Download Muscle function in Juvenile Idiopathic Arthritis A two-year follow-up Hans Lindehammar

Linköping University Medical Dissertations
No. 847
Muscle function in Juvenile Idiopathic Arthritis
A two-year follow-up
Hans Lindehammar
Department of Neuroscience and Locomotion, Division of Neurophysiology
Faculty of Health Sciences
Linköpings Universitet, SE-581 85 Linköping, Sweden
Linköping 2004
© Hans Lindehammar 2004
Published articles have been reprinted with permission of the copyright holder: Journal of Rheumatology and
Acta Paediatrica
Printed in Sweden by Unitryck, Linköping, Sweden, 2004
ISSN 0345-0082
ISBN 91-7373-819-0
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Imagine no possessions
I wonder if you can
No need for greed or hunger
A brotherhood of man
Imagine all the people
Sharing all the world…
John Lennon
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Abstract
This is a study of muscle function in Juvenile Idiopathic Arthritis (JIA). Rheumatoid arthritis
(RA) is a disease that primarily affects the synovial membrane of joints. Muscle weakness,
atrophy and pain occur in adult RA. This may be a consequence of joint pain, stiffness and
immobility. Muscle inflammation and neuropathy occur as complications in adults. Muscle
function in JIA has been much less studied.
The aim of the study was to examine whether muscle weakness and atrophy also occur in
children with JIA.
This was a longitudinal study over a two-year period, where muscle strength and thickness
were measured repeatedly in a group of 20 children and teenagers with JIA. Muscle strength
was measured using different methods and in several muscle groups. Muscle biopsies were
obtained and nerve conduction velocity studies performed.
The study concludes that, compared to healthy people, children and teenagers with JIA have
as a group reduced muscle strength and muscle thickness. For most of these children and
teenagers, muscle strength is only slightly lower than expected, but a few have marked muscle
weakness. This is most apparent in patients with severe polyarthritis where the weakness
seems to be widespread. Patients with isolated arthritis may also have greatly reduced strength
and thickness of muscles near the inflamed joint.
There is a risk of decreasing strength in patients with polyarthritis and in muscles near an
active arthritis.
Minor changes are common in muscle biopsies, and findings may indicate immunological
activity in the muscles.
Atrophy of type II fibres, as in adult RA, was not found in JIA.
No patient had signs of neuropathy.
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Original publications
This thesis is based on the following papers:
I.
Lindehammar H, Bäckman E. Muscle function in Juvenile Chronic Arthritis. Journal
of Rheumatology 1995;22:1159–65
II.
Lindehammar H, Sandstedt P. Measurement of Quadriceps Muscle Strength and Bulk
in Juvenile Chronic Arthritis. A Prospective, Longitudinal, 2 Year Survey. Journal of
Rheumatology 1998;25:2240–8
III.
Lindehammar H. Hand strength in juvenile chronic arthritis: a two-year follow-up.
Acta Paediatrica 2003;92:1291–6
IV.
Lindehammar H, Lindvall B. Muscle involvement in juvenile idiopathic arthritis.
Submitted to Rheumatology 2004
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Contents
ABSTRACT........................................................................................................................................................... 5
ORIGINAL PUBLICATIONS............................................................................................................................. 7
CONTENTS........................................................................................................................................................... 9
INTRODUCTION............................................................................................................................................... 11
Rheumatoid arthritis.................................................................................................................................... 11
Rheumatoid arthritis in childhood............................................................................................................... 11
Muscles ........................................................................................................................................................ 12
Muscles during growth ................................................................................................................................ 14
Strength measurement ................................................................................................................................. 14
Strength measurement in children ............................................................................................................... 16
Muscle function in joint disorders ............................................................................................................... 16
Muscle function in rheumatoid arthritis ...................................................................................................... 17
Muscle function in juvenile idiopathic arthritis........................................................................................... 17
Immunology and muscle .............................................................................................................................. 18
AIMS OF THE STUDY...................................................................................................................................... 19
MATERIAL......................................................................................................................................................... 21
PATIENTS .......................................................................................................................................................... 21
CONTROL AND REFERENCE GROUPS .................................................................................................................. 24
Reference groups ......................................................................................................................................... 24
Controls ....................................................................................................................................................... 24
METHODS .......................................................................................................................................................... 27
MUSCLE STRENGTH ........................................................................................................................................... 27
Isometric muscle strength ............................................................................................................................ 27
Isokinetic muscle strength ........................................................................................................................... 27
Handgrip strength ....................................................................................................................................... 27
Non-voluntary strength................................................................................................................................ 28
MUSCLE THICKNESS .......................................................................................................................................... 29
MUSCLE BIOPSY ................................................................................................................................................ 30
Muscle biopsy .............................................................................................................................................. 30
Staining........................................................................................................................................................ 30
Immunohistochemistry................................................................................................................................. 30
Fibre types and areas .................................................................................................................................. 31
NERVE CONDUCTION STUDY ............................................................................................................................. 31
JOINT EVALUATION ........................................................................................................................................... 31
DATA ANALYSIS ................................................................................................................................................ 32
STATISTICAL ANALYSIS ..................................................................................................................................... 32
STUDY DESIGN .................................................................................................................................................. 32
ETHICAL CONSIDERATION ................................................................................................................................. 32
RESULTS AND DISCUSSION.......................................................................................................................... 33
PAPER I ............................................................................................................................................................. 33
PAPER II............................................................................................................................................................ 51
PAPER III........................................................................................................................................................... 70
PAPER IV .......................................................................................................................................................... 74
SUMMARY OF RESULTS................................................................................................................................ 81
GENERAL CONSIDERATIONS...................................................................................................................... 83
MAIN CONCLUSIONS ..................................................................................................................................... 87
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ACKNOWLEDGEMENTS................................................................................................................................ 89
REFERENCES.................................................................................................................................................... 91
PAPER I
PAPER II
PAPER III
PAPER IV
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Introduction
Impaired muscle function is a consequence of rheumatoid arthritis (RA) and other joint
disorders, with muscle weakness, atrophy and pain common symptoms. Reduced joint
mobility and inactivity are likely causes. RA is primarily a disease that affects the joints with
inflammation of the synovial membrane. The synovitis can damage the joint capsule, the
cartilage and bone. Joint stiffness and pain can impair muscle strength and reduce physical
capacity. In clinical practice atrophy of the quadriceps muscle is a well-known consequence
of knee arthritis. Occasionally, muscle weakness and atrophy develop near an inflamed joint
even without much pain or joint stiffness. Neuromuscular complications such as neuropathy
and myopathy sometimes occur in RA. It is difficult to know to what extent muscle weakness
contributes to the reduced functional capacity in chronic joint disease.
Rheumatoid arthritis in childhood, Juvenile Idiopathic Arthritis (JIA) is not as common as in
adults and the aspects of muscle function have been much less studied.
The present thesis is an attempt to increase our knowledge of muscle impairment in JIA. It is
a longitudinal study with a two-year observational survey of muscle strength and thickness.
The work was carried out between 1988 and 1992. The analyses were carried out later.
Rheumatoid arthritis
Rheumatoid arthritis in adults is a chronic idiopathic arthritis occurring in about 0.8% of the
population. In most cases it is a symmetric distal polyarthritis, but all joints can be affected.
The aetiology is not clearly understood, but there is a genetic component and some unknown
factors that triggers activation of the immune system. Many patients have autoantibodies as
rheumatoid factor (RF) in the blood. Inflammation starts in the synovial membrane lining the
joint. The synovitis damages cartilage, bone and tendons. There is also sometimes
inflammation in other tissues in the body. In most cases the disease is chronic, but the
outcome can be influenced by treatment. The arthritis causes reduced mobility of the joints
and deformities. Pain, stiffness, weakness and reduced functional capacity are common.
Rheumatoid arthritis in childhood
Chronic arthritis of unknown aetiology also occurs in children but is much rarer than RA in
adults, with a prevalence of about 0.06% of children [1]. This is a heterogeneous group of
chronic arthropathies.
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The disease has several names depending on the criteria for diagnosis. The most commonly
used term at present is juvenile idiopathic arthritis (JIA). This is defined as a disease
predominately of arthritis with an onset before 16 years of age, a duration of at least six
weeks, and having no known cause. The term was proposed by the International League of
Associations for Rheumatology (ILAR) [2]. The term juvenile chronic arthritis (JCA) was
proposed by the European League Against Rheumatism (EULAR); it has almost the same
definition but requires a duration of three months. The subtypes have somewhat different
labels, but both terms include arthritis associated with psoriasis, spondylitis and inflammatory
bowel disease. The term juvenile rheumatoid arthritis (JRA), proposed by the American
Rheumatism Association (ARA), was the earliest classification and is mostly used in North
America.
Although the cause of the disease is unknown, there are genetic factors and some unknown
environmental factors that trigger the activation of the immune system. Probably, there are
different factors for the different subtypes of the disease.
The subtypes according to the JIA criteria are polyarthritis (RF positive or RF negative),
oligoarthritis, systemic onset, psoriatic arthritis, enthesitis-related arthritis, and other arthritis.
