

(< 1.5

yr, 9

pts)

M

CP

syn

ovial

activi

ty, eff

usion

,

0–

3, of

each o

f 7

t

he MC

P join

ts of p

ts w/RA

+ Es

t (13 p

ts)

joint

space

narro

wing,

M

RI var

iables

ma

crosco

pically

using

mini

arthro

scopy.

bon

y alter

ations,

t

enosyn

ovitis

, BME

Takase

, et al

27

Cro

ss-sec

tional

study

of 10

RA

Est

Arthr

oplast

ic/knee

24 h

No

/no

K

nee/bi

opsy

Sy

novit

is

1

.5T +

contra

st

OME

RACT

-

and 5

OA. T

o sim

ultane

ously

exami

ne

si

te dete

rmine

d by

R

AMRIS

SQ, 0

–3

US, M

RI, an

d histo

pathol

ogy of

joint

preop

erativ

e US s

can

lesio

ns in

RA or

OA pt

s who

requir

ed

knee

joint

arthr

oplas

ty.

Ax

elsen,

et al2

8 Cr

oss-se

ctional

study

of 17

RA.

Est

Arthr

oplast

ic/knee

0

–25 da

ys

No

/no

Knee

/yes

S

ynov

itis

1

.5T +

D

CE (se

miaut

omatic

T

o dete

rmine

wheth

er DC

E-MRI

evalua

ted

con

trast

quant

ificatio

n)

using

semiau

tomatic

image

proce

ssing

softw

are ca

n accu

rately

asses

s

s

ynovia

l infla

mmatio

n in R

A knee

joint

s.

Buch,

et al3

3

Pr

ospect

ive co

hort st

udy

Est

A

rthros

copic/k

nee

0–2

days

Yes/y

es, sta

ble

Knee

/no

S

ynov

itis

1.5T +

contr

ast

DCE

(in

terven

tional

open-

label c

linica

l trial)

doses

of DM

ARD 2

8 days

of 16

TNFi-

resista

nt RA

pts. M

RI and

pri

or to

inclus

ion/ lo

w dose

synovi

al biop

sy we

re per

forme

d at

cor

ticoste

roids

permi

tted.

b

aselin

e and

16 we

eks fo

llowi

ng IV

ABA

therap

yto d

eterm

ine th

e syno

vial

eff

ect of

ABA.

Ki

rkham

, et al

38

Pros

pectiv

e coho

rt stud

y of

Early

(34%

A

rthros

copic/

B

aselin

e stud

y

N

o/no

2n

d–5th

B

one er

osion

1.5T

OMER

ACT-

60 pt

s w/RA

. To e

xplain

the w

ide

< 2 y

rs) +

Est

knee

asses

sment

s

MCP

joint

s/no

R

AMRIS

MRI

score

var

iabilit

y in j

oint d

amage

progr

ession

from

measu

res of

patho

logic c

hanges

in

th

e syno

vial m

embra

ne.

Vo

rdenbä

umen,

et al3

1 Cros

s-sect

ional s

tudy o

f

NA

Arthr

oscopi

c/MCP

U

p to 1

week

prior

P

artial

all

MC

P2/N

o

Syn

ovitis

3

T + co

ntrast

DCE

9

pts. T

he obj

ective

was to

analy

ze

p

ts MTX

,

wh

ether

MRI sy

novit

is rela

tes to

+

6 pts

hi

stolog

ical si

gns of

synov

itis in

biol

ogic/N

A

s

mall R

A join

ts.

Vor

denbäu

men, et al

35

Cross-

sectio

nal stu

dy of

NA

Arthr

oscopi

c/MCP

U

p to 1

week

prior

Part

ial, all

on

Do

minan

t MCP

/no

Syno

vitis/B

ME/

3T

+ con

trast

RAM

RIS

10 pt

s to an

alyze

wheth

er

M

TX +/

eros

ion

(6 pt

s), 0.2

T +

s

ynovia

l mark

ers wi

thin

adal

imum

ab/NA

c

ontra

st (4 p

ts)

an MC

P join

t refle

ct glob

al

dis

ease a

ctivity

meas

ures in

RA.

An

andara

jah, et al

32 R

etrosp

ective

cohor

t study

Est

A

rthrop

lastic/

knee,

1–4 m

os pri

or

No/no

Kn

ee (5)

, wris

t (5),

Syn

ovial

prolife

ration

,

1.5T

+ con

trast

S

Q scor

e, 0–3

of 1

5 pts r

ecruit

ed to

exami

ne

wrist,

hip,

elbow

,

h

ip (2)

, elbow

(2),

BME

, effus

ion,

wh

ether

RA pt

s who

meet

t

humb

thum

b (1)/

no

eros

ion

remi

ssion

criter

ia mani

fest

infl

amma

tory s

ynovit

is. 7 p

ts

inc

luded

with p

aired

MRI/sy

novial

tissue.





Table 2.

Conti

nued.

Study

D

escrip

tion

E

arly v

s S

ynovia

l Sam

pling

Time f

rom M

RI

Conc

omitan

t

Jo

int As

sessed

MRI

E

st RA

T

echniq

ue/joi

nt

to Sy

novial

D

MARD

/steroi

d

by M

RI/bi

opsy

F

eature

Score

d

Acqu

isition

Asse

ssment

Sam

pled

Sam

pling

T

herapy

Contr

olled?

Site

Predet

ermine

d

by M

RI Im

age?

Param

arta, e

t al29

Cros

s-sect

ional s

tudy i

n 41 p

ts

Early

Mini-

arthro

scopy/

Not

report

ed

Yes/y

es

Knee,

ankle

/no

S

ynov

itis, en

thesiti

s

1.

5T +

contra

st

SQ s

core, 0

–3

(2

0 RA,

13 Sp

A, 8 o

ther)a

imed

(

< 12 m

os)

kne

e, ankl

e

to c

ompar

e the p

resenc

e and

extent

of

synovi

tis and

enthe

sitis in

early

untre

ated S

pA an

d RA b

y pair

ed MR

I

a

nd syn

ovial h

istopat

hology

.

Kenne

dy, et al3

4

Pro

spectiv

e coh

ort stu

dy of

Est

N

eedle a

rthros

copy/

2

4–72 h

r prio

r

N

o/no

Kn

ee/no

Syno

vitis

1.5T

+ con

trast

D

CE SQ

, 0–3

1

6 RA a

nd 4 P

sA. T

he aim

was to

k

nee

comp

are th

e effe

ct of T

NF-bl

ocking

the

rapy o

n hyp

oxia in

vivo,

macr

oscop

ic

and

micro

scopic

infla

mmatio

n, and

MRI

variab

les us

ing se

quenti

al MRI

and sy

novial

biopsy

.

