MAGNETIC RESONANCE IMAGING OF MUSCULOSKELETAL
INFLAMMATION IN CHILDREN
Eva Kirkhus
Division of Radiology and Nuclear Medicine
Oslo University Hospital
Institute of Clinical Medicine
Faculty of Medicine
University of Oslo
Oslo, February 2016
© Eva Kirkhus, 2016 Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8333-263-6 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard Printed in Norway: 07 Media AS – www.07.no
iii
ACKNOWLEDGEMENTS
This studies presented in this thesis were carried out at the Department of Radiology and
Nuclear Medicine, Oslo University Hospital in cooperation with the Department of
Rheumatology, Oslo University Hospital, and the Department of Maxillofacial Radiology,
Faculty of Dentistry, University of Oslo, with contributions from the Departments of
Paediatrics and Radiology at Akershus University Hospital and Buskerud Hospital.
Most of all I thank the patients, their parents and the controls, who made this work possible.
I would like to express my deepest gratitude to my supervisors: Professor Hans-Jørgen Smith,
for fast feedback, analytic comments, high scientific standards, and for sharing his extensive
knowledge of MRI research. Professor Berit Flatø, for always being positive and helpful, for
sharing her knowledge of paediatric rheumatism, and for engaging me in paediatric research.
Professor Tore A. Larheim for scoring and interpretation of the MRIs of the TMJs, friendly
collaboration, challenging and constructive discussions, and for sharing his knowledge about
TMJs.
I would like to express my sincere gratitude to Therese Seierstad, for constructive criticism
and discussions, positive attitude, confidence and valuable support in the completion of this
thesis.
I am grateful for the valuable contributions from all my co-authors: Tor Reiseter, Linda Z.
Arvidsson and Else Merckoll for scoring and interpretation of the MRIs, and inspiring
thoughts and discussions, Øystein Riise and Helga Sanner for sharing their knowledge of
paediatrics and rheumatology, Helga for her engagement for the JDM patients, and Siri O.
Hetlevik, Benedicte A. Lie, Eli Taraldsrud, Mona Røisland, Anita Tollisen and Jan Tore Gran
for important contributions. I want especially to thank Benedicte for many supportive
discussions.
I would like to thank Øystein H. Horgmo for drawing the illustrations of detailed anatomy,
and Are Hugo Pripp for guidance and advice in the statistical analyses.
iv
I would like to thank Ragnhild B. Gunderson, Else Merckoll, Sigrun Skaar Holme, my highly
skilled colleagues, for encouragement and many years with inspiring scientific discussions,
and for offering me working conditions enabling me to fulfil this thesis.
I am especially grateful for the warm support from my friends, and in particular Bjørg Åse
Rue Gotaas.
Finally, my warmest thanks go to my family, my parents, my sister and her family, and
especially Henrik and Hanne for their patience and encouragement.
Oslo, February 2016
Eva Kirkhus
v
TABLE OF CONTENTS
ACKNOWLEDGEMENTS .................................................................................................................................. iii
ABBREVIATIONS ............................................................................................................................................... vii
1. LIST OF PAPERS .............................................................................................................................................. 1
2. INTRODUCTION .............................................................................................................................................. 3
3. BACKGROUND ................................................................................................................................................. 5
3.1 The musculoskeletal system in children ......................................................................................................... 5 3.1.1 The skeleton ............................................................................................................................................ 5 3.1.2 The joints ................................................................................................................................................ 6 3.1.3 The temporomandibular joint ................................................................................................................. 7 3.1.4 The muscles ............................................................................................................................................ 8
3.2. Childhood arthritis ........................................................................................................................................ 9 3.2.1 Epidemiology and clinical manifestations .............................................................................................. 9 3.2.2 Infectious arthritis ................................................................................................................................. 10 3.2.3 Post-infectious arthritis ......................................................................................................................... 12 3.2.4 Transient arthritis .................................................................................................................................. 12 3.2.5 Juvenile idiopathic arthritis ................................................................................................................... 12
3.3 Juvenile dermatomyositis ............................................................................................................................. 13 3.3.1 Epidemiology and clinical manifestations ............................................................................................ 13 3.3.2 Diagnostic criteria ................................................................................................................................. 13 3.3.3 Clinical manifestations .......................................................................................................................... 13 3.3.4 Pathogenesis .......................................................................................................................................... 14
3.4 MRI ............................................................................................................................................................... 14 3.4.1 Basic principles of MRI ........................................................................................................................ 14 3.4.2 Pulse sequences in musculoskeletal imaging ........................................................................................ 15 3.4.3 Specific absorption rate ......................................................................................................................... 17
3.5 Assessment of muscle strength and health status ......................................................................................... 17
3.6 MRI in childhood arthritis ............................................................................................................................ 18
3.7 MRI in juvenile dermatomyositis .................................................................................................................. 20
4. AIMS .................................................................................................................................................................. 22
5. MATERIAL AND METHODS ....................................................................................................................... 23
5.1 Study design and patients ............................................................................................................................. 23 5.1.1 Paper 1 .................................................................................................................................................. 23 5.1.2 Paper 2 .................................................................................................................................................. 24 5.1.3 Paper 3 .................................................................................................................................................. 25
5.2 MRI and scoring systems .............................................................................................................................. 25
5.3 Statistical approach ...................................................................................................................................... 31
6. SUMMARY OF RESULTS ............................................................................................................................. 32
vi
6.1 Paper 1: Differences in MRI findings between subgroups of recent-onset childhood arthritis ................... 32
6.2 Paper 2: Disk abnormality coexists with any degree of synovial and osseous abnormality in the TMJs of children with JIA ................................................................................................................................................ 32
6.3 Paper 3: Long-term muscular outcome and predisposing and prognostic factors in JDM: a case control study .................................................................................................................................................................... 33
7. DISCUSSION .................................................................................................................................................... 34
7.1 Methodological considerations .................................................................................................................... 34 7.1.1 Study design and study population ....................................................................................................... 34 7.1.2 MRI technique and sequences .............................................................................................................. 36 7.1.3 MRI-based scoring systems .................................................................................................................. 38
7.2 Radiological and clinical implications of study findings ............................................................................. 39 7.2.1 MRI as a tool to differentiate subgroups of childhood arthritis (paper 1) ............................................ 39 7.2.2 Disk abnormalities in the TMJs of children with JIA (paper 2) ........................................................... 41 7.2.3 Muscle damage shown at MRI corresponds with clinical findings in patients with long-term JDM (paper 3) ......................................................................................................................................................... 42
8. MAIN CONCLUSIONS ................................................................................................................................... 44
8.1 Concluding remarks ..................................................................................................................................... 45
8.2 Implications for further research ................................................................................................................. 45
9. REFERENCES ................................................................................................................................................. 46
vii
ABBREVIATIONS
C-HAQ Child health assessment questionnaire
CMAS Child myositis assessment scale
CRP C-reactive protein
DWI Diffusion weighted imaging
DAS Disease activity score
DCE MRI Dynamic contrast enhanced magnetic resonance imaging
dGEMRIC Delayed gadolinium enhanced magnetic resonance imaging of cartilage
EMG Electromyography
ESR Erythrocyte sedimentation rate
GRE Gradient echo
HAQ Health Assessment Questionnaire
HLA Human leucocyte antigen
IA Infectious arthritis
ILAR International League of Association for Rheumatology
IMACS International Myositis and Clinical Studies Group
JAMRIS Juvenile MRI scoring
JIA Juvenile idiopathic arthritis
JDM Juvenile dermatomyositis
MDI Myositis damage index
MMT Manual muscle testing
MRI Magnetic resonance imaging
NMR Nuclear magnetic resonance
NSF Nephrogenic systemic fibrosis
OMERACT Outcome measures in rheumatoid arthritis clinical trials
PA Post-infectious arthritis
PACS Picture archiving and communication system
PD Proton density
PROPELLER Periodically rotated overlapping parallel lines with enhanced reconstruction
RA Rheumatoid arthritis
RF Radiofrequency
SAR Specific absorption rate
viii
SE Spin echo
SF-36 Short Form 36
SI Signal intensity
STIR Short tau inversion recovery
TA Transient arthritis
TE Echo time
TMJ Temporomandibular joint
TR Repetition time
TSE Turbo spin echo
UTE Ultra-short echo time
WBC White blood cells
WBMRI Whole body MRI
1
1. LIST OF PAPERS
1. Kirkhus E, Flatø B, Riise Ø, Reiseter T, Smith HJ. Differences in MRI findings between
subgroups of recent-onset childhood arthritis. Pediatr Radiol. 2011;41(4): 432-440
2. Kirkhus E, Arvidsson LZ, Smith HJ, Flatø B, Hetlevik SO, Larheim TA. Disk damage
coexists with any degree of synovial and osseous abnormality in the temporomandibular
joints of children with juvenile idiopathic arthritis. Pediatr Radiol. 2015 (Epub ahead of
print)
3. Sanner H, Kirkhus E, Merckoll E, Tollisen A, Røisland M, Lie BA, Taraldsrud E, Gran JT,
Flatø B. Long term muscular outcome, predisposing and prognostic factor in juvenile
dermatomyositis: a case control study. Arthritis Care Res 2010;62(8):1103-11
2
3
2. INTRODUCTION
This thesis explores the use of magnetic resonance imaging (MRI) as a diagnostic tool for
juvenile idiopathic inflammatory musculoskeletal diseases, with focus on three different issues:
the differentiation of subgroups in early childhood arthritis, disk damage in the
temporomandibular joint (TMJ) of patients with juvenile idiopathic arthritis (JIA), and the
correlation of MRI findings and clinical outcome in patients with juvenile dermatomyositis
(JDM).
MRI and ultrasonography do not rely on the use of ionizing radiation and are therefore often
the preferred examinations in children. X-ray imaging does not show early bone affection. MRI
gives a more complete depiction of the musculoskeletal system than ultrasonography, but it is
more resource demanding and may, especially in young children, require sedation.
Musculoskeletal inflammatory disorders may be infectious, due to bacteria, viruses or parasites,
or autoimmune-mediated as in rheumatic disorders. An autoimmune disorder occurs when there
is inflammation against the patient’s own tissue. The cause of autoimmunity is not fully
understood, but an interaction between environmental factors and multiple genes has been
proposed. Important issues in the immune response are the endocrine and the autonomic nerve
system as mediators (1).
Paediatric rheumatic diseases comprise childhood arthritides and childhood connective tissue
diseases, including JIA, reactive arthritis, systemic lupus erythematosus, JDM, scleroderma, the
vasculitis syndromes, and other diseases (2). As childhood arthritis and JDM have
predominantly musculoskeletal involvement, they are the focus of this thesis.
MRI provide high soft tissue contrast and high spatial resolution imaging of bone, joints and
muscles, and it is presumably the most accurate method to depict soft tissue and bone marrow
involvement in musculoskeletal inflammation (3-7). Early inflammation may be detected
before visible skeletal destruction on conventional x-ray imaging (8, 9). An early and specific
diagnosis will therefore be important for treatment stratification and treatment outcome. Today,
effective medications, e.g. intra-articular steroid injections, methotrexate and biological
4
medication, have improved the outcome for several of the children with paediatric rheumatic
diseases (10). Validated and reliable diagnostic and monitoring tools are therefore crucial.
5
3. BACKGROUND
3.1 The musculoskeletal system in children
3.1.1 The skeleton
The development of the musculoskeletal system is not complete until approximately the age of
20 years. In foetal life the bones are preformed in hyaline cartilage. At birth the skeleton is only
partly ossified, whereas the mature adult bone consists of compact cortical bone and medullary
cancellous bone (11). Diseases that involve the skeleton will alter the structures during a period
of growth and will therefore appear differently in children than in adults (12).
Figure 1: The skeletal ossification of the femur and the red bone marrow (red) conversion to yellow marrow (yellow) in a): a new born with cartilaginous epiphysis (blue), b): a child with growth plates and partly ossified epiphysis and c): an adult with closed growth plates. Illustration: Øystein H. Horgmo, University of Oslo.
The gradual change of cartilage into bone (osteogenesis) starts in ossification centres. In a
tubular bone the persistence of a cartilage layer (growth plate) between the metaphysis and the
6
epiphysis allows increase in bone length and bone shape modelling. From about one year of age
until bony fusion, the vascular communication between the metaphysis and the epiphysis is
minimal, but finally metaphyseal and epiphyseal vessels unit through channels of resorbed
calcified cartilage in the growth plate, followed by the final bony fusion. The articular
cartilaginous surfaces remain unossified (11).
The ossification process starts at a certain time and continues at a rate characteristic for each
bone. There are individual differences, and females antedate males, but the sequences of events
show minimal variation (11).
The bone marrow (progenitor cells for blood), vessels and nerves (autonomic and sensory
nerves) are present in between the medullary cancellous bone. Simultaneous with the skeletal
maturing, the red bone marrow converts to yellow bone marrow also with sequences of events
that show minimal variation (Fig. 1). It occurs first in the long bones in the extremities, first in
the epiphysis, then in the diaphysis, then takes place in the distal metaphysis and finally in the
proximal metaphysis. In the adult, red marrow remains mainly in the axial skeleton (13).
3.1.2 The joints
A synovial joint is a freely movable joint with articulating cartilage (usually hyaline) surfaces
and a synovial joint cavity between the articulating bones.
The joint capsule encloses the cavity (Fig. 2) and is composed of an outer fibrous layer and an
inner synovial membrane, 1-3 cells thick. Due to the lack of a basement membrane, the
synovial layer is an imperfect membrane. Through the perivascular supply, the synovial
membrane therefore leaks fluid into the joint, lubricating and providing nutrients to the joint
and the cartilage (14).