Polyarthritis is the subtype that most resembles adult RA with symmetric distal arthritis. Five
or more joints must be inflamed. Some of these children are RF positive, and their disease is
often more severe. Oligoarthritis has one to four asymmetrically located inflamed joints. This
is the most common subtype and mainly involves large joints, most commonly the knee. One
subgroup is young girls, with positive antinuclear antibodies (ANA) and a considerable risk of
uveitis. The systemic onset type is called Still’s disease, with fever for at least two weeks and
signs of systemic involvement. It often subsequently proceeds to severe chronic polyarthritis.
The prognosis is generally better than adult RA, but remains uncertain and depends on the
subtype and age of onset. About half of patients are expected to have continuing disease after
five years [3]. In a long-term study by Koivuniemi et al [4], 60% of patients with JCA
followed into adult life were in remission at follow-up. The prognosis is better for some
children with an oligoarthritis subtype, and worse for polyarthritis. There is sometimes a
progression from one subtype to another. About 50% of children with oligoarticular onset will
progress to polyarthritis [5].
Muscles
The function of the skeletal muscle is to generate force. The long contractile cells building the
muscles are the muscle fibres. They are tubular and vary from a few to several centimetres in
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length and from 50 to 70 µm in diameter. The muscle fibres contain the contractile apparatus,
the myofibrils. Each muscle fibre contains bundles of myofibrils that are surrounded by
membranes in contact with the cell membrane of the muscle fibre. The contractile property is
dependent on the protein actin and myosin arranged in myofilaments. These proteins have the
ability to shorten in the presence of calcium ions. Calcium ions are released inside the cell as
a response to stimulation of the motor nerve, and the increase in intracellular calcium
concentration activates the contractile proteins. The process of contraction is energy requiring.
The mitochondria are energy producers in muscle fibres, and the energy is released from
degradation of adenosine triphosphate (ATP) by action of the enzyme ATPase. Muscle fibres
are grouped into functional units, the motor units, consisting of one motor neurone with the
cell body in the anterior horn of the spinal cord, its axon, and a group of muscle fibres
innervated by this nerve cell. The number of muscle fibres in one motor unit is between five
and several thousand, scattered within an area of 5 to10 mm. The motor unit is the smallest
functional unit of the muscle, since all muscle fibres in one motor unit contract at the same
time. Increasing the frequency of discharges in the motor neurone, and activating more and
more motor units, gradually increases the muscle force. Muscle contraction can be isometric,
i.e. static without shortening of the muscle or movement, or dynamic with a shortening of the
muscle and movement of the limb.
The muscle fibres are of three basic types, classified according to their characteristics. Type I
fibres are red, slow twitch, resistant to fatigue and metabolically aerobic-oxidative. Type IIA
fibres are white, fast twitch, fatigue resistant, and both oxidative and glycolytic. Type IIB
fibres are white, fast twitch, fatigue sensitive and glycolytic. These three fibre types occur in
approximately equal proportions in muscles, though this may vary in different muscles. All
muscle fibres in a motor unit are of the same fibre type. Sometimes immature muscle fibres,
called type IIC fibres, are seen in biopsies.
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Figure 1. Muscle fibres in cross section. Type I fibres are light and type II fibres are dark.
Muscles during growth
Muscle volume increases between birth and puberty. This occurs by an increase in muscle
fibre diameter and length – the number of muscle fibres does not increase [6]. The amount of
myofilaments increases and with this muscle strength. Only small changes occur after puberty
[7, 8], but adult males usually have larger muscle fibres than females. In healthy adults, type
II fibres have slightly larger areas than type I fibres, especially in men [9]. From childhood to
adulthood, the proportion of type I fibres decreases and the proportion of type II fibres
increases, probably caused by a transformation of type I to type II fibres [6].
Strength measurement
Muscle function includes different muscles properties, for example strength and endurance.
Muscle strength can be estimated by manual testing, providing an approximate grading of
weakness. Functional tests, for instance walking speed, can also be used to evaluate muscle
function in different muscle groups.
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If more detailed information on the strength of different muscles is required, more
quantitative methods must be used. For muscle strength measurements, isometric, isotonic
and isokinetic tests are available. Strength can be measured during shortening (concentric
contraction) or during lengthening (eccentric contraction) of the muscle.
Isometric measurement implies no movement and only slight shortening of the tested muscle.
The test can be performed with a simple dynamometer that prevents the tested limb from
moving, i.e. a static contraction. This is an easy and accurate way of measuring strength, but
gives no information on the dynamic capacity of the muscle. It measures the tension
developed at one point only of the dynamic range. The test can be performed in two different
ways. In this study the breaking force technique was used. This implies that the tested person
takes the specified position and is asked to maintain this position when force is applied. The
maximal strength is measured when the force on the transducer is so great that the position
cannot be held. The other type of measurement is contraction, where the tested person is
asked to contract against the transducer as hard as possible.
Isotonic measurement means that the muscle contracts against a constant load, but at variable
speed. This is much like movements in daily life, for example lifting an object. Since the
speed is not predetermined it is difficult to standardise the test situation.
Isokinetic measurement requires more sophisticated dynamometers. The strength is measured
with a movement at a controlled and fixed speed. It measures strength through the whole
range of motion and gives information on the dynamic capacity of the muscle, though the test
situation is somewhat artificial.
Strength is measured in newtons (N) as a measure of the developed force in the movement.
However, the measured value is not only dependent on the power produced by the muscle, but
also on the length of the limb and where on the limb the test device is placed. For this reason
torque is sometimes measured instead, taking into consideration the length of the lever.
Torque is measured in newton metres (Nm). In some cases it may be necessary to correct the
measured strength because of the effect of gravitation, especially when proximal limb muscles
are tested in weak individuals.
All these tests are carried out to measure maximal voluntary strength. The results are therefore
highly dependent on the individual’s motivation to perform a maximal contraction of the
muscle. It is also important that the test positions and placements of the test device are
standardised. There is a learning effect in strength measurement, as it is common to perform
better in subsequent tests than on the first occasion. Measuring strength during electrical
stimulation of the nerve can also be used to test muscle function. This is a way of reducing the
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effect of motivation during the test. However, the procedure is a little painful and is best
performed on small muscles.
Strength measurement in children
The methods described above can also be used on children. In very young children the results
may be unreliable because of an inability to cooperate during the test. Muscle strength
increases during a child’s growth, and reference values must therefore be age-related. It is not
only the power of the muscle itself that increases during growth, but also the length of the
limbs, making the lever longer. When measuring strength over a period of time one must take
the expected change in strength, caused by growth, into consideration. The topic has been
reviewed by Jones et al [10]. Not all methods of strength measurement have been tested for
reliability in children. However, the isometric strength test with a handheld dynamometer
used in this study has. The coefficient of variation ranged between 6 and 16% [11]. The
reliability can be increased by using one single examiner and by standardising the test
procedure.
Muscle function in joint disorders
In clinical practice weakness and atrophy of the quadriceps muscle of the thigh is frequently
observed in knee joint disorders. This has been studied in osteoarthritis of the knee [12-14],
where reduced knee extensor muscle strength and volume have been found compared to
healthy people. The same was found in patients with knee ligament injuries [15, 16].
Nakamura et al [17] found muscle fibre atrophy of the quadriceps muscle in knee joint
disorders. This is probably caused partially by knee joint pain and inactivity. However,
Slemenda et al [13] found weakness in knee extensors in persons with osteoarthritis without
pain. The effect of unloading on skeletal muscles has been studied in healthy persons. In one
study on healthy subjects, strength, cross-sectional area and muscle biopsies were analysed in
the quadriceps muscle after six weeks of bed rest [18]. Knee extensor torque was reduced by
25%, cross-sectional muscle area was reduced by 14% and muscle fibre cross-sectional area
was reduced by 18%. The effect of artificially induced knee effusion on muscle strength has
also been studied experimentally in healthy subjects. Both reduction of knee extensor strength
and inhibition of reflex-evoked muscle contraction were found [19, 20]. A relationship
between the degree of knee effusion and reduction in knee extensor muscle strength has also
been found in chronic knee arthritis. Geborek et al [21] found that a progressive inhibition
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occurred in knee extensor torque when the intra-articular volume and pressure increased.
Fahrer et al [22] found that joint aspiration of knee effusion immediately increased quadriceps
muscle strength. This arthrogenous muscle weakness is apparently caused by reflex
inhibition, since it is partly dependent on afferent stimuli from the joint [23]. Experimental
studies in rats [24] have shown rapid muscle atrophy one week after artificially induced
arthritis. Muscle strength and volume in joint disorders in children has not been extensively
studied. Robben et al [25] showed that muscle atrophy was present in the quadriceps muscle
in children with painful hip.