Ma

ijer, et al

36

Prospe

ctive c

ohort s

tudy

Early

(< 1

yr)

Arthr

oscopi

c

Not d

efined

D

MARD

-naive

/

Knee

Sy

novit

is

1

.5T +

contra

st D

CE (q

uantita

tive

of 47

early

arthr

itis pt

s (14 R

A,

not de

fined

as

sessm

ent us

ing

22 unc

lassifi

ed, 6 S

pA, an

d

phar

m. m

odelin

g)

5 o

ther a

rthriti

des). T

he aim

was

to

exam

ine wh

ether

DCE-M

RI can

be

used

as an

object

ive m

easure

of

s

ynovia

l infla

mmatio

n usin

g phar

m. m

odelin

g.

* Exac

t timi

ng not

speci

fied.

MRI: m

agnetic

reson

ance i

magin

g; Est

: esta

blishe

d; RA

: rheum

atoid

arthri

tis; D

MARD

: dise

ase-m

odifyi

ng ant

irheum

atic dr

ug; O

A: ost

eoarth

ritis; G

d: gad

oliniu

m; RC

T: ran

domi

zed co

ntroll

ed tria

l; MCP

:me

tacarp

ophala

ngeal;

US: u

ltrasou

nd; DC

E: dyn

amic c

ontras

t-enha

nced;

TNFi:

tumo

r necr

osis fa

ctor in

hibito

r; ABA

: abata

cept; S

pA: sp

ondylo

arthri

tis; Ps

A: pso

riatic

arthri

tis; pt

s: patie

nts; N

A: no

t availa

ble; M

TX: m

ethotr

exate;

BME:

bone m

arrow

edem

a; ROI

: regio

n of in

terest

; SQ:

semiqu

antitat

ive; O

MERA

CT: O

utcom

e Meas

ures in

Rheum

atolog

y; RA

MRIS:

Rheum

atoid A

rthriti

s Magn

etic Re

sonanc

e Ima

ging S

coring

; phar

m.: p

harma

cokine

tic; IV

: intra

venou

s; .





Table 3.

Summ

ary of

studie

s dire

ctly co

rrelati

ng MR

I featu

res wi

th syn

ovial p

athobi

ology:

histo

biolog

ical ch

aracte

ristics

.

Study

No. B

iopsie

s

Macr

oscopi

c Asse

ssment

R

outine

H&E A

ssessm

ent

IH

C Anal

ysis

S

ynov

ial Ge

ne

M

ain Co

nclusi

on

of Sy

novium

Expre

ssion

Analy

sis

Konig

, et al

30

8–1

2 from

diffe

rent lo

cation

s

No

Grade

d into

1 of

3 grou

ps: fib

rous,

No

No

DC- M

RI is a

ble to

distin

guish

joint

effus

ion fro

m

sligh

tly hy

pervas

cular,

and hy

pervas

cular

hyp

ervasc

ular p

annus

and to

grade

the v

ascula

rity of

sy

novit

is (on

ly des

cripti

ve sta

tistics

repo

rted)

Tamai, et al2

1

1 s

ample

from

each o

f 3 sit

es

No

8 hi

stolog

ical fe

atures

asses

sed SQ

(0–3)

N

o

No

Rate

and d

egree

of sig

nal en

hancem

ent wi

th dy

namic

(tota

l no. n

ot def

ined)

f

ibrin

exudat

ion, P

MN ce

ll infi

ltratio

n, mo

nonucl

ear

im

aging

signif

icantl

y corr

elated

with

histol

ogica

l

cell i

nfiltra

tion,

multip

licatio

n of sy

novioc

yte lin

ing

inflam

matio

n (p <

0.05

, Mann

-Whit

ney U)

laye

r, villo

us hyp

ertrop

hy of

synovi

al surf

ace,

pro

liferat

ion of

blood

vesse

ls, for

matio

n of g

ranula

tion

t

issue,

and f

ibrosi

s

Gaffn

ey, et al2

4

Not d

efined

No

S

Q histo

logica

l score

0–3,

3 histo

logica

l

No

N

o

Rate

of sy

novia

l mem

brane

enhanc

ement

corre

lated w

ith

fe

atures

: PMN

infilt

ration

, fibri

n, and

hyper

emia

h

istolog

ic feat

ures o

f acute

inflam

matio

n (r =

0.63, p

< 0.01

)Ga

ffney,

et al2

5

No

t defi

ned

N

o

N

ot ass

essed

E

ndothe

lial ce

ll mark

er

No

G

d-DTP

A–enh

anced

MRI c

orrela

tes wi

th his

tolog

ically

(Qb

end30)

asses

sed by

DIA

det

ermine

d syn

ovial

vascul

arity

(r = 0.

55, p

< 0.0

2)Os

tergaa

rd, et al2

2

4

biop

sy site

s

SQ m

acrosc

opic

9 feat

ures:s

ubsyno

vial in

filtrat

ion of

PMN

N

o

No

MRI-d

eterm

ined s

ynov

ial vo

lumes

are co

rrelate

d with

(tota

l no. n

ot def

ined)

as

sessm

ent

l

eukocy

tes, su

bsynov

ial inf

iltratio

n of

s

ynov

ial inf

lamma

tory a

ctivity

(r = 0

.55, p

< 0.0

01)

int

ra-ope

rative

ly, 0–3

mo

nonucl

ear leu

kocyte

s, surf

ace fib

rin

depos

ition,

multip

licatio

n of th

e syno

vial li

ning,

vil

lous h

ypertro

phy of

synov

ial sur

face, p

rolife

ration

of b

lood v

essels

, peri

vascul

ar ede

ma, fo

rmatio

n of

granu

lation

tissue,

and f

ibrosi

s(SQ s

core 0

–3)

Oster

gaard,

et al2

3

4 biop

sy site

s

No

Same a

s Oste

rgaard

, et al

22

N

o

No

Early

enhan

cement

rate o

f the to

tal

(t

otal n

o. not

define

d)

syn

ovial

memb

rane w

as sig

nifica

ntly c

orrela

ted

w

ith hi

stolog

ic grad

e of sy

novia

l infla

mmato

ry

ac

tivity

(r = 0

.73, p

< 10

–7)

Veale

, et al

37

1 b

iopsy

from

each s

ite Hy

perem

ia (0–1

), gran

ulatio

n L

ining

layer

hyperp

lasia (

SQ 0–

3)

T c

ells [C

D3, C

D4

No

Th

e most

signif

icant

correl

ations

were

obser

ved

(total

no. no

t defi

ned)(0

–1), o

r villo

us hyp

ertrop

hy

(

OKT4

), CD8

], B ce

lls

betwe

en the

MRE

at the

SPP R

OI an

d

(0–2)