7
Figure 2: A synovial joint. The synovial membrane (red) lines the joint cavity, and does not cover the articulating cartilage. Illustration: Øystein H. Horgmo, University of Oslo.
3.1.3 The temporomandibular joint
The TMJ is a bicondylar articulation involving the articular fossa and the mandibular condyle
(Fig. 3). The growth plate is beneath the fibrocartilaginous articular surface of the condyle. At
about 12-14 years of age, the cortical bone plate begins to form and is fully developed around
the age of 20 (15, 16). The TMJ is divided (often completely) in an upper and a lower
compartment by a biconcave non-vascularized fibrocartilaginous disk. The saddle-shaped disk
with an anterior two millimetre thick band, a thin centre and a three millimetre thick posterior
band, accommodates motion. The retrodiskal tissue is a bilaminar region with two layers of
fibres separated by loose, highly vascularized and innervated connective tissue responsible for
the production of synovial fluid. The superior temporal lamina (composed of elastic fibres) is
attached to the postglenoid process, whereas the inferior lamina (composed of collagen fibres
without elastic tissue) fuses with the capsule and the back of the condylar neck. The laminae
prevents extreme movement of the disk. The junction of the posterior band and the laminae is
normally within ten degrees of the vertical position (11). The anterior extension of the disk is
attached to the fibrous capsule partly inserting on the lateral pterygoid muscle (17).
8
Figure 3: The TMJ in closed (a) and open mouth (b) position. The disk (D) is anteriorly anchored to the lateral pterygoid muscle (LP) and posteriorly to the retrodiskal tissue (RDT) with the superior lamina (S) and the inferior lamina (I). Illustrations: Øystein H. Horgmo, University of Oslo.
3.1.4 The muscles
The skeletal striated muscles are via tendons attached to bones or cartilage. The muscle is
sheathed by epimysium, anchoring the muscle tissue to the tendons. The muscle comprises
bundles of fascicles each sheathed by perimysium, where the main nerves and blood vessels
run (Fig. 4). Each fascicle comprises multiple muscle fibres (muscle cells) each sheathed by
9
endomysium (18). At birth the muscle fibres have a fixed size. During childhood the muscle
fibres increase in diameter and length (19).
Figure 4: The skeletal striated muscle, sheathed with the epimysium (Ep), the fascicles (Fa) sheathed with the perimysium (P) and the main blood vessels (V), and the muscle fibers (Fi) sheathed with endomysium (En). Illustration: Øystein H. Horgmo, University of Oslo.
3.2. Childhood arthritis
3.2.1 Epidemiology and clinical manifestations
Arthritis is inflammation of one or several joints, defined as swelling of a joint or limited
range of motion in combination with pain, heat and/or tenderness (20, 21). Childhood arthritis
comprises the main subgroups JIA, infectious arthritis (IA), post-infectious arthritis (PA) and
transient (also called serous) arthritis (TA), but may also be associated with other conditions.
The incidence of childhood arthritis (<16 years) is about 1/1,000 children per year (22-24).
The incidence of IA is about 7/100,000 (22, 24), and TA (the most common subgroup)
including PA, is about 80/100,000 (23). PA is a heterogeneous group, but the incidence of TA
alone is 40-50/100,000 (22-24). The incidence of JIA is 13-23/100,000 children per year (22,
24-27) and the prevalence is 90-150/100,000 (26-28). IA has no gender predominance, TA
and PA are most frequent in boys (22), whereas JIA is most frequent in girls (27). IA is most
frequent before the age of 3 years (Fig. 5). Patients with PA are usually older at disease onset
10
and are hardly found before the age of 5. TA is most frequent in the ages 3-8 years (24, 29).
JIA has a bimodal age distribution with observed age of onset at 1-3 years and at about 9
years (24, 27).
The knee and the hip, followed by the ankle, are the most frequently affected joints in
childhood arthritis (Fig. 6). In TA, the most frequently affected joint is the hip, while in JIA
the knee and the ankle are the most frequent first manifestations (24, 30). In JIA the TMJ is
frequently reported to be involved (31-33).
Diagnosis is based on laboratory tests, joint fluid aspiration and/or radiological imaging. The
treatment and follow-up depend on the diagnosis.
3.2.2 Infectious arthritis
IA is usually defined as the presence of bacteria in the synovial fluid by Gram’s stain or culture,
or as a white blood cell (WBC) count of at least 50 x 109/L (34). Staphylococcus aureus is the
most common cause (35, 36). Kingella kingae is also an important pathogen in young children
(35, 37). IA may be predicted by erythrocyte sedimentation rate (ESR) > 40 mm/h and WBC >
12 x 109 cells/L (38). Adjacent arthritis (septic or aseptic) has been found in up to 40% of
children with acute osteomyelitis (39). Misdiagnoses of IA have been reported, and blood-
and synovial fluid cultures are often negative (40, 41). It is important to exclude IA at an early
stage as IA is potentially life-threatening and requires immediate surgical drainage and/or
antibiotics (36, 42).
11
Figure 5: Age distribution of children with early onset arthritis by diagnostic groups. Adapted after Riise et. al 2006 (24).
Figure 6: Distribution of hip, knee and ankle involvement in children with early onset arthritis by diagnostic groups. Adapted after Riise et. al 2006 (24).
12
3.2.3 Post-infectious arthritis
PA comprises a heterogenic group including acute rheumatic fever, post-streptococcal
arthritis, Lyme arthritis (arthritis following Borrelia burgdorferi infection), and arthritis after
genitourinary tract or gastrointestinal tract infections (43-45). Disease duration and long-term
course vary.
3.2.4 Transient arthritis
TA is defined as arthritis < six weeks duration (usually lasting 3-10 days) with unknown
triggering agent. TA is a self-limiting disease, treated symptomatically (29, 46).
3.2.5 Juvenile idiopathic arthritis
JIA is defined by the International League of Association for Rheumatology (ILAR) as
arthritis of unknown aetiology that has persisted for > six weeks with the onset before the age
of 16 years, and when other known conditions are excluded (21). JIA is classified after
clinical appearance into the following subtypes:
1. Systemic arthritis
2. Oligoarticular arthritis (persistent and extended)
3. Polyarticular arthritis rheumatoid factor negative
4. Polyarticular arthritis rheumatoid factor positive
5. Undifferentiated arthritis
6. Enthesitis related arthritis
7. Psoriasis related arthritis
JIA may lead to permanent disability, and early treatment is needed to prevent joint destruction
and secondary growth disturbances (10, 47).
The inflammatory target in JIA is the articular synovial membrane (14). The inflammatory
process is a complex biological cascade leading to vasodilation, increased blood flow,
increased vascular permeability, exudate and invasion by leukocytes. The synovium may
hypertrophy and extend over the articular surfaces (pannus). Pro-inflammatory mediators, such
as cytokines, stimulate the inflammatory process including production of enzymes that lead to
13
damage of supportive tissue, cartilage and bone. More destructive processes may follow
instability and dislocation, and the end result may be osseous fusion (14). The inflammation in
the bone with hyperaemia and invasion of leucocytes changes the metabolic regulation,
inducing the osteoclasts, leading to resorption and local osteoporosis, making the bone
vulnerable to damage. Both osteonecrosis and erosions may occur. The growth zones may be
affected leading to bone shape abnormalities, bone length discrepancy and axis deviation (48).
3.3 Juvenile dermatomyositis
3.3.1 Epidemiology and clinical manifestations
JDM is a rare disease, but the most frequent juvenile idiopathic inflammatory myopathy (49).
Other subtypes are very rare. In contrast to adult dermatomyositis, there is no increased
likelihood for developing cancer. The incidence is 0.19-0.32/100,000 children < 16 years per
year (49, 50). In the Western world there is a female predominance (50) in contrast to a male
predominance in Japan and Saudi Arabia (51, 52). The average age at disease onset is 7 years
(50).
3.3.2 Diagnostic criteria
Bohan and Peter´s revised diagnostic criteria for dermatomyositis and polymyositis (53, 54) are
not validated for the juvenile population, but are also used in children (55). The criteria are
symmetrical reduced muscle strength, elevation of serum muscle enzymes (e.g. creatinine
kinase), a characteristic electromyography (EMG), a typical histological pattern in the biopsy
and a characteristic rash. For definitive JDM diagnosis, the skin criterion and at least three
other criteria must be present, for probable diagnosis, the skin criterion and at least two other
criteria must be present.
3.3.3 Clinical manifestations
The onset symptoms are symmetric proximal reduced muscle strength and a characteristic rash;
purple discoloration over the eyelids (heliotrope rash) and erythematous patchy skin on
extensor surfaces (Gottron papules). Sustained weakness can be caused by chronic
inflammation, inactivity or be the consequence of muscle damage (atrophy, fatty infiltration
and/or calcinosis). Calcinosis (dystrophic calcifications) occurs in about 30% of the patients
14
and may occur in muscle, fascia, subcutaneous and/or cutaneous tissue and give persistent soft
tissue irritation and oedema. Lipodystrophy, slow loss of subcutaneous and visceral fat and
lipoedema may also be a late sequela. Manifestations can be generalized, subtle localized or
unilateral (56).
Clinical arthritis has been found to be a common manifestation in patients with JDM, and has
been reported to occur in 23–64% of the patients (57). The varying results may indicate that
clinical signs of arthritis may be difficult to separate from inflammation in tissues surrounding
the joint. The arthritis is often non-erosive.
With treatment the outcome, including the physical function, has improved, and the mortality
has been reduced from 30% (before 1960) to less than 2%. Still about 60% of the children
have a polycyclic or chronic continuous course (56, 58).
3.3.4 Pathogenesis
JDM is a systemic autoimmune vasculopathy. The inflammatory target is the perivascular
tissue, which involves endomysial and perimysial capillaries and arterioles. Endothelial
swelling is followed by endothelial necrosis and capillary loss leading to perifascicular
atrophy (56).
3.4 MRI
3.4.1 Basic principles of MRI
MRI exploits the magnetic properties of hydrogen atoms. When these positively charged nuclei
are placed within the static magnetic field, the hydrogen atoms will align either parallel or anti-
parallel to the direction of the magnetic field and precess with the Larmor frequency (ω) around
the axis of the static magnetic field. The Larmor frequency is given by the gyromagnetic ratio
(γ) of the hydrogen atom (42.576 MHz/tesla) and the strength of the magnetic field (B0) as
expressed in the equation:
0B⋅= γω
15
Applying an electromagnetic radiofrequency (RF) pulse with Larmor frequency, the hydrogen
atoms will absorb the energy and become excited. The magnetic direction is then destabilized,
and the net magnetization vector is titled away from the z-axis. Once the RF transmitter is
turned off, the hydrogen atoms return to equilibrium by energy absorption in the tissue (T1
relaxation) and loss of phase coherence (T2 relaxation). The radiation emitted by the relaxation
nuclei is the nuclear magnetic resonance (NMR) signal being the basis for all MR applications.
By advanced computing the distribution of hydrogen atoms and their relaxation properties are
identified (59).
3.4.2 Pulse sequences in musculoskeletal imaging
A large variety of pulse sequences are used to obtain different types of diagnostic information
in musculoskeletal imaging. Different information is obtained by altering the MR acquisition
parameters. The most important acquisition parameters are the echo time (TE) and the
repetition time (TR). Slice thickness, slice gap, matrix (number of phase and frequency
encodings), field of view, flip angle, and echo trains will also affect signal to noise ratio and
contrast to noise ratio of the MR images. The most frequently used sequences in
musculoskeletal imaging and their application at the time of our studies are summarized in
Table 1.
16
Table 1. Commonly used pulse sequences in musculoskeletal MRI.
Pulse sequences Image characteristics Application
T1-weigthed TSE Fat appears bright Water and fibrous tissue appear dark
Anatomical imaging Volume loss of muscle Fatty infiltration of muscle Bone marrow
T2-weigthed TSE Fat and water appear bright Fibrous tissue appears dark
Fluid collections, oedema and highly vascularized tissue Ligaments
STIR Water appears bright Fat and fibrous tissue appear dark
Fluid collections, oedema and highly vascularized tissue Bone marrow
PD-weighted TSE Water appears medium bright Fat appears medium bright Fibrous tissue appears dark
Fluid collections, oedema and highly vascularized tissue Cartilage and menisci
PD-weighted TSE with fat saturation**
Water appears bright against dark fat Fat and fibrous tissue appear dark
Fluid collections, oedema and highly vascularized tissue
Contrast-enhanced T1-weigthed TSE with fat saturation**
Water and fat appear dark Enhanced tissue appears bright against non-enhanced tissue and dark fat
Inflammation and other vascularized tissue Ischemia
T2*-weighted GRE Cartilage, fat and water appear bright Fibrous tissue and degraded blood products appear dark
Cartilage and menisci
TSE: turbo spin echo; STIR: Short tau inversion recovery; PD: Proton density; GRE: gradient echo; **frequency selective
Recent advances in MRI technology may also be included in the protocols of musculoskeletal
imaging:
1. High-resolution isotropic 3D sequences give multi-planar reformatted images of high image
quality (60).
2. Periodically rotated overlapping parallel lines with enhanced reconstruction,
(PROPELLER), is a specialized technique for reducing motion artefacts (61).
3. Dynamic contrast enhanced (DCE) MRI provides high temporal resolution, depicts the
exchange of contrast agent between the vascular space and the extravascular extracellular
space as a function of time and yields information about microvasculature and thereby the
grade of inflammation (62).