Muscle function in rheumatoid arthritis
Reduced strength and muscle volume are known to occur in adult RA. This is most obvious in
muscles near an inflamed joint and is mainly described in thigh muscle in knee arthritis
though also in other muscles [26-29]. The mechanisms are probably the same as for other
joint disorders. The muscles of the forearm were studied by Helliwell et al [30], who found
reduced grip strength and a reduction in forearm muscle bulk, though muscle wasting was
small compared to the reduction in strength. Inactivity due to the disease can lead to a
generalised reduction in muscle volume and strength. This is often obvious in patients with
severe polyarthritis. Inflammation of the muscles, i.e. polymyositis and dermatomyositis, is
known to occur as a complication in adult RA [31-34]. In muscle biopsies there are signs of
inflammation and muscle fibre degeneration. Changes in muscles are also known to occur as a
complication with medicines used in RA, e.g. corticosteroids, chloroquine and
d-penicillamine. Complications from the nervous system are known to occur in RA and may
have affect muscle function. Studies have shown the presence of vasculitic neuropathy, distal
symmetric neuropathy and compression neuropathy in some cases of adult RA [35-38]. Some
authors have tried to relate the muscle weakness to functional capacity [39-42]. Ekdahl et al
[26] found a significant correlation between muscle strength and activities of daily living.
Muscle function in juvenile idiopathic arthritis
Muscle function in juvenile idiopathic arthritis has been studied much less than in adults, but
localised muscle atrophy of thigh muscle in knee arthritis is well known in clinical practice.
Overgrowth of the leg resulting in leg-length discrepancy is known to occur as a result of
knee arthritis in childhood [43]. In a few studies on muscle strength in children with juvenile
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idiopathic arthritis, reduced muscle strength, physical capacity and gait velocity have been
found [44-51].
Immunology and muscle
Major histocompatibility complexes (MHC) are important molecules in the immunological
response to antigens. These glycoproteins bind antigens and present them for immune reactive
cells. There are two main types: MHC class I and class II. These molecules are not found on
muscle cells in normal muscles. They have been found on muscle fibres in inflammatory
myopathies in adults [52, 53] and also in muscles from adult patients with RA [54].
Membrane attack complex (MAC) is formed during complement activation, which is part of
the immunological response to antigens. It is not found in normal muscles, but has been found
in myositis associated with Sjogren’s syndrome and in juvenile dermatomyositis [55, 56].
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Aims of the study
The aims of the present study were:
-
to determine whether there is muscle weakness and atrophy in children with JIA (paper I)
-
to analyse how the intensity of arthritis in JIA influences juxta-articular muscle strength
and muscle thickness (paper II)
-
to describe muscle strength in the hands of children with JIA, changes over time, and the
relationship to local arthritis and disease subtype (paper III)
-
to study changes in muscle structure and nerve function in JIA (paper IV)
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Material
Patients
All patients in the study were selected from the Swedish county of Östergötland, which has
400 000 inhabitants. Paediatricians and paediatric clinics in the county were asked to report
all patients with JIA/JCA. This yielded 26 children and teenagers between 7 and 18 years of
age. Children below the age of seven were not expected to be able to perform all the tests
correctly and were therefore not included in the study. All of the 26 children and teenagers
fulfilled the EULAR (European League Against Rheumatism) criteria for active JCA, with
onset before 16 years of age, duration of arthritis of more than three months, and exclusion of
other diseases. Twenty of the 26 (77%) gave informed consent and joined the study. Six did
not wish to participate. The patients were between 7 and 16 years of age at the start of the
study. Ten were girls and ten were boys. The patient characteristics are shown in Tables 1 and
2. Two of the patients had severe disabling disease.
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Table 1. Patients in the study
Patient
Sex Age
Age at
onset
Height (cm)
Weight (kg)
JH
F
7.2–9.3
5
121–131
20–28
Patient’s number in
paper
I–III
IV
1
1
MB
F
8.2–10.2
2
115–126
18–22
2
PM
F
8.5–11.2
7
140–160
27–41
3
2
SP
F
12.7–14.8 7
132–142
36–35
4
3
MGT
F
13.6–15.6 12
159–166
39–50
5
CF
F
14.7–16.8 14
162–163
44–49
6
4
HG
F
14.9–16.9 13
172–174
54–60
7
6
SH
F
15.6–17.6 12
165–166
72–72
8
7
LE
F
15.8–17.8 14
166–166
46–48
9
8
MW
F
15.7–17.7 14
166–166
62–65
10
5
ML
M
9.8–12.0
9
138–145
29–32
11
JL
M
10.8–13.1 4
146–163
34–42
12
JK
M
11.7–13.7 5
154–165
55–64
13
JW
M
13.8–15.9 13
163–175
54–63
14
12
FJ
M
14.0–16.0 9
151–163
50–65
15
10
MGN
M
14.3–16.3 6
161–166
46–52
16
11
BP
M
14.8–16.8 14
159–173
53–70
17
13
AA
M
14.8–16.8 9
180–185
54–65
18
14
JO
M
16.3–18.3 10
168–170
45–52
19
15
HP
M
16.3–18.3 14
169–171
75–83
20
F: female, M: male
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9
Table 2. Patients in the study
Patient Subgroup/
serotype
JH
Oligo/
neg
MB
Poly/
neg
PM
SP
MGT
CF
HG
SH
LE
MW
ML
JL
JK
JW
FJ
MGN
BP
AA
JO
HP
Oligo/
neg
Poly/
HLA B27
Oligo/
neg
Poly/
neg
Poly/
neg
Poly/
neg
Oligo/
neg
Oligo/
neg
Oligo/
neg
Mono/neg
Oligo/
neg
Oligo/
HLA B27
Oligo/
HLA B27
Oligo/
neg
Oligo/
HLA B27
Poly/
neg
Poly/
RF, ANA
Oligo/neg
Disease history
Treatment
Arthritis in right elbow and both knees, stable
disease, good capacity
Systemic onset, symmetric polyarthritis, small and
large joints, stable disease, slightly reduced
capacity
Arthritis in right hip, both knees, stable disease,
good capacity
Symmetric polyarthritis, small and large joints,
active disease, reduced capacity
Arthritis in both knees, stable disease, good
capacity
Symmetric polyarthritis, fingers, knees, TMJ,
stable disease, slightly reduced capacity
Symmetric polyarthritis, fingers, hips, knees, stable
disease, slightly reduced capacity
Asymmetric polyarthritis, small and large joints,
active disease, reduced capacity
Arthritis in knees, toes, wrist, stable disease, good
capacity
Arthritis in wrists, right knee, stable disease, good
capacity
Arthritis in right knee and left hip, active disease,
reduced capacity
Arthritis in left knee, stable disease, good capacity
Systemic onset, arthritis in ankles, hips, stable
disease, good capacity
Arthritis in finger, toes, right knee, stable disease,
good capacity
Arthritis in ankles, hips, stable disease, good
capacity
Arthritis in knees, wrist, ankle, finger, stable
disease, reduced capacity
Arthritis in ankles, elbow, stable disease, good
capacity
Arthritis in wrist, ankles, knees, stable disease,
reduced capacity
Symmetric polyarthritis, small and large joints,
stable disease, reduced capacity
Arthritis in ankles, stable disease, reduced capacity
NSAID, IAS
CS, D-pen, ASA,
IAS
NSAID
CS, NSAID, PD,
D-pen, IAS
HCQ, IAS
NSAID
NSAID
NSAID, AU
NSAID
NSAID, HCQ
ASA, HCQ, SSZ,
IAS
ASA
NSAID
NSAID, AU
ASA
ASA, HCQ, SSZ,
IAS
NSAID, SSZ,
IAS
NSAID, SSZ,
IAS
CS, NSAID,
SSZ, D-pen, IAS
NSAID, SSZ
Oligo: oligoarticular, Poly: polyarticular, Mono: monoarticular, TMJ: temporomandibular joint, IAS:
intra-articular steroids, CS: corticosteroid, NSAID: non-steroidal anti-inflammatory drugs, ASA:
acetylsalicylic acid, AU: auranofin, D-pen: D-penicillamine, SSZ: sulphasalazine, HCQ:
hydroxychloroquine, PD: podophylline
23
Control and reference groups
Reference groups
The methods used in the current study were chosen to match existing published reference
values for healthy children and young adults. The ages and number of persons included in the
different reference groups are summarised in Table 3.
For the isometric, isokinetic, non-voluntary and handgrip strength measurements, the late Eva
Bäckman examined healthy children and young adults with the same equipment used in the
present study. The reference values were published earlier [11, 57-60].
For measurement of muscle thickness with ultrasound, the reference values published by
Heckmatt et al were used [61]. The control group was also used to establish the reference
values for muscle thickness in children over the age of 12.
For muscle biopsies we used a group of healthy physiotherapy students. This group was first
examined to serve as controls in a different hitherto unpublished study, and biopsies were
therefore taken from the gastrocnemius muscle rather than the anterior tibial muscle as in the
patients. The biopsies were prepared at the same laboratory, using the same methods as the
patients. It was not considered ethical to perform muscle biopsies on healthy age-matched
children.