+ ove

rall im

pressi

on of

(C

D20),

macr

ophage

s

art

hrosco

pic VA

S for

synov

itis (r

= 0.77

,

the

synov

ial inf

lamma

tion

(C

D68),

and M

HC

p =

0.00

3) and

betwe

en the

MRE

and

VAS 0

–100 m

m

class

II.SQ a

nalysi

s 0–5

imm

unoh

istolog

ical C

D4 sc

ore (r

= 0.70

, p =

0.11)

Osten

dorf, et al26

4–6 bi

opsies

6

variab

les (e

xtent

Syno

vial h

yperpl

asia, f

ibrosi

s,

No

No

S

ynov

ial enh

ancem

ent on

MRI

correl

ated

from

2 pts

of sy

novitis

,

vas

culari

ty, lym

phocyt

e and

strom

al

with

mini

arthro

scopy

findin

gs of

hyper

emia

syn

ovial t

hicken

ing,

cell

infiltr

ation,

and fib

rin

(

p = 0.

0038

), and

vascu

larity

(0.00

58).

hyper

emia,

prolife

ration

,

d

epositi

on

S

ynov

ial thi

ckenin

g on m

iniart

hrosco

py wa

s

v

ascula

rity, fi

brosis

) +

si

gnific

antly

associ

ated w

ith sy

novia

l

1 i

tem ea

ch for

bony

and

p

rolife

ration

on M

RI (p

= 0.00

63).

cart

ilagino

us cha

nges

No

form

al eval

uation

of m

icroh

istolog

ical

(SQ

asses

sment

, 0–3)

ass

ociatio

ns rep

orted

Takase

, et al

27

No

t defi

ned

No

Sy

novitis

score

(infla

mmato

ry cel

l

DIA I

HC as

sessm

ent

No

M

RI syn

ovitis

signif

icantl

y corr

elated

with

in

filtrat

es, sy

novial

lining

layer

of

sublin

ing m

acrop

hages

total s

ynov

itis sc

ore (r

= 0.48

,

thick

ness +

vascu

larity

), SQ 0

–3

(CD68)

, cell p

rolife

ration

p

< 0.0

5) and

infla

mmato

ry cel

l

(

Ki67)

, and n

eoangi

ogenes

is (CD

31)

infiltr

ates (0

.47, p

< 0.0

5)Ax

elsen,

et al2

8

4 (to

tal no

. not d

efined

)

No

SQ

synov

itis sc

ore (0

–3,

N

o

No

Init

ial rat

e of e

nhanc

ement

from

the qu

ick

9 his

tologi

cal fe

atures

)

RO

I and

the p

recise

ROI re

vealed

high

co

rrelati

ons w

ith th

e grad

e of h

istolog

ical

in

flamm

ation (

r = 0.

70, p

< 0.0

01 an

d

r = 0.

74, p

< 0.0

01, re

spectiv

ely)





Table 3.

Conti

nued.

Study

No. B

iopsie

s

Macr

oscopi

c Asse

ssment

Rout

ine H&

E Asse

ssment

IH

C Anal

ysis

S

ynov

ial Ge

ne

Main

Concl

usion

of

Synov

ium

Ex

pressi

on An

alysis

Buch,

et al3

3

6

No

No

T

cells (

CD3,

CD154

, CD4

),

qRT

-PCR

S

ignific

ant co

rrelati

on be

tween

MRI sy

novit

is

APC

(CD8

0, CD

86), B

cells

(CD20

, (IL-1

, IL-6,

scor

es (in

itial ra

te of e

nhanc

ement

C

D79),

synov

ial fib

roblas

ts (CD

55),

MMP

-1,

and

maxi

mum

enhanc

ement

) and

IFN-

γ

in

tracel

lular

adhesi

on mo

lecule

s M

MP-3,

wa

s obse

rved (

r = 0.

63 an

d r =

0.79,

(

CD54)

, macr

ophage

s (CD6

8) and

IF

N-γ)

re

spectiv

ely)

CD11b

+ neut

rophil

s, macr

ophag

es,

and de

ndritic

cells.

SQ as

sessm

ent,

0–4,

of all

variab

les in

lining

and

subli

ning

Kirkha

m, et al3

8

3–4

(total

no.

N

o

SQ

analy

sis of

lining

layer

No

qRT-P

CR

Histo

logic f

eature

s had

no re

lation

ship t

o

no

t defi

ned)

thi

ckness

, vasc

ularity

, subli

ning

IFN-

γ,

d

amage

prog

ressio

n. mR

NA lev

els of

fibros

is, and

cellu

lar in

filtrat

es

T

NF-α,

IL-1

β, TN

F-α, IL

-17, an

d IL-1

0 were

predi

ctive

an

d patte

rns (p

erivas

cular,

diffus

e,

IL-

16,

of

joint

damage

prog

ressio

n (mu

ltivari

ate

or

focal

aggre

gates)

IL

-1β,

regres

sion a

nalysi

s, r2 = 0

.57)

IL-1

7,

R

ANKL

,

an

d IL-1

0Vo

rdenbä

umen,

et al3

1

6 b

iopsie

s

Limited

to di

rectio

n

Krenn

score

39

Su

blinin

g CD6

8 scor

e

No

M

aximu

m enh

ancem

ent of

the M

CP sig

nifica

ntly

of

biops

ies

co

rrelate

d with

subli

ning C

D68 s

taining

(r =

0.750

, p =

0.02)

and sy

novit

is scor

e

(r = 0

.743,

p = 0.

02)

Vorde

nbäum

en, et al3

5

6 b

iopsie

s

No

Kr

enn sc

ore39

Subli

ning C

D68 s

core,

No

VEGF

staini

ng co

rrelate

d with

BME (

r = 0.

676,

VEG

F, and

hypoxi

a-ind

ucible

p =

0.03

2) and

erosi

on sc

ores (r

= 0.6

95,

fac

tor 1α

(HIF-

1α)

p

= 0.0

26) o

f RAM

RISAn

andara

jah, et al

32

N

A

No

Krenn

score

39(m

odifie

d)

No

No

No s

tatistic

al corr

elatio

nbetw

een sy

novia

l

score

s on M

RI and

syno

vial h

yperp

lasia o

n histo

logy

Param

arta, e

t al29

As

sume 6

biops

ies

No

No

CD3

, CD2

2, CD

68, CD

163,

vWF

No

Sign

ificant

assoc

iation

betwe

en MR

I syno

vitis

and

CD68

+ sub

lining

macr

ophag

e num

ber

in

RA/Sp

A (r =

0.68

6, p =

0.00

1)Ke

nnedy

, et al

34

NA

Syno

vitis a

nd vas

culari

ty

N

ot rep

orted

CD3

, CD6

8, CD

4,

No

Chan

ge in

MRI sc

ore af

ter TN

F bloc

king t

herapy

(V

AS 0–

100 m

m)

CD8,

CD20,

CD19

, and

w

as sig

nifica

ntly a

ssocia

ted wi

th cha

nges

fact

or VI

II/αSM

A

in

macro

scopic

syno

vitis (

p = 0.