17
4. Modern Dixon techniques (fat suppression techniques named after WT Dixon) combine
images acquired at different TEs to produce four image sets: water only, fat only, in-phase,
and out-of-phase (63). The images achieve both high spatial and high contrast resolution,
and the techniques reduce fat inhomogeneity artefacts (64).
5. Diffusion weighted imaging (DWI) measures the random Brownian motion of water
molecules (65).
6. T1ρ mapping, delayed gadolinium enhanced MRI of cartilage (dGEMRIC), and T2
mapping are techniques used to visualize the cartilage biochemical composition
(proteoglycans and collagen) (66).
7. UTE (ultra-short echo time) T2*-sequences detect signals from tissue with very short T2,
such as cortical bone, osteochondral junction, meniscus, tendon, ligaments, synovium and
deep layers of articular cartilage (67).
3.4.3 Specific absorption rate
The RF pulses used in MRI interact with the tissue and produce heating due to energy
absorption. The absorption of RF fields in tissues is measured as a Specific Absorption Rate
(SAR) and measured in watts per kilogram (59). Children are more vulnerable than
adults with increased risk for heating because of a greater body surface to weight ratio. It is
therefore lower SAR limits for children than for adults. 3-tesla machines have improved the
image quality, but have also increased the RF deposition.
3.5 Assessment of muscle strength and health status
The International Myositis and Clinical Studies (IMACS) Group has developed a consensus
on core set domains and measures for the assessment of disease activity in idiopathic
inflammatory myopathy (68, 69). Commonly used measures of muscle strength and
endurance are:
• Childhood Myositis Assessment Scale (CMAS): Comprises observation of performance
of 14 functional tasks. Muscles are weighted differently; proximal > axial muscles and
lower extremities > than upper. Scores range from 0-52. Performance time is about 15
minutes (70).
18
• Manual muscle testing (MMT): Unilateral MMT 8 (shown to be comparable with bilateral
MMT 24) comprises tests of 8 muscles using a 0-10 scale (0 = no contraction, 10 = full
muscle strength). Score ranges from 0-80. Performance time is < 10 minutes (71).
Commonly used measures of assessment of health and disease status are:
• The Norwegian version of Short Form 36 health survey (SF-36), version 1.0 measuring a
physical and a mental component summary scale (72).
• The Disease Activity Score (DAS), consisting of a skin score and a muscle score (73).
• The Myositis Damage index (MDI) measures cumulative organ damage; damage defined
in 11 organ systems (muscular, skeletal, cutaneous, gastrointestinal, pulmonary,
cardiovascular, peripheral, vascular, endocrine, and ocular organ systems, and infection
and malignancy). MDI muscle damage is muscle atrophy, reduced muscle strength due to
damage or muscle dysfunction (74).
• The Health Assessment Questionnaire (HAQ) and the Childhood Health Assessment
Questionnaire (C-HAQ) measures physical function in patients ages ≥ 18 and ages < 18
years, respectively (75).
3.6 MRI in childhood arthritis
MRI detects joint effusion, synovitis, bone marrow and soft tissue oedema, articular and
epiphyseal cartilage changes, changes in the menisci or discs and tendinopathy, all of which
can be manifestations of childhood arthritis. Knowing the normal age-dependent appearance,
growth disturbance may be acknowledged.
When our study of childhood arthritis (paper 1) was initiated, it was known that MRI was
sensitive for joint inflammation (Fig. 7), but its ability to separate subgroups of arthritis in
children was questioned (4-6, 76). Studies of MRI findings that could differentiate the
subgroups of acute arthritis were few with the focus so far being the differentiation between TA
and IA in the hips (77-79). Studies in hips and knees in JIA patients had been performed (80-
84), but the MRI characteristics during the early phase of the disease had not been investigated.
19
Figure 7. Sagittal fat-saturated contrast-enhanced T1-weighted MR image of the knee in a child with JIA shows joint effusion and thickened pathologically enhanced synovium.
The TMJs are frequently involved in JIA (31). Inconsistent definitions and reporting of TMJ
involvement may be one reason for the variation in the frequency of TMJ involvement in the
literature (32, 33, 85-87). Normal variations of MRI findings in children are not well known,
and there are only few studies of healthy TMJs (88-90).
A number of studies have demonstrated MRI abnormalities that may occur in the TMJs of
patients with JIA. Little attention has been given to the disk abnormalities, and in the majority
of studies disk abnormalities were not reported (33, 85, 87, 91-95). To our knowledge only
three studies have reported disk abnormalities, two in children (32, 96) and one in adults with
JIA (31). In both studies on children, disk abnormalities predominantly occurred in joints with
long-standing changes; the frequencies of abnormal bone shape were 87% and 96% (32, 96). In
20
adults with JIA with long-standing TMJ involvement, disk abnormalities were frequently
observed (31).
MRI-based scoring systems have been developed for arthritis in adults (97), but at the start of
our study there was no established scoring system for arthritis in children.
3.7 MRI in juvenile dermatomyositis
MRI may distinguish active inflammation (symmetric, widespread muscle oedema) from signs
of muscle damage such as fatty infiltration and/or volume loss, typical findings in JDM patients,
and may thus have a role both in detecting early disease and long-term complications of JDM.
Long-term complications as calcifications, lipodystrophy and lipoedema may also be depicted
at MRI (98-100).
The STIR sequence is very sensitive in detecting muscle oedema, and therefore in showing the
most inflamed areas. This may guide the surgeon to choose the optimal site for biopsy and thus
increase the accuracy of the biopsies (101). In children, however, invasive methods as EMG
and biopsy are often not indicated when MRI has proven bilateral and symmetrical muscle
oedema (Fig. 8) accompanied by a characteristic rash (55).
At the start of the study there was no consensus about MRI scoring methods, but several
attempts of MRI-based scoring systems for evaluation of oedema and fatty infiltration of
muscle (99, 102, 103) besides a widely used CT-based scoring system for fatty infiltration of
muscles (104).
21
.
Figure 8: Axial T1-weighted (a) and STIR (b) MR images of the thighs in a child in the early phase of JDM show no fatty infiltration of the muscles, but symmetrical, extensive muscle oedema. Figure 9: Axial T1-weighted MR image of the thighs of a long-term adult JDM patient show extensive muscular, fascial and subcutaneous calcifications (* and other dark soft tissue regions).
22
4. AIMS
The main aim of this thesis was to explore MRI as a diagnostic tool for the assessment of
paediatric musculoskeletal inflammatory disease.
The specific aims were to:
1. Describe and assess the extent of MRI findings in recent onset childhood arthritis.
2. Investigate whether MRI can distinguish between subgroups of childhood arthritis.
3. Describe, define and assess MRI findings in symptomatic TMJs in children with JIA.
4. Assess the frequency of effusion, bone marrow oedema, erosions and disk abnormalities in
four categories of TMJs in children with JIA. The categories were based on the presence of
synovitis and/or abnormal bone shape.
5. Assess the extent of thigh muscle involvement at MRI in patients with long-term JDM.
6. Establish the correlation of MRI assessed muscle damage and muscle strength.
7. Correlate the MRI assessed muscle damage with early disease characteristics to identify
early predictors for organ damage.
23
5. MATERIAL AND METHODS
5.1 Study design and patients
5.1.1 Paper 1
The study population was from a cross-sectional prospective epidemiological multicentre study
of recent-onset arthritis and osteomyelitis in three counties in south-eastern Norway (255,303
children < 16 years) performed between May 2004 and June 2005 (24).
Patients with suspected inflammatory disease in bone or joint with duration < 6 weeks, were
referred from primary care, paediatricians, orthopaedic surgeons and rheumatologists. All
patients were examined within three days at one of the paediatric or paediatric rheumatologic
departments in the counties.
The inclusion criteria were: 1) joint swelling, 2) limited range of motion in ≥ 1 joint, walking
with a limp or other functional limitations affecting arms and legs, 3) pain in ≥ 1 joint or
extremity together with C-reactive protein (CRP) level > 20 mg/L and/or ESR > 20 mm/h
and/or WBC > 12 x 109/L.
Four hundred and twenty-seven children fulfilled the recruitment criteria for possible arthritis;
of these 216 had recent onset arthritis. The diagnosis was based on clinical findings, laboratory
tests, joint fluid aspiration, and ultrasonography of the affected joint, and the children were
followed up with clinical examination after six weeks and six months. Final diagnosis was
made after six months of follow-up and re-evaluated by chart review after two years.
The arthritis was classified as IA, PA/TA or JIA. A diagnosis of IA was made when there were
verified bacteria in the joint fluid, arthritis combined with positive blood culture and/or
adjacent osteomyelitis, or at least 50 x 109 WBC/L in the joint fluid in combination with
clinical signs consistent with IA. PA was diagnosed when evidence of recent infection was
verified by antibodies against bacterial agents such as Streptococcus pyogenes, Borrelia or
Enterobacter, or a positive throat culture for Streptococcus pyogenes. TA was defined as
arthritis < six weeks duration with no verified triggering agent. JIA was diagnosed according to
the preliminary criteria for the classification of JIA.
24
The indications for MRI were clinical suspicion of inflammatory joint or bone disease
combined with fever > 38.5°, ESR > 30 mm/h, CRP > 30 mg/L, WBC > 12 × 109/L and/or an
excessively painful joint. MRI was also obtained if clinical signs of arthritis continued for > 2
weeks. Based on these criteria, MRI was performed in 59 children (mean age 3 years (1.5-10
years). Written informed consent was obtained from the parents of the children included in the
study. The Regional Committee for Medical Research Ethics approved the study (REC S-
04097).
5.1.2 Paper 2
The study was a cross-sectional study of MRI of symptomatic TMJs in children with JIA. It
was part of a retrospective study of ultrasonography compared to MRI as the gold standard,
with a time interval less than seven days between the two examinations.
The patients were younger than 18 years and identified through search in the institutional
picture, archiving and communication system (PACS). The patients were referred to the
Department of Radiology and Nuclear Medicine, Oslo University Hospital during the period
2005-2012 due to symptoms or clinical findings like TMJ pain, joint sounds, restricted mouth
opening or facial growth disturbances suspicious of TMJ arthritis.
Forty-six patients (mean age 12 years, range 5-17) diagnosed with JIA according to the criteria
of the ILAR (21) were included in the MRI part of the study. The patients were mostly under
medical treatment.
Chart reviews were performed. Laboratory tests (CRP, ESR), the number of active joints and
medications were registered. Active joints were defined as swollen joints or mobility restricted
plus tender or painful joints (21).
The study was approved as a quality assurance study by the Data Protection Officer Authority
at Oslo University Hospital (2010/537).
25
5.1.3 Paper 3
The study was a cross-sectional case-control study performed in the period 2005-2009.
Inclusion criteria were disease onset ≤ 18 years of age, age ≥ 6 years at follow-up, minimum 24
months of disease duration, and a probable or definitive diagnosis of DM according to the
criteria by Bohan and Peter (53, 54).
Norwegian JDM cases diagnosed from 1970-2006 were identified through search in the chart
archives at the Department of Rheumatology, Oslo University Hospital, and through contact
with the other Departments of Paediatrics and Rheumatology in Norway (105).
Sixty-six patients fulfilled the inclusion criteria and four were diseased. Of the remaining 62
patients, 59 participated in the study (mean age 21.5 years, range 6.7-55.4). MRI was
performed in 58 patients. The median time between disease onset and examination was 16.8
years (range 2.0-38.1). There were age- and gender-matched controls for the clinical tests, but
not for the MRI.
Human leucocyte antigen (HLA) DRB1 genotyping was performed, and laboratory measures
were obtained. Outcome domains and core sets (SF-36, DAS, MDI, HAQ, C-HAQ, MMT 8
and CMAS) for idiopathic inflammatory myopathy were assessed. A retrospective chart review
was done, where the DAS and MDI total score (including MDI muscle score) were calculated 1
year post-diagnosis.
Informed consent was obtained from all of the patients and the controls (and their parents if age
< 16 years). The study was approved by the Regional Committee for Medical Research Ethics
(REC S-05144).
5.2 MRI and scoring systems
All MRIs were performed on 1.0 or 1.5 tesla scanners. The MRI sequences included in the
examinations were predefined and centrally devised. Pre-contrast sequences were T1-weighted
TSE, and STIR or PD/T2-weighted TSE with fat suppression. In order to avoid metal artefacts
from braces, some of the TMJ examinations were performed with PD/T2-weighted TSE
without fat suppression. The sequences were used to detect bone marrow oedema, effusion and
26
soft tissue oedema (including muscle oedema), and to evaluate anatomical details. Post-contrast
T1-weighted TSE with or without fat suppression was acquired for the patients included in
papers 1 and 2. Synovial enhancement and bone marrow vascularity were evaluated. T2*-
weighted GRE at open mouth (paper 2) was used to evaluate disk displacement. Choice of
contrast agents varied because the institution changed product. The post-contrast imaging
started immediately after contrast medium injection.
In paper 1, two radiologists in consensus registered the presence of excessive amounts of joint
fluid and synovitis. One of the radiologists assessed the additional findings. In papers 2 and 3,
the MRI findings were scored in consensus by two radiologists. An intra-observer evaluation
was performed in paper 2.
Self-designed scoring schemes were used in all three papers. These were deduced from
available literature at the time of scoring.
Arthritis-related changes at MRI in bone, joint and soft tissue were scored in papers 1 and 2.
Myositis-related changes at MRI in muscles, fascia, subcutaneous and cutaneous tissue were
scored in paper 3.
In paper 1, synovitis and/or effusion at MRI were considered consistent with arthritis when no
other obvious causes were present. In paper 2, a joint was considered to be affected by JIA
when synovitis and/or abnormal bone shape was present.