Table 3. Age and number of healthy children and adults in the different reference group
Isometric
strength
Original
reference
Used in the
present study
Isokinetic
strength
3.5–70 years 6–34 years
Handgrip
strength
Muscle
thickness
Muscle
biopsy
9–18 years
Nonvoluntary
strength
9–15 years
0–12 years
18–39 years
(n = 345)
(n = 163)
(n = 97)
(n = 77)
(n = 276)
(n = 58)
7–18 years
7–18 years
9–18 years
9–15 years
7–12 years
18–23 years
(n = 174)
(n = 94)
(n = 97)
(n = 77)
(n = 118)
(n = 33)
Controls
Twenty healthy children volunteered in the study as controls. They were most often a
classmate of the patient, and not randomly selected. The controls were matched for age and
sex. The age difference was less than one year. Isometric muscle strength in knee extensors,
ankle dorsiflexors, elbow flexors and wrist dorsiflexors were measured. Thickness of the
24
quadriceps muscle was measured with ultrasound. They were examined using the same
equipment and methods, and generally at the same time as the patients. They were examined
every three months for two years, as were the patients. The examiner was the same as for the
patients (HL). The reasons why they were examined were that the reference group for
ultrasound measurement was up to 12 years of age and, secondly, to evaluate the effect of
growth on strength and muscle thickness.
25
26
Methods
Muscle strength
Muscle strength was measured in several muscle groups and by different methods. All test
procedures, positions and equipment were chosen to match the existing reference values. In
the voluntary strength measurements the tested person was encouraged to perform a maximal
contraction.
Isometric muscle strength
Isometric muscle strength was measured using a hand-held electronic dynamometer
(Myometer®, Penny & Giles Ltd, Christchurch, Dorset, UK). The maximal voluntary strength
was measured by the breaking force technique. The padded transducer head was placed on
defined sites and resistance was applied until it was lost. The test positions were standardised
(see Table 4). Three measurements were taken at each location, at intervals of 3–5 minutes,
and the peak value recorded. Both the right and left sides were tested. The test was repeated
every three months for two years in patients and controls. The muscle groups tested were knee
extensors, ankle dorsiflexors, elbow flexors and wrist dorsiflexors. The variation between
repeated tests is about 10% for this method [62]. The test was carried out by HL.
Isokinetic muscle strength
Isokinetic muscle strength in ankle dorsiflexors was measured using a Cybex® II
dynamometer (Lumex Inc., Bayshore, New York). The position was the same as for isometric
strength measurement in ankle dorsiflexors. Maximal strength was measured at six different
speeds: constant angular velocities at 15, 30, 60, 120, 180 and 240 degrees/sec. Two
measurements were made on each side. The maximal developed torque was measured and the
peak value used for presentation. The test was conducted three times one year apart in the
patients. The test was carried out by Eva Bäckman.
Handgrip strength
Handgrip strength was measured with a mechanical dynamometer (Rank Stanley, Cox, UK).
The child was instructed to grip the device as hard as possible. The dominant hand was tested,
e.g. the right hand in right-handed individuals. The test was performed in patients three times
one year apart. The test was conducted by Eva Bäckman.
27
Non-voluntary strength
Strength was measured using a special device measuring the force in thumb adduction during
electrical stimulation of the ulnar nerve. The hand and arm were fixated and with the thumb in
abduction. A supramaximal electrical stimulation at 50 Hz was given to the ulnar nerve,
causing a contraction of the thumb adductor muscle. The developed force was measured with
a mechanical dynamometer. The construction of the device made it possible to test the right
hand only. The test was performed twice two years apart in the patients. The youngest patient
refused to do this test. The test was carried out by Eva Bäckman.
28
Table 4. Test positions for muscle strength measurements
Knee extensors (isometric)
Position: sitting
Knee extended.
Resistance applied on anterior aspect of
lower leg, just above the malleoli.
Fixation: posterior aspect of thigh, just
above the knee.
Ankle dorsiflexors (isometric)
Position: sitting
Knee flexed 90 deg., foot in neutral
position.
Resistance applied on dorsal aspect of
foot, proximal to metatarsophalangeal
joints.
Fixation: posterior aspect of lower leg
just above the ankle.
Elbow flexors (isometric)
Position: sitting
Elbow flexed 90 deg., arm supinated.
Resistance applied on volar aspect of
forearm, just above the wrist.
Fixation: posterior aspect of upper arm,
just above the elbow
Wrist dorsiflexors (isometric)
Position: supine
Elbow extended, wrist in 90 deg.
dorsiflexion.
Resistance applied on dorsum of hand.
Fixation: ventral aspect of lower arm.
Handgrip strength
Position: sitting
Elbow flexed 90 deg., arm supinated.
Gripping the device as hard as possible.
Ankle dorsiflexors
(isokinetic)
Position: sitting
Knee flexed 90 deg.
Resistance applied on
dorsal aspect of foot,
proximal to
metatarsophalangeal joints.
Fixation: thigh and lower
leg.
Non-voluntary strength (electrical stimulation)
Position: sitting
Elbow slightly flexed, arm supinated.
Thumb abducted, arm and hand fixated in a special
device.
Electrical stimulation of the ulnar nerve causing the
thumb to adduct.
Muscle thickness
The muscle bulk of the quadriceps muscle was measured by ultrasound imaging (ATL
Ultrasound, Advanced Technology Laboratories, Bothell, WA, USA). The thickness of the
29
anterior part of the quadriceps muscle at mid-thigh level was measured in a standardised way.
The child was supine, relaxed and the knee extended. Mid-thigh level was located by
ultrasound, halfway between the top of the greater trochanter and the knee joint. The distance
between the outer fascia of the quadriceps muscle and the femur was measured with
electronic callipers. Special precautions were taken to avoid compressing the tissue with the
transducer and to keep it perpendicular to the skin. Three measurements were taken on each
side and the mean value calculated. This test was conducted every three months for two years
in patients and controls. The examination was performed by HL at the same time as the
isometric strength measurements.
Muscle biopsy
Muscle biopsy
Biopsies were obtained once from the anterior tibial muscle using local anaesthesia and the
semi-open conchotome biopsy technique [63]. A standard histopathological examination was
carried out for all biopsies. Serial sections (more than 100 sections) were analysed by light
microscopy. In the control group, biopsies from the gastrocnemius muscle were examined in a
similar way.
Staining
Routine stainings were performed after formalin fixation and paraffin embedding. Stainings
were carried out with Mayer’s haematoxylin-eosin, Weigert’s haematoxylin-van Gieson and
Weigert’s elastin-van Gieson. Frozen specimens were stained for myofibrillar adenosine
triphosphatase (after preincubation at pH 9.4 and 4.6), NADH-tetrazolium reductase,
phosphorylase and acid phosphatase. A modified Gomori trichrome, Ehrlich’s haematoxylineosin and Weigert’s haematoxylin-van Gieson were also used on the frozen material. Periodic
acid Schiff (PAS) was used for staining glycogen and oil red O for lipids.
Immunohistochemistry
Immunohistochemical stainings were made on 6 mm thick frozen sections for analysis of cell
surface markers with monoclonal antibodies. Mouse monoclonal antibodies from DAKO
Corporation (Glostrup, Denmark) were used: MHC class I (HLA-ABC M736, IgG2a, 1:100),
30
MHC class II (HLA-DR M704, IgG2a, 1:50) and MAC (anti-human C5b-9 M777, aE11,
1:25).
The following criteria were used for evaluation of abnormal expression of inflammatory
markers. MHC class I: expression involving the total circumference of the muscle fibre
membrane in parts of the biopsy; MHC class II: dense accumulations of capillary expression
in isolated parts of the biopsy; MAC: expression in capillaries. Grading of expression was
made according to scales earlier described [55, 64].
Fibre types and areas
The fibre types and fibre areas were measured using the Tema® system (Check Vision ApS,
Hadsund, Denmark). ATPase staining at pH 4.3, 4.6 and 9.4 was used to differentiate fibre
types, and an antibody against the sarcolemmal protein merosin was used to delineate fibre
areas. The number, percentage and mean areas of fibre types I, IIA, IIB and IIC were
measured. In each biopsy between 90 and 265 muscle fibres were analysed. Because of a
sparse amount of muscle tissue in the biopsy, the muscle fibre analysis could not be reliably
performed for two patients.
All evaluations of the muscle biopsies were made by one person (Björn Lindvall) using the
same criteria for patients and controls.
Nerve conduction study
Nerve conduction velocity was measured twice in all patients, at the start of the study and two
years later. The median and ulnar nerves in the dominant arm were examined for motor and
sensory conduction velocity, distal latencies and amplitudes. A nerve conduction study was
also carried out in the non-dominant leg. The peroneal nerve was tested for motor nerve
conduction velocity, motor response amplitude and distal latency. The sural nerve was tested
for sensory nerve conduction velocity and sensory nerve action potential.