056),

sublin

ing CD

68 (p

< 0.0

02), a

nd su

blinin

g

CD4

cell n

umber

(p =

0.032

)Ma

ijer, et al

36

6 bi

opsies

No

No

vW

F

No

De

monst

rates

that D

CE-M

RI ph

arm.

vari

ables

differ

betwe

en dif

ferent

diagn

ostic

ca

tegori

es and

corre

late wi

th loc

al (syn

ovial

vWF)

an

d syst

emic m

arkers

of di

sease

activi

ty

MRI: m

agnetic

reson

ance im

aging

; IHC:

immu

nohisto

chemi

cal; N

A: no

t availa

ble; S

Q: se

miqua

ntitati

ve; VA

S: vis

ual an

alog s

cale; P

MN: p

olymo

rphonu

clear;

DIA:

digital

image

analy

sis; V

EGF:

vascul

ar end

othelia

l grow

th fac

tor; v

WF:

von W

illebra

nd fac

tor; qR

T-PCR

: quant

itative

real-ti

me PC

R; IL-

1: inte

rleuki

n 1; M

MP: m

atrix m

etallo

protea

se; IF

N-γ: i

nterfe

ron-γ;

TNF-α

: tumo

r necr

osis fa

ctor-α

; RAN

KL: re

ceptor

activ

ator o

f nucl

ear fac

tor-κB

ligand

; Gd: g

adolin

ium;

SPP:

suprap

atellar

pouch

; phar

m.: p

harma

cokine

tic; RO

I: regi

on of

inter

est; M

CP: m

etacar

pophal

angeal

; BME

: bone

marr

ow ed

ema; R

AMRI

S: Rh

eumato

id Arth

ritis M

agnetic

Reson

ance I

magin

g Scor

ing; R

A: rhe

umato

id art

hritis;

SpA:

spond

yloart

hritis;

DCE:

dynam

ic cont

rast-e

nhance

d; APC

: antig

en-pre

sentin

g cell;

HIF:

hypoxi

a-indu

cible f

actor;

MRE

: maxi

mal ra

te of e

nhance

ment.



327 had RA, 19 spondyloarthropathy, 4 psoriatic arthritis, 55osteoarthritis, 2 healthy controls, and 35 other arthritic condi-tions. Eleven studies were cross-sectional observationalstudies21–30,31 and 1 study was a retrospective analysis32.Four studies were prospective open-label clinical trials33,34,35,36,1 study was a blinded RCT37, and 1 study was a prospectiveobservational clinical study38. Fifteen studies includedpatients only with established RA (although exact diseaseduration was not specified in 2 of these studies31,35) and 3studies specifically included patients with disease durationof < 2 years26,36,38. Fourteen studies sampled synovium fromthe knee joint and 4 studies included samples from smalljoints26,31,32,35. Variable methods for synovial sampleretrieval were reported: 7 studies using arthro-scopy29,31,33,34,36,37,38, 4 arthroplasty21,27,28,32, and 3 usingboth22,23,30. Two studies used blind needle biopsy24,25 and 2miniarthroscopy (Table 2)26,35. Acquisition of images wasperformed on a 1.5T MRI scanner with contrast adminis-tration in 13 studies21,22,23,26,27,28,29,30,32,33,34,36,37 andwithout in 1 study38. Two studies used a 0.5T + contrastadministration24,25 and 2 a 3T+ contrast protocol31,35,although the latter study used a 0.2T scanner in a significantproportion of patients (4/10) with claustrophobia (Table 2).Quality assessment of studies. A summary of quality scoringof studies is provided in supplementary data (SupplementaryTable 4, available from the authors on request). Qualityscores were converted to percentages of the maximum scorewithin each class of study. The mean (range) quality scorewas 56% (25–75) for cross-sectional studies and 68%(46–93) for cohort studies indicating a broad range of scores.The 1 RCT had a quality score of 71%.Synovitis. MRI synovitis can be assessed by static anddynamic protocols. Subsequent to the acquisition ofT1-weighted images (Figure 2A), static protocols assess thevolume of enhancing synovitis following the administrationof a Gd-based contrast agent (Figure 2B) at a fixed timepoint.Synovitis volume can then be assessed manually or using asemiautomated method by outlining the synovial tissue.Static images can also be assessed using the widely validatedsemiquantitative Outcome Measures in Rheumatology(OMERACT)-Rheumatoid Arthritis Magnetic ResonanceImaging Scoring (RAMRIS) synovitis score40. Dynamiccontrast-enhanced (DCE)-MRI involves the rapid acquisitionof sequential images during and after administration ofcontrast and assesses rate of enhancement of synovial tissue.Results can be influenced by factors such as synovialperfusion and capillary permeability; thus, dynamic versusstatic protocols may be able to more sensitively reflect localsynovial inflammatory activity41,42.Does MRI synovitis reflect histopathological inflammation?Sixteen studies were identified that directly examined therelationship between the degree of MRI synovitis and localsynovial pathobiology21,22,23,24,26,27,28,29,30,31,32,33,34,35,36,37.Macroscopic synovitis and MRI synovitis was assessed in 3

