muscle function in juvenile idiopathic arthritis - diva...

Linköping University Medical DissertationsNo. 847

Muscle function in Juvenile Idiopathic Arthritis

A two-year follow-up

Hans Lindehammar

Department of Neuroscience and Locomotion, Division of NeurophysiologyFaculty of Health Sciences

Linköpings Universitet, SE-581 85 Linköping, Sweden

Linköping 2004

2

© Hans Lindehammar 2004

Published articles have been reprinted with permission of the copyright holder: Journal of Rheumatology andActa Paediatrica

Printed in Sweden by Unitryck, Linköping, Sweden, 2004

ISSN 0345-0082ISBN 91-7373-819-0

3

Imagine no possessionsI wonder if you canNo need for greed or hungerA brotherhood of manImagine all the peopleSharing all the world…

John Lennon

5

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.

7

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

9

ContentsABSTRACT........................................................................................................................................................... 5

ORIGINAL PUBLICATIONS............................................................................................................................. 7

CONTENTS........................................................................................................................................................... 9

INTRODUCTION............................................................................................................................................... 11

Rheumatoid arthritis.................................................................................................................................... 11Rheumatoid arthritis in childhood............................................................................................................... 11Muscles ........................................................................................................................................................ 12Muscles during growth ................................................................................................................................ 14Strength measurement ................................................................................................................................. 14Strength measurement in children ............................................................................................................... 16Muscle function in joint disorders ............................................................................................................... 16Muscle function in rheumatoid arthritis ...................................................................................................... 17Muscle function in juvenile idiopathic arthritis........................................................................................... 17Immunology and muscle .............................................................................................................................. 18

AIMS OF THE STUDY...................................................................................................................................... 19

MATERIAL......................................................................................................................................................... 21

PATIENTS .......................................................................................................................................................... 21CONTROL AND REFERENCE GROUPS .................................................................................................................. 24

Reference groups ......................................................................................................................................... 24Controls ....................................................................................................................................................... 24

METHODS .......................................................................................................................................................... 27

MUSCLE STRENGTH........................................................................................................................................... 27Isometric muscle strength............................................................................................................................ 27Isokinetic muscle strength ........................................................................................................................... 27Handgrip strength ....................................................................................................................................... 27Non-voluntary strength................................................................................................................................ 28

MUSCLE THICKNESS.......................................................................................................................................... 29MUSCLE BIOPSY ................................................................................................................................................ 30

Muscle biopsy .............................................................................................................................................. 30Staining........................................................................................................................................................ 30Immunohistochemistry................................................................................................................................. 30Fibre types and areas .................................................................................................................................. 31

NERVE CONDUCTION STUDY ............................................................................................................................. 31JOINT EVALUATION ........................................................................................................................................... 31DATA ANALYSIS................................................................................................................................................ 32STATISTICAL ANALYSIS..................................................................................................................................... 32STUDY DESIGN .................................................................................................................................................. 32ETHICAL CONSIDERATION ................................................................................................................................. 32

RESULTS AND DISCUSSION.......................................................................................................................... 33

PAPER I ............................................................................................................................................................. 33PAPER II ............................................................................................................................................................ 51PAPER III........................................................................................................................................................... 70PAPER IV .......................................................................................................................................................... 74

SUMMARY OF RESULTS................................................................................................................................ 81

GENERAL CONSIDERATIONS...................................................................................................................... 83

MAIN CONCLUSIONS ..................................................................................................................................... 87

10

ACKNOWLEDGEMENTS................................................................................................................................ 89

REFERENCES.................................................................................................................................................... 91

PAPER I

PAPER II

PAPER III

PAPER IV

11

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 arthritisRheumatoid 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 childhoodChronic 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.

12

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].

MusclesThe 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

13

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.

14

Figure 1. Muscle fibres in cross section. Type I fibres are light and type II fibres are dark.

Muscles during growthMuscle 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 measurementMuscle 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.

15

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

16

effect of motivation during the test. However, the procedure is a little painful and is best

performed on small muscles.

Strength measurement in childrenThe 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 disordersIn 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

17

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 arthritisReduced 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 arthritisMuscle 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

18

idiopathic arthritis, reduced muscle strength, physical capacity and gait velocity have been

found [44-51].

Immunology and muscleMajor 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].