Joint evaluation
The severity of the arthritis in various joints was graded according to the severity score
proposed by the Pediatric Rheumatology Collaborative Study Group. This instrument has
been used in other studies [45, 65, 66]. Four clinical indices were assessed: swelling (0–3),
pain on movement (0–3), tenderness to palpation (0–3), and limitation of passive movement
31
(0–4). Swelling was graded as 0 = no swelling, 1 = mild swelling, 2 = moderate swelling, 3 =
marked swelling. Pain on movement and tenderness to palpation were graded as 0 = none, 1 =
mild (subjective complaint only), 2 = moderate (wincing or withdrawal), 3 = severe (marked
response). Limitation of movement was graded as 0 = full range, 1 = 25% limitation, 2 = 50%
limitation, 3 = 75% limitation, 4 = no movement. This score gives values from 0–13 for each
joint. A score of 0 means no signs of arthritis. A patient with a score > 0 was considered to
have arthritis in that joint. None had limitation of movement only. The joint scoring was
carried out by the author (HL) every three months, at the same time as the other tests.
Data analysis
Strength values and muscle thickness were compared to the reference values and expressed as
a percentage of the mean of the reference group for the actual muscle, age and sex, i.e. the
expected value. Values were also expressed in standard deviations from the mean of the
reference group.
Statistical analysis
To compare patients and controls, and patients with reference values, parametric (t-test) and
non-parametric (Wilcoxon and sign tests) were used, depending on the nature of the data. To
evaluate changes over time a linear regression model was used. Qualitative data were
analysed in 2 x 2 contingency tables using Fisher’s exact test. A p-value less than 0.05 was
considered significant.
Study design
This was an observational study and no treatment effects were evaluated. The children
continued their normal treatment during the whole study period. The examinations were
carried out at defined intervals irrespective of symptoms or treatment. Changes in treatment
were made and intra-articular steroid injections were given when necessary. Articles I and IV
were cross-sectional studies. Articles II and III were longitudinal surveys carried out over a
period of two years.
Ethical consideration
The studies were approved by the ethics committee of the University Hospital, Linköping
(registration numbers 87110 and 97140).
32
Results and discussion
Paper I
The patients in the thesis were tested at 6–9 occasions, but the data presented in this paper all
come from the test in the middle of the study, i.e. the fourth or fifth test.
Paper I is a cross-sectional study of muscle function in JIA/JCA. Muscle strength and
thickness were measured by all methods on one occasion. The results were compared to controls
and reference values.
To enable comparison of results of patients of different ages and gender, all measured values
were related to the mean of the reference group. This is called the expected value. Muscle
strength at 100% of the expected value means that the strength is identical to the mean of the
reference group for the patient’s age and gender. A test result of less than 100% means that
the strength or muscle thickness is lower than expected.
The age difference between patient and control in each pairing was less than four months. As
a group there were no significant differences between patients and controls in weight or
height.
For the main results see Figure 2–10 and Table 5–13.
33
Figure 2. Isometric muscle strength in knee extensors
strength % of expected
Knee extensors
200
patient right
patient left
100
control right
control left
0
1 2 3 4 5 6 7 8 9 1011121314151617181920
patient and control number
Knee extensors
strength % of expected
200
0
34
right
100
left
with local arthritis
without local arthritis
Table 5. Isometric muscle strength in knee extensors
Compared to reference values
Isometric
strength
Knee
extensors
All patients
Right
Left
Right
Patients
with local
Left
arthritis
Patients Right
without
Left
local
arthritis
Percentage Number
of expected below
value
expected
value
78
15/20
74
18/20
64
4/5
Compared to matched
controls
Significance Percentage
Significance
of control
group’s
value
0.021
78
0.0034
0.0007
75
0.0001
ns
64
0.043
65
6/6
0.016
66
0.028
83
11/15
ns
82
0.044
77
12/14
0.006
78
0.0012
35
Figure 3. Isometric muscle strength in ankle dorsiflexors
strength % of expected
Ankle dorsiflexors
200
patient right
patient left
100
control right
control left
0
1 2 3 4 5 6 7 8 9 1011121314151617181920
patient and control number
Ankle dorsiflexors
strength % of expected
200
0
36
right
100
left
with local arthritis
without local arthritis
Table 6. Isometric muscle strength in ankle dorsiflexors
Compared to reference values
Right
Left
Right
Percentage Number
of expected below
value
expected
value
94
15/20
93
12/20
79
6/6
Compared to matched
controls
Significance Percentage Significance
of control
group’s
value
0.021
89
0.012
ns
96
ns
0.016
80
0.028
Left
78
7/7
0.008
84
0.028
Right
102
9/14
ns
93
ns
Left
103
5/13
ns
103
ns
Isometric
strength
Ankle
dorsiflexors
All patients
Patients
with local
arthritis
Patients
without
local
arthritis
37
Figure 4. Isometric muscle strength in elbow flexors
strength % of expected
Elbow flexors
200
patient right
patient left
100
control right
control left
0
1 2 3 4 5 6 7 8 9 1011121314151617181920
patient and control number
Elbow flexors
strength % of expected
200
0
38
right
100
left
with local arthritis
without local arthritis
Table 7. Isometric muscle strength in elbow flexors
Compared to reference values
Right
Percentage Number
of expected below
value
expected
value
83
16/20
Compared to matched
controls
Significance Percentage Significance
of control
group’s
value
0.006
77
0.0001
Left
86
18/20
0.0002
81
0.0013
Right
64
2/3
ns
68
ns
Left
62
2/2
ns
66
ns
Right
86
14/17
0.006
78
0.0003
Left
89
16/18
0.0007
83
0.003
Isometric
strength
Elbow
flexors
All patients
Patients
with local
arthritis
Patients
without
local
arthritis
39
Figure 5. Isometric muscle strength in wrist dorsiflexors
strength % of expected
Wrist dorsiflexors
200
patient right
patient left
100
control right
control left
0
1 2 3 4 5 6 7 8 9 1011121314151617181920
patient and control number
Wrist dorsiflexors
strength % of expected
200
0
40
right
100
left
with local arthritis
without local arthritis
Table 8. Isometric muscle strength in wrist dorsiflexors
Compared to reference values
Right
Percentage Number
of expected below
value
expected
value
82
13/20
Compared to matched
controls
Significance Percentage Significance
of control
group’s
value
ns
75
0.002
Left
74
16/20
0.006
76
0.002
Right
47
5/6
ns
43
0.046
Left
43
6/6
0.016
45
0.028
Right
97
8/14
ns
88
0.03
Left
88
10/14
ns
89
0.04
Isometric
strength
Wrist
dorsiflexors
All patients
Patients
with local
arthritis
Patients
without
local
arthritis
41
Figure 6. Isokinetic muscle strength in ankle dorsiflexors
strength % of expected
Isokinetic strength in ankle dorsiflexors
200
patient right
100
patient left
0
1 2 3 4 5 6 7 8 9 1011121314151617181920
patient number
Isokinetic strength in ankle dorsiflexors
strength % of expected
200
0
42
right
100
left
with local arthritis
without local arthritis
Figure 7. Isokinetic muscle strength at different angular velocities
strength % of expected
Isokinetic strength ankle dorsiflexors
120
100
80
all patients
60
with local arthritis
40
without local arthritis
20
0
0
50
100
150
200
250
angular velocity (deg/sec)
Table 9. Isokinetic muscle strength in ankle dorsiflexors
Isokinetic strength
Ankle dorsiflexors
All velocities
All patients
Right
Compared to reference values
Percentage of
Number below
expected value
expected value
89
13/20
Significance
ns
Left
83
13/20
ns
Patients with
local arthritis
Right
72
6/7
ns
Left
70
9/9
0.002
Patients without
local arthritis
Right
100
7/13
ns
Left
97
4/11
ns
43
Figure 8. Handgrip strength
strength % of expected
Handgrip strength
200
100
patient right
0
1 2 3 4 5 6 7 8 9 1011121314151617181920
patient number
Handgrip strength
strength % of expected
200
100
0
44
right
with local arthritis
without local arthritis
Table 10. Handgrip strength
Right
Compared to reference values
Percentage of
Number below
expected value
expected value
80
17/20
Patients with
local arthritis
Right
56
6/6
0.016
Patients without
local arthritis
Right
89
11/14
0.029
Handgrip strength
All patients
Significance
0.002
45
Figure 9. Non-voluntary muscle strength
strength % of expected
Non-voluntary strength
200
right
100
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
patient number
Non-voluntary strength
strength % of expected
200
100
0
46
right
with local arthritis
without local arthritis
Table 11. Non-voluntary muscle strength
Right
Compared to reference values
Percentage of
Number below
expected value
expected value
91
13/18
Right
85
8/8
0.004
Patients without Right
local arthritis
96
5/10
ns
Non-voluntary
strength
All patients
Patients with
local arthritis
Significance
0.048
47
Figure 10. Quadriceps muscle thickness
Muscle thickness
50
mm
40
patient right
30
patient left
20
control right
10
control left
0
1 2 3 4 5 6 7 8 9 1011121314151617181920
patient and control number
Muscle thickness
% of expected
200
0
48
right
100
left
with local arthritis
without local arthritis
Table 12. Quadriceps muscle thickness
Compared to reference values
Quadriceps
muscle
thickness
All patients
Right
Left
Right
Patients
with local
Left
arthritis
Patients
Right
without
local
Left
arthritis
Percentage Number
of expected below
value
expected
value
88
14/20
83
17/20
73
5/5
Compared to matched
controls
Significance Percentage Significance
of control
group’s
value
ns
88
0.003
0.001
85
0.0009
0.031
77
ns
71
6/6
0.016
75
0.046
93
9/15
ns
91
0.02
89
11/14
0.029
89
0.008
Table 13. Muscle strength in healthy controls compared with reference values
Knee extensors
Right
Compared with reference values
Percentage of
Number below
expected value
expected value
100
9/20
Ankle dorsiflexors
Left
Right
99
105
10/20
8/20
ns
ns
Left
97
8/20
ns
Right
109
6/20
ns
Left
106
9/20
ns
Right
110
4/20
0.006
Left
98
11/20
ns
Controls
Elbow flexors
Wrist dorsiflexors
Significance
ns
Muscle strength was reduced for knee extensors, elbow flexors and wrist dorsiflexors in the
JCA/JIA group. The findings were almost the same whether the results were compared to
reference values or to matched controls. The reduction was found mainly in patients with
arthritis in a joint near the examined muscle. For ankle dorsiflexors the strength was reduced
in this group only. The strength in most muscles was about 60–70% of the expected value for
49
patients with local arthritis. This means that the strength is slightly reduced, but probably
within the normal range in most patients. For a few patients the strength was more markedly
reduced. This is most obvious in patients with arthritis near the examined muscle. For local
arthritis the following joints were judged as important: knee and hip for knee extensors, ankle
for ankle dorsiflexors, elbow and shoulder for elbow flexors, wrist for wrist dorsiflexors, and
wrist and fingers for handgrip strength and non-voluntary strength. In some tests a small
reduction of strength was found even in muscles far from an inflamed joint. In ankle
dorsiflexors the results were comparable for isometric and isokinetic strength measurement.