studies both semiquantitatively22 and using dynamic MRIprotocols34,37 with all 3 suggesting a significant correlationbetween macroscopic and MRI synovitis. Sixstudies21,22,23,24,28,31 using dynamic MRI and 3 studies26,27,32using static MRI protocols also directly examined therelationship between MRI-determined synovitis and synovialinflammation assessed microscopically following routine H&Estaining. Eight out of 9 of these studies21,22,23,24,26,27,28,31concluded that histological inflammation correlated witheither semiquantitative or DCE-MRI synovitis. Althoughimmunohistochemical analysis of the synovial cell infiltratewas performed in 7 studies27,29,31,33,35,36,37, only 6 directlyreported the relationship between histological markers andsynovitis with a significant relationship reported betweenMRI synovitis and CD4+ T cells37, CD68+ subliningmacrophage number27,29,31, cell proliferation (Ki67)27, andneoangiogenesis (CD31)27. Three of the 4 studies alsoreported a significant relationship between MRI synovitis anddegree of histological vascularity through semiquantitativeassessment of H&E stained tissues30 expression of the neoan-giogenesis marker CD3127, endothelial cell markerQBend3025, and von Willebrand factor expression36.Conversely, Vordenbäumen, et al35 reported no significantrelationship between either sublining macrophage number orvascular endothelial growth factor (VEGF; an immunhisto-chemical marker of vascularization) and RAMRIS synovitis.Does MRI synovitis identify modulation of synovial pathobi-ology following effective therapeutic intervention? Longi-tudinal data examining whether MRI is sensitive enough todetect modulation of histological synovitis followingeffective therapeutic intervention was evaluated in 4 studiesincorporating serial MRI scans and paired synovial biopsies.First, an open-label placebo-controlled study of intraarticularanti-CD437 reported a significant correlation between MRIsynovitis and macroscopic synovitis with a trend towardimprovement in both histological and MRI synovitis only inpatients receiving active treatment. Second, Buch, et al33 ina prospective open-label trial reported on the synovial effectof abatacept in a cohort of 13 patients. Although the studydid not report directly on the relationship between modulationof MRI synovitis and synovial histology, it did report on therelationship between synovial gene expression and MRIsynovitis, documenting a significant association betweendownregulation of the T cell cytokine interferon-γ andreduction in MRI synovitis scores in responders to treatment.Third, a prospective open-label trial of 16 patients with RAinvestigated the effect of tumor necrosis factor (TNF)inhibitor therapy on hypoxia, macroscopic and microscopicsynovial inflammation, and MRI synovitis34. Patientsunderwent a baseline needle arthroscopic synovial biopsy andDCE-MRI of the knee, both of which were repeated 3 monthsafter starting anti-TNF therapy. The study demonstrated asignificant inverse relationship between hypoxia and clinicalresponse to anti-TNF therapy. The investigators also looked





directly and found a significant relationship between macro-scopic synovitis/vascularity and MRI synovitis. There werealso significant associations demonstrated between falls inCD4+ T cells and CD68+ sublining macrophages and MRIsynovitis. Finally, Vordenbäumen, et al35 reported resultsfrom 6 patients who underwent sequential metacarpopha-langeal (MCP) joint biopsy and MRI and found no significantassociation between change in sublining macrophage numberand RAMRIS synovitis score, although given the smallsample size the significance of the results is unclear. The data identified within our review provides an initialbasis for the use of MRI as a surrogate measure of histo-logical synovitis. Of particular importance is the relativelyconsistent demonstration of a significant relationship betweenCD68+ sublining macrophage number and MRI synovitis,the only current synovial biomarker validated as a measureof disease activity43. However, it is also important to considera number of limitations when interpreting results from thesestudies21,22,23,25,26,27,28,29,30,35,37. First, it is now recom-mended that to overcome significant synovial pathologicalheterogeneity, 6 synovial samples from different sites shouldbe analyzed for large joint procedures44 and 4 for smalljoints45. Although 10 studies reported number of synovialsamples retrieved per procedure21,22,23,26,28,30,33,35,37,38, only

4 cohorts reported retrieving 6 or more biopsies30,31,33,35.Further, only a selected number of studies specified a biopsysite predetermined by the MRI21,22,23,28,30,37 and so were ableto directly compare local synovial pathology. Synovialpathology is also influenced by disease course as well astherapeutic intervention46,47,48 factors that were not routinelycontrolled for in a number of studies21,22,23,28,30,32 because awide variability in time from MRI assessment to synovialsampling was reported. In addition, only 2 studies21,29reported that intraarticular steroid injections were notpermitted in this period and only 3 studies29,33,37 controlleddoses of steroids and DMARD prior to study inclusion. Itshould also be noted that the majority of studies identifiedharvested synovial tissue from arthroplastic knee joint proce-dures21,22,23,27,28,30,32, which restricts sampling of tissue toendstage joints. Indeed, there were only limited data evalu-ating pathobiology at distinct disease stages from homo-geneous cohorts, with only 1 study29 including patientsspecifically with disease duration of less than 1 year and only2 studies26,38 including patients with disease duration of lessthan 2 years26,38. Importantly, of the 18 studies identified, 13sampled knee joints, with only 426,31,32,35 examining therelationship in small joints.Bone marrow edema. MRI is unique among currently



Figure 2. Assessment of RA joint abnormalities by magnetic resonance imaging. Coronal T1-weighted (A) image of wrist jointdemonstrating extensive synovial thickening that enhances following administration of gadolinium (B). (C) T2 fat-suppressed coronalimage demonstrating bone marrow edema within the head of the proximal and base of the middle phalanx. (D) Axial T1-weightedimage demonstrating erosions of bone cortex within second and third metacarpal heads. (E) Coronal T1-weighted image of MCPjoints demonstrating significant joint space narrowing within second MCP joint. RA: rheumatoid arthritis; MCP: metacarpopha-langeal.



available imaging modalities in its ability to detect BME(Figure 2C) and although outside the remit of our systematicreview, it is worth noting that BME has been shown toequate to histological osteitis49. Importantly, the occurrenceof BME has been tightly correlated with the presence ofsynovitis50; however, whether BME is driven and/ormaintained by synovial pathobiological signals is unknownand very limited data examining this relationship wereidentified. Takase, et al27 report that in a cohort of 15patients with RA, no significant relationship betweenhistopathological changes of inflammation (neoangio-genesis, inflammatory cell infiltrates, and lining layerthickness) and MRI BME were found. In a further cohort of7 patients in clinical remission32, no correlation betweenMRI BME and histological synovitis was reported; this islikely to be explained by the small number of patients withinthe study. Finally, in a cohort of 10 patients, Vordenbäumen,et al35 reported that synovial staining for VEGF significantlycorrelated with RAMRIS BME scores in MCP joints.Certainly, more complex synovial analysis in larger cohortsat different stages of disease will be required to fullyinterpret whether synovial signals are involved or requiredin the initiation and/or maintenance of BME.Bone erosion. MRI has been increasingly recognized as amore sensitive marker of erosions (Figure 2D) than plainradiography51. The validation of the OMERACT-RAMRISMRI score40 as a robust and sensitive tool to documentpresence and/or erosive progression in patients with RAsuggests that incorporating MRI progression data withsynovial pathobiology may reveal important signatures ofdisease. In 2 cross-sectional cohorts, Andarajah, et al32reported in 7 patients with established RA no clear associ-ation between histological synovitis and erosions32, andVordenbäumen, et al35 reported a significant relationshipbetween synovial VEGF staining and the RAMRIS erosivescore in MCP joints in 10 patients. Interpretation of thesignificance of these results is complicated by the smallnumbers, the cross-sectional approach, and the lack ofvalidated MRI erosion score in the former report. However,in a prospective study of 60 patients, Kirkham, et al38 aimedto examine whether synovial pathobiology could explainjoint damage progression, as assessed by progression in theOMERACT-RAMRIS score52. Although the authorsidentified no specific synovial histological features, usingmultivariate analysis of gene expression they identified inter-leukin (IL)-1, TNF-α, IL-17, and IL-10 as predictive of jointdamage progression. The study had a number of limitations:(1) a wide range of disease durations in patients recruited tothe study, (2) lack of control of concomitant dis-ease-modifying therapies, and (3) joint damage progressionin the small joints of the hands was related to distant synovialsampling sites in the knee. Notwithstanding this, the reportis highly instructive in identifying synovial mediators of jointdamage progression and it remains important, therefore, to