MRI-detected muscle damage was defined as at least one of the following: calcinosis in the
muscle or fascia, muscle atrophy, or muscle fatty infiltration. Oedema in muscle or fascia was
interpreted as possible inflammatory disease activity.
MRI findings defined in the papers:
• Synovitis was defined as evident post-gadolinium enhancement on T1-weighted images in
thickened synovium. Thickened synovium was ≥ 2 mm (paper 1) and more than dots or thin
lines (paper 2). “Low signal intensity synovial tissue” was defined as the presence of non-
enhancing focal synovial areas with low signal intensity at all contrast weightings (paper 1).
27
• Effusion was defined as joint fluid more than dots or lines (traces) with high signal on T2-
weighted images, and showing no contrast enhancement on T1-weighted images (paper 1
and 2).
• Bone marrow oedema was defined as diffusely circumscribed areas in trabecular bone
with low signal intensity on T1-weighted images and corresponding high signal intensity
on T2-weighted images, typically higher signal intensity than that of red bone marrow,
indicating increased water content (paper 2).
• Bone erosion was defined as a sharply marginated bone lesion visible in more than one
slice. The definition did not include cortical breaks due to undeveloped cortical bone plate
(which is not fully developed before the approximate age of 20 years). Irregular but intact
articular surfaces were not considered erosions but abnormal bone shape. Erosion alone
was not considered abnormal bone shape (paper 2).
• In the TMJ, a flat disk was either evenly thin or thin at the anterior band. An adherent disk
did not move normally together with the condyle at the mouth opening. A displaced disk
could have an anterior, posterior, lateral or medial position relative to the condyle at
closed mouth. At mouth opening, anteriorly displaced disks could reduce to normal
position or remain anteriorly displaced (paper 2).
• Calcinosis was tumour-like, linear or speckled areas with low signal on both T1-weighted
spin-echo sequences and STIR sequences. Despite the lack of radiographic confirmation
of density, we chose to name these findings as calcinosis, but fibrosis may have the same
appearance (paper 3).
The assessments of MRI findings in the three papers are summarized in Tables 2-4.
28
Table 2: Assessment of MRI findings in paper 1.
MRI findings Score values
Amount of joint fluid*
0 - no 1 - trace of effusion 2 - continual effusion 3 - effusion with distension of the capsule
Synovial thickness Maximum thickness of the synovium in any part of the joint (pathological thickness ≥2millimetres)
Synovial surface appearance
0 - smooth, 1 - irregular 2 - villous extensions
Synovial enhancement
0 - no 1 - yes
Synovial non-enhancing and low SI** focal areas
0 - no 1 - yes
Amount of bone marrow oedema
0 - none, 1 - ≤1/3 involvement of the epi-, meta- or diaphysis 2 - >1/3 involvement of the epi-, meta- or diaphysis
Amount of soft-tissue oedema
0 - none 1 - trace of oedema 2 - marked oedema
Reduced perfusion of bone or cartilage
0 - no 1 - yes
Focal contrast-enhancing lesions in the epiphyseal cartilage or in the knee menisci
0 - no 1 - yes
Regional lymph nodes (knee)
Short axis diameter of the largest lymph node (millimetres) Number
Tenosynovitis (hands / ankles)
0 - no 1 - yes
*adapted after Mitchell at al. (106); **SI: signal intensity
29
Table 3: Assessment of MRI findings in paper 2.
MRI findings Score values
Amount of synovitis*
0 - no 1 - slight synovial thickening more than dots or lines 2 - moderate band-like thickening including slight distension of the joint space 3 - extensive thickening with extensive distension of the joint space
Abnormal bone shape of fossa/eminence or the condyle
0 - no 1 - yes
Effusion 0 - no 1 - yes
Bone marrow oedema 0 - no 1 - yes
Bone erosion 0 - no 1 - yes
Disks
1 - absent, 2 - atrophic 3 - ruptured/fragmented 4 - displaced 5 - adherent
*adapted after Mitchell at al. (106)
30
Table 4: Assessment of MRI findings in paper 3.
MRI findings Score values
Muscle oedema* 0 - no (inactive) 1 - yes: scale 1 (mild) - 4 (extremely active)
Muscle calcification 0 - no 1 - yes
Muscle volume loss 0 - no 1 - yes
Fatty infiltration of muscle **
0 - no fatty depositions 1 - some fatty streaks 2 - more muscle than fat area 3 - as much muscle as fat area 4 - less muscle than fat area
Fascial oedema 0 - no 1 - yes
Fascial calcification 0 - no 1 - yes
Subcutaneous oedema 0 - no 1 - yes
Subcutaneous calcification 0 - no 1 - yes
Subcutaneous volume loss 0 - no 1 - yes
Cutaneous oedema 0 - no 1 - yes
Cutaneous calcification 0 - no 1 - yes
*adapted after Kimball et al. (107); **adapted after Goutallier et al. (104)
31
5.3 Statistical approach
Statistical analyses were performed using SPSS version 15 and 16 (SPSS inc., Chicago, IL,
USA) and SPSS version 20 (Armonk, NY: IBM Corp.). Continuous data was described by
means and standard deviation when normally distributed and by median and range when
skewed. Categorical data were described as frequency and percentage.
In paper 1, the Kruskal-Wallis test and in cases of statistical significance, pair-wise analyses
by the Mann–Whitney U test were used to determine differences between groups. For
categorical variable Pearson chi-square or Fisher exact test, and for continual variables one-
way ANOVA test were used. Logistic regression analyses were performed for each diagnostic
subgroup to assess the most important correlates among the MRI joint characteristic variables,
with the diagnosis of JIA or IA versus other types of arthritis as the dependent variables.
In paper 2, Cohen kappa statistics were performed to determine intra-observer consistency.
Odds ratio was calculated in order to explore the associations between the patient
characteristics and MRI findings suggestive of TMJ involvement.
In paper 3, differences between patients and matched controls were tested by the paired-
sample t-test, Wilcoxon’s rank sum test, or McNemar’s test. Differences between patient
groups were tested by the independent-sample t-test, the Mann-Whitney U test, or the Pearson
chi-square test. Correlations were determined by the Spearman’s correlation coefficient. In
order to identify possible early risk factors for an unfavourable muscular outcome (low MMT
score, low CMAS score, and MRI-assessed muscle damage), logistic regression analyses were
performed on the relationship between the outcome variables and the patient characteristics
(disease variables) assessed at diagnosis and one year post-diagnosis.
32
6. SUMMARY OF RESULTS
6.1 Paper 1: Differences in MRI findings between subgroups of recent-onset
childhood arthritis
Of the 59 included children, 16 were clinically classified as having IA, 16 as PA/TA and 27 as
JIA. All IA patients had soft-tissue oedema. Reduced contrast enhancement in the epiphyses
was only found in four of the IA patients and in none of the JIA and PA/TA patients. Bone
marrow oedema (OR 7.46, P=0.011) and absence of T1-weighted and T2-weighted low signal
intensity synovial tissue (OR 0.06, P=0.015) was suggestive of IA. Low signal intensity
synovial tissue (OR 13.30, P<0.001) and soft-tissue oedema (OR 0.20, P=0.018) were
suggestive of JIA. No significant positive determinants were found for PA/TA, but bone
marrow oedema, soft-tissue oedema, irregular thickened synovium and low signal intensity
synovial tissue were less frequent than in IA/JIA.
This study showed that in children with clinical suspicion of recent onset arthritis, there was a
significant difference in the distribution of specific MRI findings among the diagnostic groups.
6.2 Paper 2: Disk abnormality coexists with any degree of synovial and
osseous abnormality in the TMJs of children with JIA
Of the 46 patients, 78% had synovitis and 72% had abnormal bone shape, most frequently in
combination (65%). Disk abnormalities; flat disk, fragmented disk, adherent disk and displaced
disk, were found in 63% of the 46 patients. The 92 TMJs (46 patients) were categorized as A:
No synovitis and normal bone shape (30/92; 33%), B: Synovitis and normal bone shape (14/92:
15%), C: Synovitis and abnormal bone shape (38/92; 41%) and D: No synovitis, but abnormal
bone shape (10/92; 11%). Disk abnormalities were found in all categories of JIA involved
TMJs (A: 3%; B: 57%; C: 66% and D: 70%). We found displaced disks to be most frequent in
category B; flat disk most frequent in category C, and adherent disk most frequent in category
D. Only two TMJs had fragmented disk, both in category C. Disk displacement was found in
half of the joints in category B, and synovitis was most pronounced in this category.
33
Our results show that disk abnormalities together with synovitis and abnormal bone shape were
frequent in symptomatic TMJs in children with JIA. Disk displacement in particular, occurred
in joints with early TMJ arthritis, i.e., with normal bone shape. Other disk abnormalities were
found in joints with bone abnormalities. Thus, attention should be paid to disk abnormalities
both in early and long-standing TMJ arthritis in children with JIA.
6.3 Paper 3: Long-term muscular outcome and predisposing and prognostic
factors in JDM: a case control study
After median disease duration of 16.8 years, reduced muscle strength and endurance were
found in 42% with MMT (score <78) and in 31% with the CMAS (score <48), whereas MRI
assessed muscular damage (calcinosis of muscle or fascia, muscle atrophy, or muscle fatty
infiltration) was found in 52% of the patients. Of the 58 patients, 9% had signs of active
disease (muscle oedema), 29% had muscle atrophy (volume reduction), 43% muscle fatty
infiltration, 16% muscle calcinosis, and 19% fascia calcinosis. Subcutaneous atrophy and
subcutaneous calcinosis were found in 19% and 7% of the patients, respectively.
The results showed that many years after diagnosis, JDM patients have reduced muscle strength
and poorer physical health compared to the general population. Early predictors of
unfavourable outcome, including MRI assessed muscle damage, were high MDI muscle score
and high DAS score one year post-diagnosis.
34
7. DISCUSSION
7.1 Methodological considerations
7.1.1 Study design and study population
All the three studies were cross-sectional studies, but the study designs varied depending on
the research question.
Paper 1
The study was part of a large prospective and population-based study. The population of
children < 16 years in the three explored counties in South-Eastern Norway was 255,303, and
the annual incidence was found to be 71 per 100,000 children (24). TA, JIA, PA and IA were
found in 43, 14, 9 and 5 of 100,000 children, respectively. The patient population was similar
to previous epidemiological studies regarding age at onset, gender and subgroup/subtype
distribution (22-24, 27), supporting that the background patient population comprise a
representative cohort of children with recent onset childhood arthritis including JIA. The
selection criteria for MRI were however stricter and the population therefore more like a
hospital-based one.
As in hospital-based populations (79, 80, 84), the inclusion criteria in the MRI study may have
resulted in a selection of the most severely ill children, e.g. IA and polyarticular JIA. This is
supported by the high percentage of JIA/IA (73%) subjected to MRI compared to PA/TA
(27%). This also suggests that our selection criteria for MRI were sufficient to detect cases of
JIA and IA in need of early treatment, avoiding unnecessary MRIs. MRI was performed in all
patients with IA. A limitation of our study is that we did not know the patient characteristics of
those not having MRI.
Due to the limited number of milder cases of arthritis, TA and PA were considered as one
entity. This is a limitation as these two diagnoses may have different characteristics at MRI.
The strength of our study design was the epidemiological design providing the opportunity to
look at early arthritis (first doctor visit), important in our research question to differentiate
between subgroups of recent onset childhood arthritis.
35
Paper 2
The study was a hospital-based study of children with JIA referred to the Department of
Rheumatology at Oslo University Hospital. The frequency of JIA subtypes was similar to
other hospital-based studies (92, 108) and included more severely involved joints than
population-based patient groups (25).
The high frequency of severe JIA subtypes with long disease duration may be the reason for
the high frequency of TMJs in category C (synovitis and abnormal bone shape), reflecting
advanced TMJ involvement. A population-based study or a study performed at the time of the
first doctor visit would probably have included a higher frequency of newly discovered JIA
and may have resulted in more TMJs in category B (synovitis without abnormal bone shape),
a prognostic interesting category.
The main limitation of the study was the small sample size recruited from a single institution.
The patients were obtained from a study where the aim was to compare ultrasound and MRI
findings in patients with inflammatory musculoskeletal disease with TMJ symptoms. The
requirement of ultrasound and MRI obtained within the same week lead to the exclusion of
patients where the interval was longer. A new study should include a larger study population.
Paper 3
The study was a long-term follow-up of a retrospective inception cohort of Norwegian
patients with JDM diagnosed between 1970 and 2006. JDM is a rare disease and in order to
obtain a study cohort of sufficient size, patients have to be recruited from large populations. In
the present study patients were identified through search in the chart archives at the
Department of Rheumatology, Oslo University Hospital, and through contact with the other
Departments of Paediatrics and Rheumatology in Norway. A limitation was that there were no
complete search at the other departments, but Oslo University Hospital is responsible for the
care of children with rheumatic diseases in the largest region in Norway, and is referral centre
for the others (105). Thus our study cohort was referral-based and not population-based and
consequently may have comprised a predominance of severe cases. In 2000-2006 the annual
incidence was 2.9 /million children per year corresponding with other studies (49, 50). The
annual incidence before 2000 was however only 1.8/million children per year, and the study
36
cohort diagnosed these years may therefore also have comprised a predominance of severe
cases.
A limitation of our study is that MRI of the control group was not performed. MRI of the
control group may have reduced the effect of confounders like age and gender in findings like
muscle volume loss and fat infiltration (109).
Strengths of our study are that all patients alive were identified, and that 95% of them
accepted to participate, and that the matched control group reduced the influence of age and
gender as possible confounders for the clinical tests.