Isokinetic strength was most reduced at higher angular velocities. Non-voluntary strength was
slightly reduced in patients with local arthritis. Muscle thickness was reduced in the whole
group, but the reduction was greatest in patients with arthritis in the knee or hip.
The results of the current study are in accordance with findings in adults with RA. Hsieh et al
[28] found a strength of 80% of normal in the quadriceps muscle in RA patients with minimal
knee involvement. In a study by Danneskiold-Samsoe et al [29] on women with RA without
knee arthritis, a reduction of knee extensor strength to 85% of that of healthy controls was
found. In a group of patients with severe arthritis in the knee joint, Nordesjo et al [67] found a
strength in knee extensors of 30–45% of healthy controls. Hakkinen et al [68] found that
compared to healthy controls muscle strength in knee extensors was 46% lower and handgrip
strength 31% lower in women with recent onset RA. Muscle strength in JCA/JIA has been
much less studied. Giannini et al [45] examined muscle strength in JRA and found
significantly lower strength in knee extensors compared to healthy children. They found no
relationship between muscle strength and measures of articular disease severity. Hedengren et
al [46] found no reduction in knee extensor strength in children with JCA compared to
healthy children, except for a subgroup in muscles in the lower leg. In the present study,
however, muscle strength was more reduced in muscles near inflamed joints. The lowest
strength values were measured in children with either polyarticular disease or active arthritis
near the examined muscle.
50
Paper II
Paper II is a longitudinal and observational study over a two-year period. The aim was to
evaluate changes in muscle strength and muscle thickness of knee extensor muscles over time.
Knee arthritis is common in JCA/JIA, and this was the case in many of the children in the
study group. Isometric strength of knee extensors, muscle thickness of the quadriceps muscle,
and a joint severity score of knee and hip were measured repeatedly for two years. Isometric
strength was measured with a handheld electronic dynamometer (Myometer®). Muscle
thickness was measured by ultrasound imaging at mid-thigh level. The examination was
repeated every three months irrespective of symptoms.
The results were evaluated in three different ways.
First the relationship between the degree of local arthritis and muscle strength and thickness
was analysed by using one mean value for each patient. The mean value (one dot for each
patient) of a test is an average over two years.
For muscle strength there was a significant relationship between a high arthritis severity score
and a reduction in muscle strength (Figure 11). Those patients with the most intensive and
long-standing local arthritis had the most weakened muscles. Children without local arthritis
had strength close to 100% of the expected value for their age and gender.
51
Figure 11. Relationship between muscle strength in knee extensors and local arthritis severity
score
Muscle strength and local articular disease severity
score
strength % of expected
120
100
80
60
40
20
0
0
1
2
3
4
5
local arthritis severity score (units)
52
6
For muscle thickness the relationship was not significant (Figure 12).
Figure 12. Relationship between thickness of quadriceps muscle and local arthritis severity
score
Muscle thickness and local articular disease
severity score
% of expected
140
120
100
80
60
40
20
0
0
1
2
3
4
5
6
local arthritis severity score (units)
53
Some children with weakened muscle also had thin muscles (Figure 13), but the relationship
for the whole patient group was not significant. The strength was more frequently reduced
than the muscle thickness. The relationship between quadriceps muscle thickness and knee
extensor strength has been studied in healthy adults by Freilich et al [69]. They found a
significant relationship between maximum isometric strength in knee extensors and thickness
of the quadriceps muscle measured by ultrasound.
Figure 13. The relationship between muscle thickness and strength in knee extensors. One
mean value for each patient.
Muscle thickness and muscle strength
strength % of expected
120
100
80
60
40
20
0
0
20
40
60
80
100
muscle thickness % of expected
54
120
140
The second way of analysing the results was to study the relationship between the degree of
local arthritis and muscle strength and thickness for each patient. Because some patients
improved and others deteriorated during the study, an individual regression line was
calculated for those patients who had an obvious change in local arthritis score. Ten children
had a clear change in arthritis score (> 2 units) during the period. The slope of the regression
line is a measure of the relationship between arthritis severity and strength or muscle
thickness.
For eight of ten patients there was a significant negative slope of the regression line for
muscle strength (Figure 14), implying that muscle weakness is correlated to the degree of
local joint inflammation. The mean slope was significantly negative.
Figure 14. Relationship between local arthritis severity score and muscle strength in 10
patients with variation in arthritis severity score. The thick line is the mean of 10 patients.
Muscle strength and local articular disease severity
score
strength % of expected
120
100
80
60
40
20
0
0
2
4
6
8
10
12
local arthritis severity score (units)
55
For all ten patients there was a significant negative slope of the regression line for muscle
thickness (Figure 15). The mean slope was significantly negative. Muscle hypotrophy is
therefore correlated to the degree of local joint inflammation.
Figure 15. Relationship between muscle thickness and local arthritis severity score in 10
patients with variation in arthritis severity score. The thick line is the mean of 10 patients.
Muscle thickness and local articular disease
severity score
120
% of expected
100
80
60
40
20
0
0
2
4
6
8
10
local arthritis severity score (units)
56
12
The third way of analysing the results is to study patterns in the individual patients’ results.
Some patterns of the results are shown in the examples below (Figure 16–22).
57
Figure 16. Patient No. 4
strength (N)
400
350
300
250
200
150
100
50
0
12,5
40
13
13,5
14
14,5
15
14
14,5
15
14
14,5
15
muscle thickness (mm)
35
30
25
20
15
10
5
0
12,5
20
18
13
13,5
local arthritis severity score
(units)
16
14
12
10
8
6
4
2
0
12,5
13
13,5
age (ye ars)
58
Patient No. 4 (Figure 16) is a girl with severe polyarthritis whose disease worsened during the
study. She had arthritis in many joints including the left knee and hip. The figure shows left
knee extensor strength and thickness. Strength and thickness decreased both in absolute terms
and relative to reference values (lines: mean and ± 2 SD). The local arthritis continued despite
all efforts to improve the disease. There was no improvement of strength or muscle thickness
during the study period.
59
Figure 17. Patient No. 11
strength (N)
300
250
200
150
100
50
0
9,5
10
10,5
11
11,5
12
12,5
11
11,5
12
12,5
11
11,5
12
12,5
muscle thickness (mm)
45
40
35
30
25
20
15
10
5
0
9,5
10
10,5
local arthritis severity score
(units)
20
18
16
14
12
10
8
6
4
2
0
9,5
10
10,5
age (ye ars)
60
Patient No. 11 (Figure 17) is a boy with oligoarthritis and arthritis in the right knee and left
hip. The figure shows the results for the right leg. During the first year there was a
deterioration despite treatment. During the second year the patient improved and both strength
and muscle thickness increased when the intensity of the knee arthritis decreased.
61
Figure 18. Patient No. 12
450
strength (N)
400
350
300
250
right
200
left
150
100
50
0
10,5
45
11
11,5
12
12,5
13
13,5
muscle thickness (mm)
40
35
30
25
right
20
left
15
10
5
0
10,5
12
11
11,5
12
12,5
13
13,5
local arthritis severity score
(units)
10
8
6
left
4
2
0
10,5
11
11,5
12
age (ye ars)
62
12,5
13
13,5
Patient No. 12 (Figure 18) is a boy who has had low-active monoarthritis in his left knee for
many years, resulting in overgrowth of the leg. The thigh muscle in the left leg was visibly
thinner than in the right leg. Muscle thickness was lower in the left leg, but muscle strength
was normal without difference between left and right legs.