validate the results in further larger cohorts of therapy-naivepatients with early RA.Cartilage loss. Cartilage loss in RA can be assessed bydocumenting joint space narrowing (JSN) on plainradiographs as well as MRI (Figure 2E). However, no datawere identified within this systematic review to examine therelationship between cartilage loss and synovial patho-biology.

DISCUSSIONMRI has significant advantages over other imagingtechniques for patients with RA; it does not expose patientsto ionizing radiation, it can sensitively detect synovitis,erosions, and JSN, and is unique in its capacity to detectBME. This differentiates MRI from ultrasound, which,although it is a sensitive measure of histological synovitis53,cannot detect BME and does not have validated outcomemeasures for cartilage loss or bone erosion. The clinicalstudies identified in this review indicate a significantrelationship between histological and MRI evident synovitis,which is important to validate MRI as a tool to reliably assesssynovitis without the need for invasive biopsy. Further, fromthe limited data available, a critical role for synovialpathways at least in driving joint damage38 seems likely butrequires more extensive validation. However, overall the dataprovide limited information on the specific synovial patho-biological processes driving MRI abnormalities in RA. Although the past decade has seen tremendous advancesin the care of patients with RA, considerable challengesremain. These include (1) specificity/sensitivity of currentdiagnostic/classification criteria for RA, (2) prediction ofprognosis following diagnosis of RA, and (3) limitedbiomarkers of response/resistance to biologic drugs. What isrequired is a move toward an era of personalized medicinefor patients with RA with targeted treatment pathways fromdiagnosis, but this is only possible if critical pathwaysmediating both disease pathogenesis and clinical response totherapy are further elucidated. What our review highlights isthe need to validate the relationship between synovial patho-biology and MRI abnormalities at the single joint level bothin well-defined early and established RA cohorts and withinclinical trial protocols of established and novel biologicdrugs. This is particularly important because historical limita-tions such as the lack of sensitivity of clinical examinationand radiographic assessment to detect synovitis and jointdamage progression/cartilage loss, respectively, are largelyovercome by the advent of a robust validated MRI scorecapable of assessing synovitis and erosion40 and potentiallyBME and cartilage loss54. Further, the advent of techniquessuch as ultrasound-guided synovial biopsy (Figure 3) thatprovide a technically simple, minimally invasive approach totissue acquisition from small as well as large joints55, andmore recent techniques to rapidly and simultaneouslyexamine the expression of multiple genes, are likely to





overcome challenges in sampling tissue from previouslyinaccessible joints and variability in histological assessmentof synovial tissue. Overall, the data identified within our systematic reviewvalidate MRI as a tool to assess synovitis, but very limiteddata directly examining the link between synovial patho-biology and joint damage/cartilage loss and BME wereidentified. Future research should focus on clinical trialprotocols integrating synovial sampling with MRI imagingat different stages of disease to dissect critical synovialpathways mediating RA pathogenesis. Although under-standing the interrelationship of these disease biomarkersoffers the potential to enhance the predictive validity ofmodern imaging with concomitant synovial pathobiologicalanalysis, further studies integrating MRI with synovial tissueanalysis in well-controlled cohorts before and after thera-peutic intervention are required to achieve this.

REFERENCES 1. Østergaard M, Hansen M, Stoltenberg M, Jensen KE, Szkudlarek

M, Pedersen-Zbinden B, et al. New radiographic bone erosions inthe wrists of patients with rheumatoid arthritis are detectable withmagnetic resonance imaging a median of two years earlier. ArthritisRheum 2003;48:2128–31.

2. van der Helm-van Mil AH. Imaging: Use of MRI as an outcomemeasure in clinical trials in RA. Nat Rev Rheumatol 2012;8:643–4.

3. Rahman MU, Buchanan J, Doyle MK, Hsia EC, Gathany T,Parasuraman S, et al. Changes in patient characteristics in anti-tumour necrosis factor clinical trials for rheumatoid arthritis:results of an analysis of the literature over the past 16 years. AnnRheum Dis 2011;70:1631–40.

4. Nieuwenhuis WP, van Steenbergen HW, Stomp W, Stijnen T,Huizinga TW, Bloem JL, et al. The course of bone marrow edema inearly undifferentiated arthritis and rheumatoid arthritis: a longitudinal magnetic resonance imaging study at bone level.Arthritis Rheum 2016;68:1080–8.

5. Conaghan PG, O’Connor P, McGonagle D, Astin P, Wakefield RJ,Gibbon WW, et al. Elucidation of the relationship between synovitisand bone damage: a randomized magnetic resonance imaging studyof individual joints in patients with early rheumatoid arthritis.Arthritis Rheum 2003;48:64–71.

6. Schett G, Firestein GS. Mr Outside and Mr Inside: classic and alternative views on the pathogenesis of rheumatoid arthritis. AnnRheum Dis 2010;69:787–9.

7. Hetland ML, Ejbjerg B, Hørslev-Petersen K, Jacobsen S,Vestergaard A, Jurik AG, et al; CIMESTRA study group. MRI boneoedema is the strongest predictor of subsequent radiographicprogression in early rheumatoid arthritis. Results from a 2-yearrandomised controlled trial (CIMESTRA). Ann Rheum Dis2009;68:384–90.

8. American College of Rheumatology Rheumatoid Arthritis ClinicalTrials Task Force Imaging Group and Outcome Measures inRheumatology Magnetic Resonance Imaging Inflammatory ArthritisWorking Group. Review: the utility of magnetic resonance imagingfor assessing structural damage in randomized controlled trials inrheumatoid arthritis. Arthritis Rheum 2013;65:2513–23.

9. Mundwiler ML, Maranian P, Brown DH, Silverman JM, Wallace D,Khanna D, et al. The utility of MRI in predicting radiographicerosions in the metatarsophalangeal joints of the rheumatoid foot: aprospective longitudinal cohort study. Arthritis Res Ther2009;11:R94.