7.1.2 MRI technique and sequences
Challenges in performing MRI in children are communication, immobilization, energy
absorption from the RF pulses, and the exposure for gadolinium-containing contrast media.
Communication must be appropriate to the age of the child to motivate the child and if
possible make the child understand why the examination is needed. It should be sufficient
time to prepare and customize the child and its parents for the situation. In our studies this
was taken care of by radiographers experienced in MRI examination of children.
Young children (< 5 years) usually need sedation to undergo MRI. Children have small
anatomical parts, and the spatial resolution needed may increase the acquisition time and
consequently also the need for sedation. In order to minimize the examination time the
selected sequences were few and robust (T1-weighted TSE, STIR and PD/T2-weighted TSE),
sufficient to evaluate synovitis, effusion, bone marrow, cartilage and muscle. These are still
the most commonly used sequences, (71, 81, 82, 99, 100, 110-115). The protocols that we
used are similar to those in other recent reports and proposed protocols concerning MRI of
joints in children; the juvenile MRI scoring (JAMRIS) system (116-118), the outcome
measures in rheumatoid arthritis clinical trials (OMERACT) MRI in JIA working group and
health e-child (119), and a scoring system for the JIA wrist (114). To minimize scan time we
did not include pre-contrast fat-saturated T1-weighted sequences or newer MRI techniques
that possibly could have provided additional information, especially about tissue vascularity
(e.g. DCE MRI).
37
Recent technological developments such as increased field strength, more sophisticated coils
and new MR techniques (isotropic 3D sequences, DIXON, PROPELLER, DCE MRI, DWI)
may lead to a change in the protocols for musculoskeletal MRI and improved image quality
and diagnostic performance (60-62, 64, 120-123). DIXON reduces fat inhomogeneity
artefacts compared to conventional T2-weighted MRIs making T2-weighted DIXON images
an alternative to STIR, but with higher spatial resolution (64). Furthermore pre-contrast T1-
weighted DIXON has potential for quantification of fatty infiltration of muscles in JDM
patients (124), and DIXON reduces scan time doing T1 TSE with and without fat saturation at
the same time. PROPELLER techniques improve image quality and perhaps also the need for
sedation (122). The time-activity curve obtained from DCE MRI is anticipated to provide
superior information on vascularity and grade of inflammation (differentiate active from
inactive synovial disease) (62, 120, 123, 125) compared to a single series of post-contrast
images. DWI depicts early ischemia (126), osseous oedema and soft tissue oedema, and DWI
has been proposed as a contrast-free approach to imaging of synovitis (121, 127, 128). T1ρ
mapping, delayed gadolinium enhanced MRI of cartilage (dGEMRIC) and T2 mapping of the
biochemical composition of cartilage (proteoglycans and collagen) may have potential in
children since the ossification of the skeleton in children is incomplete (66). T2 mapping has
also potential to quantify muscle oedema (129). UTE T2*-sequences depict cortical bone,
osteochondral junction, meniscus, tendon, ligaments, synovium and deep layers of articular
cartilage due to their very short T2-times (67).
Although synovial thickening is depicted on high-resolution conventional pre-contrast
sequences, the use of gadolinium increases the sensitivity for detecting synovial disease in
JIA (81, 82, 84, 130). The contrast agent also leaks through the synovial membrane,
enhancing the synovial fluid. This may complicate the interpretation of synovitis (contrast
enhancement in thickened synovium) (131, 132). In our studies, the post-contrast sequence
was therefore performed shortly after the contrast-injection. In addition T2-weighted images
were helpful in differentiating synovial thickening from fluid, the fluid having higher signal
intensity than the synovium.
Since 2006, nephrogenic systemic fibrosis (NSF) has been associated with intravenous
administration of gadolinium-containing contrast media in patients with severely reduced
renal function (GFR < 30 ml/min/m2) (133-135). NSF in children is rare, but serious,
38
characterized by fibrosis of the skin and other tissues. With respect to risk of NSF, the
current gadolinium-based contrast media are divided into high-, medium-, and low-risk
agents. High-risk agents are contraindicated in newborns, and are not recommended in
children less than one year of age. Gadolinium is a heavy metal and recent studies have
indicated an accumulation of gadolinium in the brain of patients given repeated doses of
gadolinium-based contrast media, seen at T1-weighted MRI as increased signals in the dentate
nucleus and the globus pallidus (136-138). Thus, these contrast media should be minimized in
small children with immature kidneys and especially in patients requiring repeated
examinations. The goal must be to replace contrast-enhanced sequences with other sequences
providing similar information.
7.1.3 MRI-based scoring systems
Validated and reliable image based scoring systems are important for clinical diagnosis,
outcome and research of JIA-involved joints and JDM-involved muscles. An MRI based
scoring system should include the required diagnostic information, e.g. synovitis and bone
marrow oedema (predictors for erosions) (139-141). Small differences in definitions of the
MRI variables may result in significant frequency variations in the outcome variables. At the
time of the study start there was no consensus on the definitions of MRI findings of
inflammatory changes in JIA-involved joints or JDM-involved muscles or consensus on MRI
scoring systems. Consequently, the definitions of normal and inflammatory MRI findings
were based on previous studies (97), but are still similar to definitions in the most recent
reports (116).
The scoring systems for childhood arthritis, TMJ arthritis and inflammatory myopathy used in
the three studies included in this thesis were self-designed, but based on various reports in the
literature (99, 104, 106, 107). The subjective assessment of MRI findings including the
number of grades and the relative weights of the different findings may influence the outcome
of the test. Too many scoring grades do not necessarily improve diagnostic accuracy as shown
in an MRI study of carpal erosions (114) where the 0-10 score had lower reliability than the 0-
5 score. For most of the MRI findings we used binary scoring. With this approach equivocal
cases might have been wrongly assigned to one of the groups.
39
A research collaboration was recently established to develop MRI scoring systems for JIA
(117, 119, 142). Based on previous studies the research collaboration suggests different MRI
scoring systems in large joints (knee) (117), in small joints (the wrist) (114, 118), in the
tendon sheaths (143) and in the TMJ (142). The research collaboration also focuses on
technical requirements (MRI protocols, sequences, performance) and the definitions of MRI
findings. Despite being performed prior to these proposed guidelines the assessment of MRI
findings in our three papers are similar to these suggestions.
Oedema, atrophy (volume loss and fatty infiltration of muscle) and calcification in the
subcutaneous tissue, muscle fascia and muscles in the thighs were assessed in paper 3. With
the exception of the use of a 5-point score of fatty infiltration of muscle, binary scoring was
used. Multi-level scoring of muscle oedema was attempted, but due to a small number of
patients in our study cohort of long-term JDM patients, the scores were converted into a
binary score. It is likely that the extent of signal changes and the signal intensity on STIR in
muscles are related to disease activity.
Our method for scoring fatty infiltration of muscles was adapted from Goutallier et al. (104,
144) where the percentage of fatty infiltration of a muscle is visually graded from 0 (no fatty
deposits) to 4 (less muscle than fat). To account for the age-dependent amount of fat streaks
we chose to define grades 0 and 1 as normal (145). Another frequently used method, first used
in muscle dystrophy, by Mercuri et al. (103) uses a similar scale evaluating the volume of fat
in individual muscles: 0: normal; 1: scattered small areas of fat infiltration; 2: <30% of the
volume; 3: 30%-60% of the volume; and 4: >60% of the volume. The values are comparable
with the values of Goutallier et al, but it would be an advantage in disease monitoring and
research to have one standardized method. Other reports have tried to establish more objective
quantifying measure of fatty infiltration of muscles using DIXON-sequences (124, 146).
7.2 Radiological and clinical implications of study findings
7.2.1 MRI as a tool to differentiate subgroups of childhood arthritis (paper 1)
We found differences in MRI joint characteristics between subgroups of early childhood
arthritis (JIA, IA and PA/TA), and identified findings suggestive of JIA and IA. Despite the
40
heterogeneity of the subgroup PA/TA, caused by the classification as one group, our findings
of MRI’s ability to differentiate between IA and PA/TA were similar to several other groups
studying IA and TA (77-79, 125).
Except for reduced contrast-enhancement in the epiphyses seen only in the IA group, no
pathognomonic findings were identified for any of the arthritis subgroups. Furthermore,
reduced contrast enhancement as a sign of epiphyseal avascularity has also been reported in
TA and JIA, but less frequently (79). All patients in the IA group had soft tissue oedema, but
so had also half of the patients in the other subgroups. The strong association between IA and
soft tissue oedema, bone marrow oedema and avascularity is probably due to IA being a more
abrupt and aggressive form of inflammation than the two other groups. Another reason for
frequent bone marrow oedema is that osteomyelitis and infectious arthritis often co-exist due
to direct spread (42, 147).
In our study we found more frequent involvement of non-ossified cartilaginous epiphysis in
patients with IA. This is in accordance with two recent MRI studies of patients with
methicillin-resistant Staphylococcus aureus (MRSA) (148, 149). In the MRSA study,
contrast-enhanced MRI was especially important in detecting the growth cartilage
involvement (148). In a study of osteoarticular infections caused by Kingella Kingae and
gram positive cocci, epiphyseal cartilage abscesses were present only in the Kingella Kingae
group, and bone reaction and soft tissue reaction were less severe than in gram positive cocci
(149). No MRSA infections were included in this study. Thus, different infections may not
have the same appearance at MRI.
Due to the unspecific nature of MRI findings and the frequent negative blood- and synovial
fluid cultures, a combination of radiological, laboratory and clinical findings seems
mandatory in the diagnosis of IA. Of importance are recent advancements in development of
more sensitive laboratory methods for detecting bacterial infection (e.g. molecular detection
of bacterial nucleic acid, and detection of markers for bacteraemia e.g. procalcitonin) (150).
Lack of soft tissue oedema and findings of areas with decreased T2 signal in thickened
synovium had high association with early JIA. The presence of synovial thickening may be a
sign of more longstanding arthritis. The reason for such a finding in the early phase of JIA,
41
may be the clinically silent insidious onset of JIA, and consequently a longer disease duration
than assumed (81).
Our study shows that articular MRI may provide valuable information for the diagnosis of JIA
and IA, and that MRI is important for early diagnosis and treatment to prevent long-term joint
damage.
7.2.2 Disk abnormalities in the TMJs of children with JIA (paper 2)
Several studies have demonstrated various MRI findings in JIA-involved TMJs (32, 33, 85-87,
90), but little attention has been paid to the involvement of the disks. Disk-abnormalities are
often not reported (33, 85, 87, 91-95), or reported in long-standing arthritis with manifest
bone abnormalities (31, 32, 96).
We found displaced disks to be frequent in JIA-involved TMJs with synovitis before bone
abnormality (category B) had taken place, indicating that this might be part of an early
process in a diseased joint. Both early TMJ arthritis and displaced disk with reduction at
mouth opening may be clinically silent (151, 152). A recent study shows that TMJ with
condylar deformity (disks not reported) has higher association with clinical symptoms than
joints with only synovitis (153). Five out of the seven TMJs included in category B in our
study had displaced disk without reduction, and displaced disk without reduction is reported
to be symptomatic (154, 155). These patients with presumably early arthritis also had the
most extensive synovial thickening and high frequency of bone marrow oedema and effusion,
indicating a more pronounced inflammation. Rupture of the thin TMJ retro-diskal ligaments
may be caused by inflammation and result in displaced disk (156, 157).
Flat disk was most frequently found in TMJs belonging to category C (synovitis and abnormal
bone shape). Mechanical stress may play a role in the development of the flattening (158).
Due to biomechanics, displaced disks in healthy people may lead to shape deformity of the
condyle and early degenerative changes (159, 160). Synovitis is present also in degenerative
disease, but is often described as more modest with less intense contrast enhancement than the
autoimmune form (161). In our study many of the joints in category C had only modest
synovitis. This may be due to the high frequency of patients on medication, but it is also
reasonable to ask if these findings may be secondary to degeneration rather than the idiopathic
42
inflammation, and that the joint deformity and mechanical conditions itself maintain the
synovial reaction.
Our study indicated that disk displacement may provide prognostic information and should
therefore be included in a scoring system.
7.2.3 Muscle damage shown at MRI corresponds with clinical findings in patients with
long-term JDM (paper 3)
We showed that MRI findings of chronicity (calcification, fibrosis, and fatty-infiltration and
volume loss of muscles) were associated with reduced muscle strength (low MMT and CMAS
score). In accordance with other studies, we found that long term JDM patients had reduced
muscle strength. Muscle strength was persistently reduced in 42% based on MMT 8 and in
31% based on CMAS, whereas MRI-detected muscle damage was found in 52%. Low MMT
score and CMAS score have been found in 41% and 53% of JDM patients in another study
with 7 years follow-up time (162), but no controls were included in that study. The frequency
variation in muscle strength may be due to the use of different cut-off values. In our study the
cut-off values were based on the score from our control group. Normal variation and ageing
may be misinterpreted as muscle damage at MRI (109), and MMT 8 and CMAS may
underscore muscle strength, due to short performance time, patient motivation and
cooperation, and in CMAS, due to difficulties in performing complex movements allowing
compensatory strategies (74).
The MRI protocol included only the thighs, and the thigh muscles accounted only for a small
number of the muscles tested in MMT 8 and CMAS. Despite this limitation, the association
between MRI findings and muscle strength suggests that in a systemic disease such as JDM,
whole body MRI (WBMRI) may be omitted. The MRI findings in the thigh muscles may be
representative of the disease. However, WBMRI depicts the muscle-involvement more
completely and correlates with MMT and CMAS (112, 163). Besides, WBMRI has been
suggested to map subcutaneous changes (112). Subcutaneous and myofascial findings are
predictors for worse outcome and more aggressive calcification (107, 111). Other limitations
of our study were the lack of MRI of the control group, and the lack of MRI at the time of the
43
diagnosis and at one-year follow-up. This made it impossible to assess longitudinal image
changes.