63
Figure 19. Patient No. 14
strength (N)
600
500
400
300
200
100
0
14
14,5
15
15,5
16
15
15,5
16
15
15,5
16
muscle thickness
50
45
40
35
30
25
20
15
10
5
0
14
14,5
local arthritis severity score
(units)
12
10
8
6
4
2
0
14
14,5
age (ye ars)
64
Patient No. 14 (Figure 19) is a boy with oligoarthritis who developed arthritis in his right knee
in the middle of the study period. Muscle strength and thickness decreased at the same time,
but strength was much more reduced than muscle thickness.
65
Figure 20. Patient No. 19
strength (N)
700
600
500
400
300
200
100
0
16
16,5
17
17,5
18
18,5
17,5
18
18,5
17,5
18
18,5
muscle thickness (mm)
50
45
40
35
30
25
20
15
10
5
0
16
16,5
17
local arthritis severity score
(units)
20
18
16
14
12
10
8
6
4
2
0
16
16,5
17
age (ye ars)
66
Figure 21. Ultrasound images from patient No. 19 and the matched healthy control
Patient No. 19
Muscle thickness 22 mm
Age-matched control to patient
No. 19
Muscle thickness 38 mm
Patient No. 19 (Figure 20–21) is a boy with severe polyarthritis, including chronic hip and
knee arthritis in his right leg, shown here. Both strength and muscle thickness were constantly
reduced over the whole study period.
67
Figure 22. Patient No. 8
strength (N)
600
500
400
300
200
100
0
15,5
40
16
16,5
17
17,5
18
17
17,5
18
17
17,5
18
muscle thickness (mm)
35
30
25
20
15
10
5
0
15,5
14
16
16,5
local arthritis severity score
(units)
12
10
8
6
4
2
0
15,5
16
16,5
age (ye ars)
68
Patient No. 8 (Figure 22) is a girl with polyarthritis, including right hip and knee. She had
reduced muscle strength but normal muscle thickness. There was no obvious change in
muscle strength or thickness related to the increase in local arthritis severity score.
The results of the present study have shown that there is a relationship between strength,
muscle thickness and intensity of local arthritis, both during improvement and deterioration.
For some patients muscle function deteriorated despite treatment. In a study by Geborek et al
[70], an improvement of knee extensor strength was found after treatment of knee arthritis in
adults with intra-articular corticosteroid injections.
69
Paper III
Paper III is a descriptive longitudinal study chiefly focusing on hand function and changes
over time during the two-year follow-up. Isometric strength in wrist dorsiflexors was
measured every three months over two years. Handgrip strength was measured three times
one year apart. The reference values for handgrip strength are from nine years of age, so the
two youngest patients were not included in this evaluation. Strength was evaluated in relation
to the local arthritis severity score and subgroup of disease. The slope of the regression line
for the variables age and strength was used to evaluate changes over time. A negative slope
indicates a decrease in muscle strength, i.e. a muscle weakening. Low strength was defined as
values below -2 SD from the mean of the reference value.
The results are shown schematically in Figure 23 and 24.
70
Figure 23. Results from strength measurements in wrist dorsiflexors during two years
Wrist dorsiflexors
Strength
Patient nr
+2SD
3
1
14
17
16
13
7
12
2
15
10
11
5
6
mean
-2SD
9
20
8
19
4
18
start
end
71
Figure 24. Results from measurement of handgrip strength during two years
Handgrip strength
Strength
Patient nr
+2SD
3
12
10
7
5
13
9
14
6
17
15
11
20
mean
-2SD
16
18
4
8
19
start
end
Most of the patients showed normal strength in wrist dorsiflexors and hands without change
during the two years. Four children had a significant drop in muscle strength, and four had a
constant low strength.
There was a significantly increased risk of low or decreasing strength in patients with
polyarthritis or active local arthritis in the hand or wrist. In a study by Jones et al [71],
significantly impaired hand function was found in adult RA. Improvement in grip strength
72
correlated with improvement in active joint count. Early hand involvement in JRA has been
shown by Ruperto et al [72] to be a strong predictor of poor outcome.
The results of the nerve conduction velocity studies in the upper extremity were normal in all
cases. No changes appeared during follow-up. Nerve conduction studies have earlier been
performed in JRA by Puusa et al [73], who neither found signs of neuropathy.
73
Paper IV
In this cross-sectional study, muscle function was evaluated in relation to findings in muscle
biopsies. Only 15 of the 20 patients initially recruited were willing to participate in this part of
the study. Muscle biopsies were taken from the anterior tibial muscle. Before the biopsy
procedure isometric and isokinetic strength were measured in ankle dorsiflexors on the same
side according to the schedule previously described.
Muscle biopsies were analysed in three different ways.
First, a standard histopathological examination was performed.
Second, an immunohistochemical examination was carried out to evaluate any abnormal
expression of inflammatory markers.
Third, muscle fibre types and areas were measured. Because of sparse amount of muscle
tissue, this could not be performed for two patients.
The results were compared with muscle biopsies obtained from the gastrocnemius muscle in
healthy young adults. The methods and evaluations were identical.
Minor morphological changes such as increased variability of fibre diameter and presence of
some atrophic fibres were found in the majority of patients (Table 14). Such unspecific
findings are sometimes found in healthy people, but the frequency was significantly higher in
the patients compared to the controls. The presence of cellular infiltrates is not a normal
finding in muscle biopsies. In two of the patients (8 and 15) this was found (Figure 25). The
infiltrates were small, sparse and perivascular, and may be a sign of mild inflammation in the
muscle, though there was no obvious myositis.
The expression of MHC class II was found in four patients, but not in any of the controls.
This may be a sign of abnormal immunological activity in the muscle.
Table 14. Results from muscle biopsies
Histopathological and immunohistochemical findings in muscle biopsies
Minimal
Cell infiltrates MHC class I MHC class II
morphological
changes
Patients n = 15 11/15
2/15
1/15
4/15
Controls n = 33 7/33
0/33
2/33
0/33
p-value
0.046
ns
0.014
74
MAC
2/15
1/33
ns
Figure 25. Image showing perivascular cell infiltrates in the muscle
Muscle strength was significantly reduced for the whole group; three patients had muscle
strength below -2SD of the reference values (Table 15).
Table 15. Muscle strength in ankle dorsiflexors
Muscle strength in ankle dorsiflexors (% of expected value)
Isometric
Isokinetic (30 deg/sec)
Patients n = 15
86% (3 patients < -2SD)
82% (1 patient < -2SD)
p-value
0.018
0.008
75
The mean area of fibre types did not differ significantly from the control group (Table 16,
Figure 26).
Table 16. Results from fibre type analysis
Muscle fibre types and areas
Type I fibres
Type IIA fibres
Type IIB fibres
%
20
Mean
area µm²
4520
%
75
Mean
area µm²
3158
5
Mean
area µm²
3483
53
3620
33
3758
14
3681
99
ns
0.0014
%
Patients
n = 13
Controls
n = 33
p-value
ns
ns
Mean
area type
I/IIA
%
77
Figure 26. The mean area of different fibre types in patients and controls
10000
9000
8000
area
mean area of
type I fibres
mean area of
type IIA fibres
mean area of
type IIB fibres
7000
6000
5000
4000
3000
ns
ns
ns
2000
1000
0
76
patients
controls
patients
controls
patients
controls
The relationship between the mean area of type I fibres and the mean area of type IIA fibres
differed from the control group (Figure 27). Most patients had a larger area of type IIA fibres
than type I fibres. It is known from studies in healthy people that fibre type distribution and
size vary in different parts of the muscle [74, 75]. The biopsies in the current study were
obtained from patients and controls using the same technique.
Figure 27. The relationship between the mean fibre area of different fibre types
200
180
%
type I/Type IIA area
type IIA/Type IIB area
160
140
120
100
80
60
40
20
p=0.0014
patients
controls
ns
patients
controls
0
77
Figure 28. Image from biopsy taken from patient 14 (in paper IV). Type I fibres are light and
type II fibres dark.
There was a significant correlation between mean muscle fibre area and isometric strength.
There were no significant correlations between morphological changes in the biopsy and
strength, or relative areas of type I and type IIA fibres and strength. The mean muscle fibre
area was not significantly affected by the presence of active local arthritis, as might have been
assumed from the other studies (papers I–III). The study group is small, however, and the
conclusions therefore somewhat uncertain.
78
A nerve conduction study was performed on nerves in the leg. The results were normal, as
they also were in the upper extremity.