10. Palosaari K, Vuotila J, Takalo R, Jartti A, Niemelä RK, KarjalainenA, et al. Bone oedema predicts erosive progression on wrist MRI inearly RA—a 2-yr observational MRI and NC scintigraphy study.Rheumatology 2006;45:1542–8.



Figure 3. Minimally invasive technique of US-guided synovial biopsy of wrist joint. Inset depicts correspondinggreyscale US image of biopsy needle inserted into wrist joint under extensor tendon complex. US: ultrasound.



11. Bøyesen P, Haavardsholm EA, van der Heijde D, Østergaard M,Hammer HB, Sesseng S, et al. Prediction of MRI erosiveprogression: a comparison of modern imaging modalities in earlyrheumatoid arthritis patients. Ann Rheum Dis 2011;70:176-9.

12. Lisbona MP, Pàmies A, Ares J, Almirall M, Navallas M, Solano A,et al. Association of bone edema with the progression of boneerosions quantified by hand magnetic resonance imaging in patientswith rheumatoid arthritis in remission. J Rheumatol 2014;41:1623-9.

13. McQueen FM, Benton N, Perry D, Crabbe J, Robinson E, YeomanS, et al. Bone edema scored on magnetic resonance imaging scansof the dominant carpus at presentation predicts radiographic jointdamage of the hands and feet six years later in patients withrheumatoid arthritis. Arthritis Rheum 2003;48:1814–27.

14. Tan AL, Tanner SF, Conaghan PG, Radjenovic A, O’Connor P,Brown AK, et al. Role of metacarpophalangeal joint anatomicfactors in the distribution of synovitis and bone erosion in earlyrheumatoid arthritis. Arthritis Rheum 2003;48:1214–22.

15. McQueen F, Clarke A, McHaffie A, Reeves Q, Williams M,Robinson E, et al. Assessment of cartilage loss at the wrist inrheumatoid arthritis using a new MRI scoring system. Ann RheumDis 2010;69:1971–5.

16. van der Heijde D. Erosions versus joint space narrowing inrheumatoid arthritis: what do we know? Ann Rheum Dis 2011;70Suppl 1:i116–8.

17. McQueen FM, McHaffie A, Clarke A, Lee AC, Reeves Q, CurteisB, et al. MRI osteitis predicts cartilage damage at the wrist in RA: athree-year prospective 3T MRI study examining cartilage damage.Arthritis Res Ther 2014;16:R33.

18. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group.Preferred reporting items for systematic reviews and meta-analyses:the PRISMA statement. Ann Intern Med 2009;151:264–9.

19. Yusuf E, Kortekaas MC, Watt I, Huizinga TW, Kloppenburg M. Doknee abnormalities visualised on MRI explain knee pain in kneeosteoarthritis? A systematic review. Ann Rheum Dis 2011;70:60–7.

20. Lievense AM, Bierma-Zeinstra SM, Verhagen AP, van Baar ME,Verhaar JA, Koes BW. Influence of obesity on the development ofosteoarthritis of the hip: a systematic review. Rheumatology2002;41:1155–62.

21. Tamai K, Yamato M, Yamaguchi T, Ohno W. Dynamic magneticresonance imaging for the evaluation of synovitis in patients withrheumatoid arthritis. Arthritis Rheum 1994;37:1151–7.

22. Østergaard M, Stoltenberg M, Løvgreen-Nielsen P, Volck B, JensenCH, Lorenzen I. Magnetic resonance imaging-determined synovialmembrane and joint effusion volumes in rheumatoid arthritis andosteoarthritis: comparison with the macroscopic and microscopicappearance of the synovium. Arthritis Rheum 1997;40:1856–67.

23. Østergaard M, Stoltenberg M, Løvgreen-Nielsen P, Volck B, Sonne-Holm S, Lorenzen I. Quantification of synovistis by MRI:correlation between dynamic and static gadolinium-enhancedmagnetic resonance imaging and microscopic and macroscopicsigns of synovial inflammation. Magn Reson Imaging 1998;16:743–54.

24. Gaffney K, Cookson J, Blake D, Coumbe A, Blades S.Quantification of rheumatoid synovitis by magnetic resonanceimaging. Arthritis Rheum 1995;38:1610–7.

25. Gaffney K, Cookson J, Blades S, Coumbe A, Blake D. Quantitativeassessment of the rheumatoid synovial microvascular bed bygadolinium-DTPA enhanced magnetic resonance imaging. AnnRheum Dis 1998;57:152–7.

26. Ostendorf B, Peters R, Dann P, Becker A, Scherer A, Wedekind F,et al. Magnetic resonance imaging and miniarthroscopy of metacarpophalangeal joints: sensitive detection of morphologicchanges in rheumatoid arthritis. Arthritis Rheum 2001;44:2492–502.

27. Takase K, Ohno S, Takeno M, Hama M, Kirino Y, Ihata A, et al.Simultaneous evaluation of long-lasting knee synovitis in patientsundergoing arthroplasty by power Doppler ultrasonography andcontrast-enhanced MRI in comparison with histopathology. ClinExp Rheumatol 2012;30:85–92.

28. Axelsen MB, Stoltenberg M, Poggenborg RP, Kubassova O, BoesenM, Bliddal H, et al. Dynamic gadolinium-enhanced magneticresonance imaging allows accurate assessment of the synovialinflammatory activity in rheumatoid arthritis knee joints: acomparison with synovial histology. Scand J Rheumatol2012;41:89–94.

29. Paramarta JE, van der Leij C, Gofita I, Yeremenko N, van de SandeMG, de Hair MJ, et al. Peripheral joint inflammation in early onsetspondyloarthritis is not specifically related to enthesitis. Ann RheumDis 2014;73:735–40.

30. König H, Sieper J, Wolf KJ. Rheumatoid arthritis: evaluation ofhypervascular and fibrous pannus with dynamic MR imagingenhanced with Gd-DTPA. Radiology 1990;176:473–7.

31. Vordenbäumen S, Schleich C, Lögters T, Sewerin P, Bleck E, PaulyT, et al. Dynamic contrast-enhanced magnetic resonance imaging ofmetacarpophalangeal joints reflects histological signs of synovitis inrheumatoid arthritis. Arthritis Res Ther 2014;16:452.

32. Anandarajah A, Thiele R, Giampoli E, Monu J, Seo GS, Feng C, etal. Patients with rheumatoid arthritis in clinical remission manifestpersistent joint inflammation on histology and imaging studies. J Rheumatol 2014;41:2153-60.

33. Buch MH, Boyle DL, Rosengren S, Saleem B, Reece RJ, RhodesLA, et al. Mode of action of abatacept in rheumatoid arthritispatients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonanceimaging pilot study. Ann Rheum Dis 2009;68:1220–7.