Our study showed that high disease activity present one year post-diagnosis correlated with
persistently reduced muscle strength and later muscle damage at MRI. The knowledge of
early predictors for muscle damage may guide treatment and follow-up.
44
8. MAIN CONCLUSIONS
1. In children with recent onset arthritis, there were significant differences in the distribution
of certain MRI findings in the subgroups of childhood arthritis JIA, IA and PA/TA. Nearly
all MRI findings were found in all groups, but there were predominant findings in each
group.
2. IA was suggested by bone marrow oedema and absence of synovial tissue with low signal
intensity on T1-weighted and T2-weighted MR images. Furthermore, soft-tissue oedema
and reduced contrast enhancement in the epiphyses were more frequent in children with IA
than in those with other arthritides. Soft tissue oedema was always found in the IA group.
JIA was positively correlated to low signal intensity synovial tissue and negatively
correlated to soft-tissue oedema. JIA had more irregular synovia, also in the early phase.
No significant determinants were found for PA/TA, but bone marrow oedema, soft-tissue
oedema, irregular thickened synovium and low signal intensity synovial tissue were less
frequent in PT/TA than in IA/JIA.
3. A classification of the TMJs in patients with JIA was based on MRI findings of synovitis
and abnormal bone shape: A: No synovitis and normal bone shape; B: Synovitis and normal
bone shape; C: Synovitis and abnormal bone shape; D: No synovitis, but abnormal bone
shape. TMJ category C was most frequent in this hospital-based population of JIA. TMJ
category B had the most frequent findings of active inflammation as effusion and bone
marrow oedema. The synovial thickness was also highest in this category.
4. Disk abnormality was frequent in all TMJ categories: disk dislocations were most frequent
in category B; flat disks were most frequent in category C, and adherent disks were most
frequent in category D.
5. Fifty-two percent of the JDM patients at median 16.8 years follow up had muscle
involvement at MRI (fatty infiltration of muscle, 43%; muscle oedema, 9%; calcifications
in any tissue layer, 24%).
45
6. Muscle damage shown at MRI correlated with muscle strength and endurance shown in
MMT 8 and CMAS.
7. MDI muscle damage and sustained disease activity one year after JDM diagnosis, were
identified as early predictors of reduced muscle strength and MRI- detected muscle damage
at follow up.
8.1 Concluding remarks
Development of efficient medications in the treatment of inflammatory juvenile
musculoskeletal diseases in the past decade has increased the need for validated and reliable
diagnostic tools. In this respect, the present thesis is a contribution to the understanding and
the use of MRI as a tool in primary diagnosis, follow-up and research. We have focused on
several MRI findings in general joints, TMJs and muscles, and identified variables that
probably should be parts of MRI scoring systems.
8.2 Implications for further research
Future studies of childhood arthritis should focus on:
1. Improvement of MRI scoring systems in inflammatory joint disease and inflammatory
muscle disease.
2. Improvement of MRI techniques and protocols in juvenile inflammatory joint and muscle
disease with focus on reducing the exposure to gadolinium and the need for sedation.
3. Further exploration of the prognostic importance of early MRI findings of inflammatory
musculoskeletal disease in patients with JIA and JDM.
4. Comparison of MRI and other radiological methods in the diagnosis of juvenile
inflammatory joint and muscle disease.
5. Further follow-up of muscle MRI findings in the cohort of JDM patients.
46
9. REFERENCES
1. Gattorno M, Martini A. The immune system and the inflammatory response. In: Petty RE, Cassidy JT, Laxer RM, Lindsley CB, eds. Textbook of pediatric rheumatology. 5th ed. Philadelphia: Elsevier Saunders; 2005. pp 19-63.
2. Cassidy JT, Petty RE. Introduction to the study of rheumatic diseases in children. In: Cassidy JT, Petty RE, Laxer RM, Lindsley CB, eds. Textbook of pediatric rheumatology. 5th ed. Philadelphia: Elseviers Saunders; 2005. pp 2-8.
3. Blickman JG, van Die CE, de Rooy JW. Current imaging concepts in pediatric osteomyelitis. Eur Radiol. 2004;14(4):55-64.
4. Gylys-Morin VM. MR imaging of pediatric musculoskeletal inflammatory and infectious disorders. Magn Reson Imaging Clin N Am. 1998;6(3):537-59.
5. Lamer S, Sebag GH. MRI and ultrasound in children with juvenile chronic arthritis. Eur J Radiol. 2000;33(2):85-93.
6. Buchmann RF, Jaramillo D. Imaging of articular disorders in children. Radiol Clin North Am. 2004;42(1):151-68.
7. Johnson K, Gardner-Medwin J. Childhood arthritis: classification and radiology. Clin Radiol. 2002;57(1):47-58.
8. Østergaard M, Hansen M, Stoltenberg M, Gideon P, Klarlund M, Jensen KE, et al. Magnetic resonance imaging-determined synovial membrane volume as a marker of disease activity and a predictor of progressive joint destruction in the wrists of patients with rheumatoid arthritis. Arthritis Rheum. 1999;42(5):918-29.
9. Østergaard M, Hansen M, Stoltenberg M, Jensen KE, Szkudlarek M, Pedersen-Zbinden B, et al. New radiographic bone erosions in the wrists of patients with rheumatoid arthritis are detectable with magnetic resonance imaging a median of two years earlier. Arthritis Rheum. 2003;48(8):2128-31.
10. Petty RE. Prognosis in children with rheumatic diseases: justification for consideration of new therapies. Rheumatology (Oxford). 1999;38(8):739-42.
11. Soames RW. Skeletal system. In: Williams PL, ed. Gray's anatomy. 38th ed. New York: Churchill Livingstone; 1995. pp. 425-736.
12. Gardner-Medwin JM, Irwin G, Johnson K. MRI in juvenile idiopathic arthritis and juvenile dermatomyositis. Ann N Y Acad Sci. 2009;1154:52-83.
13. Siegel MJ, Luker GG. Bone marrow imaging in children. Magn Reson Imaging Clin N Am. 1996;4(4):771-96.
14. Cassidy JT, Petty RE. Structure and function. In: Cassidy JT, Petty RE, Laxer RM, Lindsley CB, eds. Textbook of pediatric rheumatology. 5th ed. Philadelphia: Elsevier Saunders; 2005. pp 9-18.
47
15. Lei J, Liu MQ, Yap AU, Fu KY. Condylar subchondral formation of cortical bone in adolescents and young adults. Br J Oral Maxillofac Surg. 2013;51(1):63-8.
16. Morimoto Y, Konoo T, Tominaga K, Tanaka T, Yamaguchi K, Fukuda J, et al. Relationship between cortical bone formation on mandibular condyles and alternation of the magnetic resonance signals characteristic of growth. Am J Orthod Dentofacial Orthop. 2007;131(4):473-80.
17. Alomar X, Medrano J, Cabratosa J, Clavero JA, Lorente M, Serra I, et al. Anatomy of the temporomandibular joint. Semin. Ultrasound CT MR. 2007;28(3):170-83.
18. Salmons S. Muscle. In: Williams PL, ed. Gray's anatomy. 38th ed. New York: Churchill Livingstone; 1995. pp. 737-900.
19. Scott JH. Muscle growth and function in relation to skeletal morphology. Am J Phys anthropol. 1957;15(2):197-234.
20. Brewer EJ, Jr., Bass J, Baum J, Cassidy JT, Fink C, Jacobs J, et al. Current proposed revision of JRA Criteria. JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Section of The Arthritis Foundation. Arthritis Rheum. 1977;20(2):195-9.
21. Petty R, Southwood T, Manners P, Baum J, Glass D, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390-2.
22. Kunnamo I, Kallio P, Pelkonen P. Incidence of arthritis in urban Finnish children. A prospective study. Arthritis Rheum. 1986;29(10):1232-8.
23. von Koskull S. Incidence and prevalence of juvenile arthritis in an urban population of southern Germany: a prospective study. Ann Rheum Dis. 2001;60(10):940-5.
24. Riise ØR, Handeland KS, Cvancarova M, Wathne KO, Nakstad B, Abrahamsen TG, et al. Incidence and characteristics of arthritis in Norwegian children: a population-based study. BMC Pediatr. 2008;121(2):299-306.
25. Berntson L, Andersson Gäre B, Fasth A, Herlin T, Kristinsson J, Lahdenne P, et al. Incidence of juvenile idiopathic arthritis in the Nordic countries. A population based study with special reference to the validity of the ILAR and EULAR criteria. J Rheumatol. 2003;30(10):2275-82.
26. Moe N, Rygg M. Epidemiology of juvenile chronic arthritis in northern Norway: a ten-year retrospective study. Clin Exp Rheumatol. 1998;16(1):99-101.
27. Gare BA, Fasth A. Epidemiology of juvenile chronic arthritis in southwestern Sweden: a 5-year prospective population study. Pediatrics. 1992;90(6):950-8.
28. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369(9563):767-78.
29. Do TT. Transient synovitis as a cause of painful limps in children. Curr Opin Pediatr. 2000;12(1):48-51.
48
30. Sharma S, Sherry DD. Joint distribution at presentation in children with pauciarticular arthritis. J Pediatr. 1999;134(5):642-3.
31. Arvidsson L, Smith H-J, Flatø B, Larheim T. Temporomandibular joint findings in adults with long-standing juvenile idiopathic arthritis: CT and MR imaging assessment. Radiology. 2010;256(1):191-200.
32. Abramowicz S, Cheon J-E, Kim S, Bacic J, Lee E. Magnetic resonance imaging of temporomandibular joints in children with arthritis. J oral maxillofac surg. 2011;69(9):2321-8.
33. Stoll ML, Sharpe T, Beukelman T, Good J, Young D, Cron RQ. Risk factors for temporomandibular joint arthritis in children with juvenile idiopathic arthritis. J Rheumatol. 2012;39(9):1880-7.
34. Mathews CJ, Coakley G. Septic arthritis: current diagnostic and therapeutic algorithm. Curr Opin Rheumatol. 2008;20(4):457-62.
35. Luhmann JD, Luhmann SJ. Etiology of septic arthritis in children: an update for the 1990s. Pediatr Emerg Care. 1999;15(1):40-2.
36. Weston VC, Jones AC, Bradbury N, Fawthrop F, Doherty M. Clinical features and outcome of septic arthritis in a single UK Health District 1982-1991. Ann Rheum Dis. 1999;58(4):214-9.
37. Yagupsky P, Dubnov-Raz G, Gene A, Ephros M. Differentiating Kingella kingae septic arthritis of the hip from transient synovitis in young children. J Pediatr. 2014;165(5):985-9.
38. Kocher MS, Mandiga R, Zurakowski D, Barnewolt C, Kasser JR. Validation of a clinical prediction rule for the differentiation between septic arthritis and transient synovitis of the hip in children. J Bone Joint Surg Am. 2004;86(8):1629-35.
39. Perlman MH, Patzakis MJ, Kumar PJ, Holtom P. The incidence of joint involvement with adjacent osteomyelitis in pediatric patients. J Pediatr Orthop. 2000;20(1):40-3.
40. Kocher MS, Zurakowski D, Kasser JR. Differentiating between septic arthritis and transient synovitis of the hip in children: an evidence-based clinical prediction algorithm. J Bone Joint Surg Am. 1999;81(12):1662-70.
41. Lyon RM, Evanich JD. Culture-negative septic arthritis in children. J Pediatr Orthop. 1999;19(5):655-9.
42. Wang CL, Wang SM, Yang YJ, Tsai CH, Liu CC. Septic arthritis in children: relationship of causative pathogens, complications, and outcome. J Microbiol Immunol Infect. 2003;36(1):41-6.
43. Hannu T, Inman R, Granfors K, Leirisalo-Repo M. Reactive arthritis or post-infectious arthritis? Best Pract Res Clin Rheumatol. 2006;20(3):419-33.
49
44. Fink CW. The role of the streptococcus in poststreptococcal reactive arthritis and childhood polyarteritis nodosa. J Rheumatol Suppl. 1991;29:14-20.
45. Szer IS, Taylor E, Steere AC. The long-term course of Lyme arthritis in children. N Eng J Med. 1991;325(3):159-63.
46. Luhmann SJ, Jones A, Schootman M, Gordon JE, Schoenecker PL, Luhmann JD. Differentiation between septic arthritis and transient synovitis of the hip in children with clinical prediction algorithms. J Bone Joint Surg Am. 2004;86(5):956-62.
47. Flato B, Aasland A, Vinje O, Forre O. Outcome and predictive factors in juvenile rheumatoid arthritis and juvenile spondyloarthropathy. J Rheumatol. 1998;25(2):366-75.
48. Simon S, Whiffen J, Shapiro F. Leg-length discrepancies in monoarticular and pauciarticular juvenile rheumatoid arthritis. J Bone Joint Surg Am. 1981;63(2):209-15.
49. Mendez EP, Lipton R, Ramsey-Goldman R, Roettcher P, Bowyer S, Dyer A, et al. US incidence of juvenile dermatomyositis, 1995-1998: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Registry. Arthritis Rheum. 2003;49(3):300-5.
50. Symmons DP, Sills JA, Davis SM. The incidence of juvenile dermatomyositis: results from a nation-wide study. Br J Rheumatol. 1995;34(8):732-6.
51. Hiketa T, Matsumoto Y, Ohashi M, Sasaki R. Juvenile dermatomyositis: a statistical study of 114 patients with dermatomyositis. J Dermatol. 1992;19(8):470-6.