Neuromuscular complications occur in adults with RA [76]. Muscle biopsies have shown
inflammation and muscle fibre degeneration [31]. Miro et al [32] examined muscle biopsies
from RA patients. They found inflammation in the muscle in 43% of patients with muscular
symptoms, mainly weakness, atrophy and pain. In a study by Halla et al [33], signs of
inflammation were found in muscles both in patients with active and inactive RA. Myopathy
may also occur as a complication of treatment with steroids, chloroquine and d-penicillamine
in RA [32, 77-79]. Electrophysiological studies have shown signs of neuropathy (distal
symmetric neuropathy, vasculitic neuropathy and compression neuropathy), sometimes
subclinically in adult RA [35, 36, 38, 80, 81]. Several studies on adult RA have found muscle
fibre atrophy, especially affecting type II fibres [31-33, 82].
Muscle weakness and atrophy sometimes develops in RA patients without any obvious
reason. Inactivity due to the disease is one probable cause. Muscle adaptation in response to
inactivity has been studied by Berg et al [18]. They found that in healthy persons after six
weeks of bed rest, knee extensor strength was decreased by 24%, quadriceps muscle crosssectional area decreased by 13%, and mean muscle fibre area decreased by 17%. The
significant change in muscle fibre area was for type I fibres. The mean area of type IIA and
type IIB fibres did not change significantly. The fibre types did not change. The change in
strength was greater than changes in fibre area and muscle cross-sectional area. This was
further examined in an experimental setting by Larsson et al [83], where isolated human
muscle fibres were analysed. The force-generating capacity of muscle fibres decreased by
about 40% after 6 weeks of bed rest. Their content of contractile myofibrillar proteins
decreased during the same time. Localised atrophy of muscles near an active arthritis may be
caused by what is termed reflex inhibition [22, 23]. Joint pain or distension may inhibit local
muscle activation and induce “immobilisation” of the muscle. The result on the cellular level
may be the same as in experimental unloading.
The expression of inflammatory markers MHC class I and class II has been found in muscles
of adult RA patients [54] and in myositis [64]. Expression of MAC has been found in juvenile
dermatomyositis [56]. No published study on these markers in muscles of children with JIA
has been found.
79
80
Summary of results
Table 17 summarises the overall results for all measurements of strength and muscle thickness
over two years.
Table 17. Overall results from all strength measurements and muscle thickness during two
years
Patient Elbow
number flexors
(isometric)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
N
N
N
L
N
N
N
SL
N
N
SL
N
N
N
N
L
N
L
L
SL
Wrist
dorsiflexors
(isometric)
N
N
N
L
N
SL
N
SL
N
N
N
N
N
N
N
SL
N
L
L
L
Knee
Ankle
extensors dorsi(isometric) flexors
(isometric)
N
N
N
N
N
N
L
L
N
N
N
N
SL
N
SL
N
N
N
N
N
L
N
N
N
N
N
SL
N
N
N
SL
N
N
N
N
N
L
L
N
SL
Ankle
dorsiflexors
(isokinetic)
N
N
N
L
N
N
N
SL
N
N
N
N
N
N
N
N
N
N
L
L
Handgrip
strength
Nonvoluntary
strength
L
L
N
L
N
N
N
L
N
N
N
N
N
N
N
N
N
L
L
N
Not done
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Muscle
thickness
(quadriceps)
N
N
N
L
N
N
N
N
N
N
N
N
N
N
N
L
N
N
L
N
N: normal (most values during two years within ± 2 SD of the mean of the reference values)
L: low (most values during two years < -2 SD)
SL: some low (some values during two years < -2 SD)
Two patients (No. 4 and 19) had very low values in nearly all tests. Clinically they had the
most severe disease of these 20 patients. They had polyarthritis and for periods required a
wheelchair. Nine patients had results within normal limits in all tests. Three had normal
results in almost all tests. Six patients had low values in some of the muscle groups, all of
which probably were due to localised arthritis.
81
82
General considerations
There are a number of methodological problems with this type of study.
The study is observational without evaluation of the effect of treatment. This means that there
are no points in time where the results before and after any measures taken can be evaluated.
Any impairment of the patients was counteracted by more intensive treatment, which
probably reduced the impact on muscle function. Some patients improved and others
deteriorated during the follow-up.
The patient group is very heterogeneous, and the disease probably includes arthritis with
different aetiologies and prognoses. The spectrum of the disease is extensive. Some patients
have isolated arthritis in a single joint which hardly influences the activity of their daily lives
and is relatively easy to treat; others have severe polyarthritis with destruction of joints and
which seems resistant to all treatment.
The patient group is small. It is not a common disease, and the youngest patients are difficult
to examine with some of these methods. Not all suitable patients are willing to participate in
this type of long-time study.
There are problems with all types of strength measurements. The results are highly dependent
on the person’s capacity to perform a maximal muscle contraction, as well as the patients’
motivation, mood and cooperation and the examiner’s ability and willingness to push the
patient. There is variability between investigators and results are very dependent on the
methods used.
There are special problems in evaluating strength in growing children. First, muscle volume
and strength increase with age. Second, the lever, i.e. the length of the limb, increases during
growth. The longer lever makes the torque greater. The reference values for strength
measurement using these methods are originally related to age. Body size at a specific age can
vary a considerably, particularly in the accelerated growth at puberty. This makes the
“normal” strength span, i.e. ± 2 SD, quite wide for some ages. For comparisons between
patients of different ages and gender, it is sometimes better to relate the measured value to the
83
mean of the reference group and express strength as a percentage of the “expected” value,
particularly when changes over time are evaluated. The strength value of one person would
otherwise change from, for instance from -2 SD to -1 SD, simply because of the variability in
muscle strength in the reference group, even if strength deviation from the mean of the
reference value were constant. In the current study a matched control group was also used.
The controls were, however, a convenience sample and not randomly selected.
When measuring strength in joint disorders, one must take the influence of pain into account.
Pain is a component of inflammation, and many people with arthritis have joint or muscle
pain. If the pain is associated with movements of the joint, it will probably influence the
results of strength measurement. In the current study most measurements were carried out
using isometric methods, where minimal movement of the joint is required. Intensive joint
pain would nevertheless reduce the effort to perform a maximal muscle contraction. In the
study group, pain on measurement was not commonly reported. Pain on movement of a joint
is one item measured in the arthritis severity score used in the study.
The main method of strength evaluation in this study, isometric strength measurement, was
chosen because it is a simple and convenient method in clinical practice. The handheld
dynamometer is easy to carry and can be used for many different muscle groups and in any
examination room. It has been used in other studies [84] and was found to be sensitive to
changes in muscle strength. The more sophisticated method of isokinetic strength
measurement has many advantages, but the equipment is not so easy to handle and the test is
more time consuming.
The ultrasound imaging method used for measurement of muscle thickness is also relatively
simple to perform, but does not give as detailed information on muscle volume as MRI or a
CT scan. Ultrasound is, however, harmless and can be repeated many times.
The main problem of the muscle biopsy study is the small number of patients and the lack of
an age-matched control group. Only 15 of the 20 patients were willing to participate in the
muscle biopsy procedure. The group was heterogeneous with different ages, genders and
disease subgroups. It was not considered ethical to perform muscle biopsies on healthy
children for research purposes. The control group for muscle biopsies was young adults, most
of them women. The muscle biopsy was taken from the gastrocnemius muscle in the controls
84
and from the anterior tibial muscle in patients. This may also explain some of the differences
between the groups.
85
86
Main conclusions
Children and teenagers with JCA/JIA have as a group reduced muscle strength and muscle
thickness compared to healthy people. For most, the strength is only slightly lower than
expected, but a few have obvious muscle weakness. This is most apparent in patients with
severe polyarthritis where the weakness appears to be widespread. Patients with isolated
arthritis may also have greatly reduced strength and thickness of muscles near the inflamed
joint. There is a risk of decreasing strength in patients with polyarthritis and in muscles near
an active arthritis.
Minor changes are common in muscle biopsies, and findings may indicate immunological
activity in the muscles.
Atrophy of type II fibres, as in adult RA, was not found in JIA.
Neuropathy may not be a feature of JIA.
87
88
Acknowledgements
To all of you who have helped me in my work, from beginning to end, I would like to express
my gratitude. There are many people, not all named individually, who have supported me
over the years in my research. I would like to thank you all:
Eva Svanborg, my supervisor, who encouraged and pushed me to finish this work.
Per Sandstedt, my initial supervisor, who inspired me to start this research project many years
ago. You never lost hope.
The late Eva Bäckman, my initial co-supervisor, who introduced me to the art of strength
measurement in children.
Magnus Vrethem and Nicola Reiser, my colleagues and friends, for help, encouragement and
for doing my clinical work when I was writing my thesis.
All the staff at the Department of Clinical Neurophysiology: Karin, Ludka, Inga-Britt,
Gunnel, Maria, Maggan, Suzanne, Carina and Per for sharing my daily work, and for skilful
help with the examination of the children in this study.
Björn Lindvall, co-author and friend, who knows everything about muscle histopathology.
Lisbeth and Gunvor at the Neuromuscular Unit, for skilful work with the muscle biopsies.
My colleagues and the staff at the Department of Paediatrics where this study started in the
late eighties.
Margareta Resjö who taught me to carry out the ultrasound examinations.
All the children and young people, both patients and controls, who participated in this study,
and their parents.
Lastly, but most important, I would like to thank my family.
89
90
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