34. Kennedy A, Ng CT, Chang TC, Biniecka M, O’Sullivan JN,Heffernan E, et al. Tumor necrosis factor blocking therapy altersjoint inflammation and hypoxia. Arthritis Rheum 2011;63:923–32.

35. Vordenbäumen S, Sewerin P, Lögters T, Miese F, Schleich C, BleckE, et al. Inflammation and vascularisation markers of arthroscopically-guided finger joint synovial biospies reflect globaldisease activity in rheumatoid arthritis. Clin Exp Rheumatol2014;32:117–20.

36. Maijer KI, van der Leij C, de Hair MJ, Tas SW, Maas M, GerlagDM, et al. Dynamic contrast-enhanced magnetic resonance imagingusing pharmacokinetic modeling: initial experience in patients withearly arthritis. Arthritis Rheum 2016;68:587–96.

37. Veale DJ, Reece RJ, Parsons W, Radjenovic A, O’Connor PJ, OrglesCS, et al. Intra-articular primatised anti-CD4: efficacy in resistantrheumatoid knees. A study of combined arthroscopy, magneticresonance imaging, and histology. Ann Rheum Dis 1999;58:342–9.

38. Kirkham BW, Lassere MN, Edmonds JP, Juhasz KM, Bird PA, LeeCS, et al. Synovial membrane cytokine expression is predictive ofjoint damage progression in rheumatoid arthritis: a two-yearprospective study (the DAMAGE study cohort). Arthritis Rheum2006;54:1122–31.

39. Krenn V1, Morawietz L, Burmester GR, Kinne RW, Mueller-LadnerU, Muller B, et al. Synovitis score: discrimination between chroniclow-grade and high-grade synovitis. Histopathology 2006;49:358-64.

40. Østergaard M, Peterfy C, Conaghan P, McQueen F, Bird P, EjbjergB, et al. OMERACT Rheumatoid Arthritis Magnetic ResonanceImaging Studies. Core set of MRI acquisitions, joint pathologydefinitions, and the OMERACT RA-MRI scoring system. J Rheumatol 2003;30:1385-6.

41. Reece RJ, Kraan MC, Radjenovic A, Veale DJ, O’Connor PJ,Ridgway JP, et al. Comparative assessment of leflunomide andmethotrexate for the treatment of rheumatoid arthritis, by dynamicenhanced magnetic resonance imaging. Arthritis Rheum2002;46:366–72.





42. Rhodes LA, Tan AL, Tanner SF, Radjenovic A, Hensor EM, ReeceR, et al. Regional variation and differential response to therapy forknee synovitis adjacent to the cartilage-pannus junction and suprapatellar pouch in inflammatory arthritis: implications forpathogenesis and treatment. Arthritis Rheum 2004;50:2428–32.

43. Bresnihan B, Pontifex E, Thurlings RM, Vinkenoog M, El-Gabalawy H, Fearon U, et al. Synovial tissue sublining CD68expression is a biomarker of therapeutic response in rheumatoidarthritis clinical trials: consistency across centers. J Rheumatol2009;36:1800-2.

44. van de Sande MG, Gerlag DM, Lodde BM, van Baarsen LG,Alivernini S, Codullo V, et al. Evaluating antirheumatic treatmentsusing synovial biopsy: a recommendation for standardisation to beused in clinical trials. Ann Rheum Dis 2011;70:423–7.

45. Humby F, Kelly S, Hands R, Rocher V, DiCicco M, Ng N, et al. Useof ultrasound-guided small joint biopsy to evaluate the histopathologic response to rheumatoid arthritis therapy: recommendations for application to clinical trials. Arthritis Rheum2015;67:2601–10.

46. Bresnihan B, Baeten D, Firestein GS, Fitzgerald OM, Gerlag DM,Haringman JJ, et al; OMERACT 7 Special Interest Group. Synovialtissue analysis in clinical trials. J Rheumatol 2005;32:2481-4.

47. Gerlag DM, Haringman JJ, Smeets TJ, Zwinderman AH, Kraan MC,Laud PJ, et al. Effects of oral prednisolone on biomarkers insynovial tissue and clinical improvement in rheumatoid arthritis.Arthritis Rheum 2004;50:3783–91.

48. Kraan MC, Reece RJ, Barg EC, Smeets TJ, Farnell J, Rosenburg R,et al. Modulation of inflammation and metalloproteinase expressionin synovial tissue by leflunomide and methotrexate in patients withactive rheumatoid arthritis. Findings in a prospective, randomized,double-blind, parallel-design clinical trial in thirty-nine patients attwo centers. Arthritis Rheum 2000;43:1820–30.

49. Dalbeth N, Smith T, Gray S, Doyle A, Antill P, Lobo M, et al.Cellular characterisation of magnetic resonance imaging boneoedema in rheumatoid arthritis; implications for pathogenesis oferosive disease. Ann Rheum Dis 2009;68:279–82.

50. McGonagle D, Conaghan PG, O’Connor P, Gibbon W, Green M,Wakefield R, et al. The relationship between synovitis and bonechanges in early untreated rheumatoid arthritis: a controlledmagnetic resonance imaging study. Arthritis Rheum 1999;42:1706–11.

51. McQueen FM, Stewart N, Crabbe J, Robinson E, Yeoman S, TanPL, et al. Magnetic resonance imaging of the wrist in earlyrheumatoid arthritis reveals a high prevalence of erosions at fourmonths after symptom onset. Ann Rheum Dis 1998;57:350–6.

52. Conaghan P, Edmonds J, Emery P, Genant H, Gibbon W, KlarlundM, et al. Magnetic resonance imaging in rheumatoid arthritis:summary of OMERACT activities, current status, and plans. J Rheumatol 2001;28:1158-62.

53. Andersen M, Ellegaard K, Hebsgaard JB, Christensen R, Torp-Pedersen S, Kvist PH, et al. Ultrasound colour Doppler isassociated with synovial pathology in biopsies from hand joints inrheumatoid arthritis patients: a cross-sectional study. Ann RheumDis 2014;73:678–83.

54. Østergaard M, Bøyesen P, Eshed I, Gandjbakhch F, Lillegraven S,Bird P, et al. Development and preliminary validation of a magneticresonance imaging joint space narrowing score for use inrheumatoid arthritis: potential adjunct to the OMERACT RA MRIscoring system. J Rheumatol 2011;38:2045-50.

55. Kelly S, Humby F, Filer A, Ng N, Di Cicco M, Hands RE, et al.Ultrasound-guided synovial biopsy: a safe, well-tolerated andreliable technique for obtaining high-quality synovial tissue fromboth large and small joints in early arthritis patients. Ann RheumDis 2013;74:611–7.





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