52. Shehata R, al-Mayouf S, al-Dalaan A, al-Mazaid A, al-Balaa S, Bahabri S. Juvenile dermatomyositis: clinical profile and disease course in 25 patients. Clin Exp Rheumatol. 1999;17(1):115-8.
53. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Eng J Med. 1975;292(7):344-7.
54. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Eng J Med. 1975;292(8):403-7.
55. Brown VE, Pilkington CA, Feldman BM, Davidson JE. An international consensus survey of the diagnostic criteria for juvenile dermatomyositis (JDM). Rheumatology (Oxford). 2006;45(8):990-3.
56. Feldman BM, Rider LG, Reed AM, Pachman LM. Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet. 2008;371(9631):2201-12.
57. Tse S, Lubelsky S, Gordon M, Al Mayouf SM, Babyn PS, Laxer RM, et al. The arthritis of inflammatory childhood myositis syndromes. J Rheumatol. 2001;28(1):192-7.
58. Huber AM, Lang B, LeBlanc CM, Birdi N, Bolaria RK, Malleson P, et al. Medium- and long-term functional outcomes in a multicenter cohort of children with juvenile dermatomyositis. Arthritis Rheum. 2000;43(3):541-9.
50
59. Westbrook C, Roth CK, Talbot J. MRI in practice. 3rd ed: Oxford UK: Blackwell publishing, 2005.
60. Naraghi A, White LM. Three-dimensional MRI of the musculoskeletal system. AJR Am J Roentgenol. 2012;199(3):283-93.
61. Pipe JG. Motion correction with PROPELLER MRI: application to head motion and free-breathing cardiac imaging. Magn Reson Med. 1999;42(5):963-9.
62. Workie DW, Graham TB, Laor T, Rajagopal A, O'Brien KJ, Bommer WA, et al. Quantitative MR characterization of disease activity in the knee in children with juvenile idiopathic arthritis: a longitudinal pilot study. Pediatr Radiol. 2007;37(6):535-43.
63. Dixon WT. Simple proton spectroscopic imaging. Radiology. 1984;153(1):189-94.
64. Brandao S, Seixas D, Ayres-Basto M, Castro S, Neto J, Martins C, et al. Comparing T1-weighted and T2-weighted three-point Dixon technique with conventional T1-weighted fat-saturation and short-tau inversion recovery (STIR) techniques for the study of the lumbar spine in a short-bore MRI machine. Clin Radiol. 2013;68(11):e617-23.
65. Bammer R. Basic principles of diffusion-weighted imaging. Eur J Radiol. 2003;45(3):169-84.
66. Keenan KE, Besier TF, Pauly JM, Smith RL, Delp SL, Beaupre GS, et al. T1rho Dispersion in Articular Cartilage: Relationship to Material Properties and Macromolecular Content. Cartilage. 2015;6(2):113-22.
67. Bae WC, Biswas R, Chen K, Chang EY, Chung CB. UTE MRI of the Osteochondral Junction. Curr Radiol Rep. 2014;2(2):35.
68. Ruperto N, Ravelli A, Pistorio A, Ferriani V, Calvo I, Ganser G, et al. The provisional Paediatric Rheumatology International Trials Organisation/American College of Rheumatology/European League Against Rheumatism Disease activity core set for the evaluation of response to therapy in juvenile dermatomyositis: a prospective validation study. Arthritis Rheum. 2008;59(1):4-13.
69. Miller FW, Rider LG, Chung YL, Cooper R, Danko K, Farewell V, et al. Proposed preliminary core set measures for disease outcome assessment in adult and juvenile idiopathic inflammatory myopathies. Rheumatology (Oxford). 2001;40(11):1262-73.
70. Lovell DJ, Lindsley CB, Rennebohm RM, Ballinger SH, Bowyer SL, Giannini EH, et al. Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies. II. The Childhood Myositis Assessment Scale (CMAS): a quantitative tool for the evaluation of muscle function. The Juvenile Dermatomyositis Disease Activity Collaborative Study Group. Arthritis Rheum. 1999;42(10):2213-9.
51
71. Rider LG, Koziol D, Giannini EH, Jain MS, Smith MR, Whitney-Mahoney K, et al. Validation of manual muscle testing and a subset of eight muscles for adult and juvenile idiopathic inflammatory myopathies. Arthritis Care Res (Hoboken). 2010;62(4):465-72.
72. Loge JH, Kaasa S, Hjermstad MJ, Kvien TK. Translation and performance of the Norwegian SF-36 Health Survey in patients with rheumatoid arthritis. I. Data quality, scaling assumptions, reliability, and construct validity. J Clin Epidemiol. 1998;51(11):1069-76.
73. Bode RK, Klein-Gitelman MS, Miller ML, Lechman TS, Pachman LM. Disease activity score for children with juvenile dermatomyositis: reliability and validity evidence. Arthritis Rheum. 2003;49(1):7-15.
74. Rider LG, Werth VP, Huber AM, Alexanderson H, Rao AP, Ruperto N, et al. Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient/Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI). Arthritis Care Res (Hoboken). 2011;63(11):118-57.
75. Singh G, Athreya BH, Fries JF, Goldsmith DP. Measurement of health status in children with juvenile rheumatoid arthritis. Arthritis Rheum. 1994;37(12):1761-9.
76. Bancroft LW. MR imaging of infectious processes of the knee. Radiol Clin North Am. 2007;45(6):931-41.
77. Kwack KS, Cho JH, Lee JH, Cho JH, Oh KK, Kim SY. Septic arthritis versus transient synovitis of the hip: gadolinium-enhanced MRI finding of decreased perfusion at the femoral epiphysis. AJR Am J Roentgenol. 2007;189(2):437-45.
78. Lee SK, Suh KJ, Kim YW, Ryeom HK, Kim YS, Lee JM, et al. Septic arthritis versus transient synovitis at MR imaging: preliminary assessment with signal intensity alterations in bone marrow. Radiology. 1999;211(2):459-65.
79. Yang WJ, Im SA, Lim GY, Chun HJ, Jung NY, Sung MS, et al. MR imaging of transient synovitis: differentiation from septic arthritis. Pediatr Radiol. 2006;36(11):1154-8.
80. Argyropoulou MI, Fanis SL, Xenakis T, Efremidis SC, Siamopoulou A. The role of MRI in the evaluation of hip joint disease in clinical subtypes of juvenile idiopathic arthritis. Br J Radiol. 2002;75(891):229-33.
52
81. Gardner-Medwin JM, Killeen OG, Ryder CA, Bradshaw K, Johnson K. Magnetic resonance imaging identifies features in clinically unaffected knees predicting extension of arthritis in children with monoarthritis. J Rheumatol. 2006;33(11):2337-43.
82. Johnson K, Wittkop B, Haigh F, Ryder C, Gardner-Medwin JM. The early magnetic resonance imaging features of the knee in juvenile idiopathic arthritis. Clin Radiol. 2002;57(6):466-71.
83. Murray JG, Ridley NT, Mitchell N, Rooney M. Juvenile chronic arthritis of the hip: value of contrast-enhanced MR imaging. Clin Radiol. 1996;51(2):99-102.
84. Gylys-Morin VM, Graham TB, Blebea JS, Dardzinski BJ, Laor T, Johnson ND, et al. Knee in early juvenile rheumatoid arthritis: MR imaging findings. Radiology. 2001;220(3):696-706.
85. Koos B, Twilt M, Kyank U, Fischer-Brandies H, Gassling V, Tzaribachev N. Reliability of clinical symptoms in diagnosing temporomandibular joint arthritis in juvenile idiopathic arthritis. J Rheumatol. 2014;41(9):1871-7.
86. Meyers AB, Laor T. Magnetic resonance imaging of the temporomandibular joint in children with juvenile idiopathic arthritis. Pediatr Radiol. 2013;43(12):1632-41; quiz 29-31.
87. Vaid Y, Dunnavant FD, Royal S, Beukelman T, Stoll M, Cron R. Imaging of the temporomandibular joint in juvenile idiopathic arthritis. Arthritis Car Res. 2014;66(1):47-54.
88. Kottke R, Saurenmann RK, Schneider MM, Muller L, Grotzer MA, Kellenberger CJ. Contrast-enhanced MRI of the temporomandibular joint: findings in children without juvenile idiopathic arthritis. Acta Radiol. 2015;56(9):1145-52.
89. von Kalle T, Winkler P, Stuber T. Contrast-enhanced MRI of normal temporomandibular joints in children--is there enhancement or not? Rheumatology (Oxford). 2013;52(2):363-7.
90. Tzaribachev N, Fritz J, Horger M. Spectrum of magnetic resonance imaging appearances of juvenile temporomandibular joints (TMJ) in non-rheumatic children. Acta radiol. 2009;50(10):1182-6.
91. Argyropoulou MI, Margariti PN, Karali A, Astrakas L, Alfandaki S, Kosta P, et al. Temporomandibular joint involvement in juvenile idiopathic arthritis: clinical predictors of magnetic resonance imaging signs. Eur Radiol. 2009;19(3):693-700.
92. Cannizzaro E, Schroeder S, Muller LM, Kellenberger CJ, Saurenmann RK. Temporomandibular joint involvement in children with juvenile idiopathic arthritis. J Rheumatol. 2011;38(3):510-5.
93. Kuseler A, Pedersen TK, Herlin T, Gelineck J. Contrast enhanced magnetic resonance imaging as a method to diagnose early inflammatory changes in the temporomandibular joint in children with juvenile chronic arthritis. J Rheumatol. 1998;25(7):1406-12.
53
94. Muller L, Kellenberger CJ, Cannizzaro E, Ettlin D, Schraner T, Bolt IB, et al. Early diagnosis of temporomandibular joint involvement in juvenile idiopathic arthritis: a pilot study comparing clinical examination and ultrasound to magnetic resonance imaging. Rheumatology (Oxford). 2009;48(6):680-5.
95. Weiss PF, Arabshahi B, Johnson A, Bilaniuk LT, Zarnow D, Cahill AM, et al. High prevalence of temporomandibular joint arthritis at disease onset in children with juvenile idiopathic arthritis, as detected by magnetic resonance imaging but not by ultrasound. Arthritis Rheum. 2008;58(4):1189-96.
96. Taylor DB, Babyn P, Blaser S, Smith S, Shore A, Silverman ED, et al. MR evaluation of the temporomandibular joint in juvenile rheumatoid arthritis. J Comput Assisted Tomogr. 1993;17(3):449-54.
97. Østergaard M, Peterfy C, Conaghan P, McQueen F, Bird P, Ejbjerg B, et al. OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging Studies. Core set of MRI acquisitions, joint pathology definitions, and the OMERACT RA-MRI scoring system. J Rheumatol. 2003;30(6):1385-6.
98. Collison CH, Sinal SH, Jorizzo JL, Walker FO, Monu JU, Snyder J. Juvenile dermatomyositis and polymyositis: a follow-up study of long-term sequelae. South Med J. 1998;91(1):17-22.
99. Summers RM, Brune AM, Choyke PL, Chow CK, Patronas NJ, Miller FW, et al. Juvenile idiopathic inflammatory myopathy: exercise-induced changes in muscle at short inversion time inversion-recovery MR imaging. Radiology. 1998;209(1):191-6.
100. Hilario MO, Yamashita H, Lutti D, Len C, Terreri MT, Lederman H. Juvenile idiopathic inflammatory myopathies: the value of magnetic resonance imaging in the detection of muscle involvement. Sao Paulo Med J. 2000;118(2):35-40.
101. Schweitzer ME, Fort J. Cost-effectiveness of MR imaging in evaluating polymyositis. AJR Am J Roentgenol. 1995;165(6):1469-71.
102. Huber AM, Feldman BM, Rennebohm RM, Hicks JE, Lindsley CB, Perez MD, et al. Validation and clinical significance of the Childhood Myositis Assessment Scale for assessment of muscle function in the juvenile idiopathic inflammatory myopathies. Arthritis Rheum. 2004;50(5):1595-603.
103. Mercuri E, Pichiecchio A, Allsop J, Messina S, Pane M, Muntoni F. Muscle MRI in inherited neuromuscular disorders: past, present, and future. Journal of magnetic resonance imaging : JMRI. 2007;25(2):433-40.
104. Goutallier D, Postel JM, Bernageau J, Lavau L, Voisin MC. Fatty muscle degeneration in cuff ruptures. Pre- and postoperative evaluation by CT scan. Clin Orthop Relat Res. 1994(304):78-83.
105. Sanner H, Gran JT, Sjaastad I, Flatø B. Cumulative organ damage and prognostic factors in juvenile dermatomyositis: a cross-sectional study median 16.8 years after symptom onset. Rheumatology (Oxford). 2009;48(12):1541-7.
54
106. Mitchell DG, Rao V, Dalinka M, Spritzer CE, Gefter WB, Axel L, et al. MRI of joint fluid in the normal and ischemic hip. AJR Am J Roentgenol. 1986;146(6):1215-8.
107. Kimball AB, Summers RM, Turner M, Dugan EM, Hicks J, Miller FW, et al. Magnetic resonance imaging detection of occult skin and subcutaneous abnormalities in juvenile dermatomyositis. Implications for diagnosis and therapy. Arthritis Rheum. 2000;43(8):1866-73.
108. Stoll ML, Good J, Sharpe T, Beukelman T, Young D, Waite PD, et al. Intra-articular corticosteroid injections to the temporomandibular joints are safe and appear to be effective therapy in children with juvenile idiopathic arthritis. J Oral Maxillofac Surg. 2012;70(8):1802-7.
109. Hogrel JY, Barnouin Y, Azzabou N, Butler-Browne G, Voit T, Moraux A, et al. NMR imaging estimates of muscle volume and intramuscular fat infiltration in the thigh: variations with muscle, gender, and age. Age (Dordr). 2015;37(3):9798.
110. Rider LG, Lachenbruch PA, Monroe JB, Ravelli A, Cabalar I, Feldman BM, et al. Damage extent and predictors in adult and juvenile dermatomyositis and polymyositis as determined with the myositis damage index. Arthritis Rheum. 2009;60(11):3425-35.
111. Ladd PE, Emery KH, Salisbury SR, Laor T, Lovell DJ, Bove KE. Juvenile dermatomyositis: correlation of MRI at presentation with clinical outcome. AJR Am J Roentgenol. 2011;197(1):W153-8.
112. Malattia C, Damasio MB, Madeo A, Pistorio A, Providenti A, Pederzoli S, et al. Whole-body MRI in the assessment of disease activity in juvenile dermatomyositis. Ann Rheum Dis. 2014;73(6):1083-90.
113. Davis WR, Halls JE, Offiah AC, Pilkington C, Owens CM, Rosendahl K. Assessment of active inflammation in juvenile dermatomyositis: a novel magnetic resonance imaging-based scoring system. Rheumatology (Oxford). 2011;50(12):2237-44.
114. Boavida P, Lambot-Juhan K, Muller LO, Damasio B, de Horatio LT, Malattia C, et al. Carpal erosions in children with juvenile idiopathic arthritis: repeatability of a newly devised MR-scoring system. Pediatr Radiol. 2015;45(13):1972-80.
115. Hemke R, Kuijpers TW, Nusman CM, Schonenberg-Meinema D, van Rossum MA, Dolman KM, et al. Contrast-enhanced MRI features in the early diagnosis of Juvenile Idiopathic Arthritis. Eur Radiol. 2015;25(11):3222-9.
116. Hemke R, van Veenendaal M, van den Berg JM, Dolman KM, van Rossum MA, Maas M, et al. One-year followup study on clinical findings and changes in magnetic resonance imaging-based disease activity scores in juvenile idiopathic arthritis. J Rheumatol. 2014;41(1):119-27.
117. Hemke R, van Rossum MA, van Veenendaal M, Terra MP, Deurloo EE, de Jonge MC, et al. Reliability and responsiveness of the Juvenile Arthritis MRI Scoring (JAMRIS) system for the knee. Eur Radiol. 2013;23(4):1075-83.
55
118. Malattia C, Damasio MB, Pistorio A, Ioseliani M, Vilca I, Valle M, et al. Development and preliminary validation of a paediatric-targeted MRI scoring system for the assessment of disease activity and damage in juvenile idiopathic arthritis. Ann Rheum Dis. 2011;70(3):440-6.
119. Nusman CM, Ording Muller LS, Hemke R, Doria AS, Avenarius D, Tzaribachev N, et al. Current Status of Efforts on Standardizing Magnetic Resonance Imaging of Juvenile Idiopathic Arthritis: Report from the OMERACT MRI in JIA Working Group and Health-e-Child. J Rheumatol. 2016;43(1):239-44.
120. Hemke R, Lavini C, Nusman CM, van den Berg JM, Dolman KM, Schonenberg-Meinema D, et al. Pixel-by-pixel analysis of DCE-MRI curve shape patterns in knees of active and inactive juvenile idiopathic arthritis patients. Eur Radiol. 2014;24(7):1686-93.
121. Neubauer H, Evangelista L, Morbach H, Girschick H, Prelog M, Köstler H, et al. Diffusion-weighted MRI of bone marrow oedema, soft tissue oedema and synovitis in paediatric patients: feasibility and initial experience. Pediatr Rheumatol online J. 2012;10:20.
122. Darge K, Anupindi SA, Jaramillo D. MR imaging of the abdomen and pelvis in infants, children, and adolescents. Radiology. 2011;261(1):12-29.
123. Malattia C, Damasio MB, Basso C, Verri A, Magnaguagno F, Viola S, et al. Dynamic contrast-enhanced magnetic resonance imaging in the assessment of disease activity in patients with juvenile idiopathic arthritis. Rheumatology (Oxford). 2010;49(1):178-85.
124. Fischer MA, Pfirrmann CW, Espinosa N, Raptis DA, Buck FM. Dixon-based MRI for assessment of muscle-fat content in phantoms, healthy volunteers and patients with achillodynia: comparison to visual assessment of calf muscle quality. Eur Radiol. 2014;24(6):1366-75.
125. Kim EY, Kwack KS, Cho JH, Lee DH, Yoon SH. Usefulness of dynamic contrast-enhanced MRI in differentiating between septic arthritis and transient synovitis in the hip joint. AJR Am J Roentgenol. 2012;198(2):428-33.
126. Menezes NM, Connolly SA, Shapiro F, Olear EA, Jimenez RM, Zurakowski D, et al. Early ischemia in growing piglet skeleton: MR diffusion and perfusion imaging. Radiology. 2007;242(1):129-36.
127. Barendregt AM, Nusman CM, Hemke R, Lavini C, Amiras D, Kuijpers TW, et al. Feasibility of diffusion-weighted magnetic resonance imaging in patients with juvenile idiopathic arthritis on 1.0-T open-bore MRI. Skeletal Radiol. 2015;44(12):1805-11.
128. Li X, Liu X, Du X, Ye Z. Diffusion-weighted MR imaging for assessing synovitis of wrist and hand in patients with rheumatoid arthritis: a feasibility study. Magn Reson Imaging. 2014;32(4):350-3.
129. Maillard SM, Jones R, Owens C, Pilkington C, Woo P, Wedderburn LR, et al. Quantitative assessment of MRI T2 relaxation time of thigh muscles in juvenile dermatomyositis. Rheumatology (Oxford). 2004;43(5):603-8.
56
130. Hemke R, Kuijpers TW, van den Berg JM, van Veenendaal M, Dolman KM, van Rossum MA, et al. The diagnostic accuracy of unenhanced MRI in the assessment of joint abnormalities in juvenile idiopathic arthritis. Eur Radiol. 2013;23(7):1998-2004.
131. Yamato M, Tamai K, Yamaguchi T, Ohno W. MRI of the knee in rheumatoid arthritis: Gd-DTPA perfusion dynamics. J Comput Assist Tomogr. 1993;17(5):781-5.
132. Østergaard 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.
133. Thomsen HS, Morcos SK, Dawson P. Is there a causal relation between the administration of gadolinium based contrast media and the development of nephrogenic systemic fibrosis (NSF)? Clin Radiol. 2006;61(11):905-6.
134. Grobner T. Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104-8.
135. Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006;17(9):2359-62.
136. Errante Y, Cirimele V, Mallio CA, Di Lazzaro V, Zobel BB, Quattrocchi CC. Progressive increase of T1 signal intensity of the dentate nucleus on unenhanced magnetic resonance images is associated with cumulative doses of intravenously administered gadodiamide in patients with normal renal function, suggesting dechelation. Invest Radiol. 2014;49(10):685-90.
137. Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology. 2014;270(3):834-41.
138. Roberts DR, Holden KR. Progressive increase of T1 signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images in the pediatric brain exposed to multiple doses of gadolinium contrast. Brain Dev. 2016;38(3):331-6.
139. Boyesen P, Haavardsholm EA, Østergaard M, van der Heijde D, Sesseng S, Kvien TK. MRI in early rheumatoid arthritis: synovitis and bone marrow oedema are independent predictors of subsequent radiographic progression. Ann Rheum Dis. 2011;70(3):428-33.
140. Haavardsholm EA, Boyesen P, Østergaard M, Schildvold A, Kvien TK. Magnetic resonance imaging findings in 84 patients with early rheumatoid arthritis: bone marrow oedema predicts erosive progression. Ann Rheum Dis. 2008;67(6):794-800.
141. Hetland ML, Ejbjerg B, Horslev-Petersen K, Jacobsen S, Vestergaard A, Jurik AG, et al. MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA). Ann Rheum Dis. 2009;68(3):384-90.
57
142. Hemke R, Doria AS, Tzaribachev N, Maas M, van der Heijde DM, van Rossum MA. Selecting magnetic resonance imaging (MRI) outcome measures for juvenile idiopathic arthritis (JIA) clinical trials: first report of the MRI in JIA special interest group. J Rheumatol. 2014;41(2):354-8.
143. Lambot K, Boavida P, Damasio MB, Tanturri de Horatio L, Desgranges M, Malattia C, et al. MRI assessment of tenosynovitis in children with juvenile idiopathic arthritis: inter- and intra-observer variability. Pediatr Radiol. 2013;43(7):796-802.
144. Goutallier D, Postel J-M, Gleyze P, Leguilloux P, Van Driessche S. Influence of cuff muscle fatty degeneration on anatomic and functional outcomes after simple suture of full-thickness tears. J Shoulder Elbow Surg. 2003;12(6):550-4.
145. Alizai H, Nardo L, Karampinos DC, Joseph GB, Yap SP, Baum T, et al. Comparison of clinical semi-quantitative assessment of muscle fat infiltration with quantitative assessment using chemical shift-based water/fat separation in MR studies of the calf of post-menopausal women. Eur Radiol. 2012;22(7):1592-600.
146. Lee YH, Kim S, Lim D, Song HT, Suh JS. MR Quantification of the Fatty Fraction from T2*-corrected Dixon Fat/Water Separation Volume-interpolated Breathhold Examination (VIBE) in the Assessment of Muscle Atrophy in Rotator Cuff Tears. Acad Radiol. 2015;22(7):909-17.
147. Merlini L, Anooshiravani M, Ceroni D. Concomitant septic arthritis and osteomyelitis of the hip in young children; a new pathophysiological hypothesis suggested by MRI enhancement pattern. BMC Med Imaging. 2015;15:17.
148. Browne LP, Guillerman RP, Orth RC, Patel J, Mason EO, Kaplan SL. Community-acquired staphylococcal musculoskeletal infection in infants and young children: necessity of contrast-enhanced MRI for the diagnosis of growth cartilage involvement. AJR Am J Roentgenol. 2012;198(1):194-9.
149. Kanavaki A, Ceroni D, Tchernin D, Hanquinet S, Merlini L. Can early MRI distinguish between Kingella kingae and Gram-positive cocci in osteoarticular infections in young children? Pediatr Radiol. 2012;42(1):57-62.
150. Arnold JC, Bradley JS. Osteoarticular Infections in Children. Infect Dis Clin North Am. 2015;29(3):557-74.
151. Arabshahi B, Cron RQ. Temporomandibular joint arthritis in juvenile idiopathic arthritis: the forgotten joint. Curr Opin Rheum. 2006;18(5):490-5.
152. Twilt M, Mobers SM, Arends LR, ten Cate R, van Suijlekom-Smit L. Temporomandibular involvement in juvenile idiopathic arthritis. J Rheumatol. 2004;31(7):1418-22.
153. Keller H, Muller LM, Markic G, Schraner T, Kellenberger CJ, Saurenmann RK. Is early TMJ involvement in children with juvenile idiopathic arthritis clinically detectable? Clinical examination of the TMJ in comparison with contrast enhanced MRI in patients with juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2015;13(1):56.
58
154. Tominaga K, Konoo T, Morimoto Y, Tanaka T, Habu M, Fukuda J. Changes in temporomandibular disc position during growth in young Japanese. Dentomaxillofac Radiol. 2007;36(7):397-401.
155. Larheim TA, Westesson P, Sano T. Temporomandibular joint disk displacement: comparison in asymptomatic volunteers and patients. Radiology. 2001;218(2):428-32.
156. Pereira FJ, Lundh H, Eriksson L, Westesson PL. Microscopic changes in the retrodiscal tissues of painful temporomandibular joints. J Oral Maxillofac Surg. 1996;54(4):461-8.
157. Tomas X, Pomes J, Berenguer J, Quinto L, Nicolau C, Mercader JM, et al. MR imaging of temporomandibular joint dysfunction: a pictorial review. Radiographics. 2006;26(3):765-81.
158. Molinari F, Manicone PF, Raffaelli L, Raffaelli R, Pirronti T, Bonomo L. Temporomandibular Joint Soft-Tissue Pathology, I: Disc Abnormalities. Semin. Ultrasound CT MR. 2007;28(3):192-204.
159. Pereira FJ, Jr., Lundh H, Westesson PL. Morphologic changes in the temporomandibular joint in different age groups. An autopsy investigation. Oral Surg Oral Med Oral Pathol. 1994;78(3):279-87.
160. Helms CA, Kaban LB, McNeill C, Dodson T. Temporomandibular joint: morphology and signal intensity characteristics of the disk at MR imaging. Radiology. 1989;172(3):817-20.
161. Kirkhus E, Bjørnerud A, Thoen J, Johnston V, Dale K, Smith HJ. Contrast-enhanced dynamic magnetic resonance imaging of finger joints in osteoarthritis and rheumatoid arthritis: an analysis based on pharmacokinetic modeling. Acta Radiol. 2006;47(8):845-51.
162. Ravelli A, Trail L, Ferrari C, Ruperto N, Pistorio A, Pilkington C, et al. Long-term outcome and prognostic factors of juvenile dermatomyositis: a multinational, multicenter study of 490 patients. Arthritis Care Res (Hoboken). 2010;62(1):63-72.
163. Castro TC, Lederman H, Terreri MT, Caldana WI, Zanoteli E, Hilario MO. Whole-body magnetic resonance imaging in the assessment of muscular involvement in juvenile dermatomyositis/polymyositis patients. Scand J Rheumatol. 2014;43(4):329-33.