19

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)

21

Material

PatientsAll 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.

22

Table 1. Patients in the study

Patient’s number inpaper

Patient Sex Age Age atonset

Height (cm) Weight (kg)

I–III IVJH F 7.2–9.3 5 121–131 20–28 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 9

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

23

Table 2. Patients in the study

Patient Subgroup/serotype

Disease history Treatment

JH Oligo/neg

Arthritis in right elbow and both knees, stabledisease, good capacity

NSAID, IAS

MB Poly/neg

Systemic onset, symmetric polyarthritis, small andlarge joints, stable disease, slightly reducedcapacity

CS, D-pen, ASA,IAS

PM Oligo/neg

Arthritis in right hip, both knees, stable disease,good capacity

NSAID

SP Poly/HLA B27

Symmetric polyarthritis, small and large joints,active disease, reduced capacity

CS, NSAID, PD,D-pen, IAS

MGT Oligo/neg

Arthritis in both knees, stable disease, goodcapacity

HCQ, IAS

CF Poly/neg

Symmetric polyarthritis, fingers, knees, TMJ,stable disease, slightly reduced capacity

NSAID

HG Poly/neg

Symmetric polyarthritis, fingers, hips, knees, stabledisease, slightly reduced capacity

NSAID

SH Poly/neg

Asymmetric polyarthritis, small and large joints,active disease, reduced capacity

NSAID, AU

LE Oligo/neg

Arthritis in knees, toes, wrist, stable disease, goodcapacity

NSAID

MW Oligo/neg

Arthritis in wrists, right knee, stable disease, goodcapacity

NSAID, HCQ

ML Oligo/neg

Arthritis in right knee and left hip, active disease,reduced capacity

ASA, HCQ, SSZ,IAS

JL Mono/neg Arthritis in left knee, stable disease, good capacity ASAJK Oligo/

negSystemic onset, arthritis in ankles, hips, stabledisease, good capacity

NSAID

JW Oligo/HLA B27

Arthritis in finger, toes, right knee, stable disease,good capacity

NSAID, AU

FJ Oligo/HLA B27

Arthritis in ankles, hips, stable disease, goodcapacity

ASA

MGN Oligo/neg

Arthritis in knees, wrist, ankle, finger, stabledisease, reduced capacity

ASA, HCQ, SSZ,IAS

BP Oligo/HLA B27

Arthritis in ankles, elbow, stable disease, goodcapacity

NSAID, SSZ,IAS

AA Poly/neg

Arthritis in wrist, ankles, knees, stable disease,reduced capacity

NSAID, SSZ,IAS

JO Poly/RF, ANA

Symmetric polyarthritis, small and large joints,stable disease, reduced capacity

CS, NSAID,SSZ, D-pen, IAS

HP Oligo/neg Arthritis in ankles, stable disease, reduced capacity 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

24

Control and reference groups

Reference groupsThe 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

Isometricstrength

Isokineticstrength

Handgripstrength

Non-voluntarystrength

Musclethickness

Musclebiopsy

Originalreference

3.5–70 years

(n = 345)

6–34 years

(n = 163)

9–18 years

(n = 97)

9–15 years

(n = 77)

0–12 years

(n = 276)

18–39 years

(n = 58)

Used in thepresent study

7–18 years

(n = 174)

7–18 years

(n = 94)

9–18 years

(n = 97)

9–15 years

(n = 77)

7–12 years

(n = 118)

18–23 years

(n = 33)

ControlsTwenty 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

25

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.

27

Methods

Muscle strengthMuscle 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.

28

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.

29

Table 4. Test positions for muscle strength measurements

Knee extensors (isometric)Position: sittingKnee extended.Resistance applied on anterior aspect oflower leg, just above the malleoli.Fixation: posterior aspect of thigh, justabove the knee.

Ankle dorsiflexors (isometric) Ankle dorsiflexors(isokinetic)

Position: sittingKnee flexed 90 deg., foot in neutralposition.Resistance applied on dorsal aspect offoot, proximal to metatarsophalangealjoints.Fixation: posterior aspect of lower legjust above the ankle.

Position: sittingKnee flexed 90 deg. Resistance applied ondorsal aspect of foot,proximal tometatarsophalangeal joints.Fixation: thigh and lowerleg.

Elbow flexors (isometric)Position: sittingElbow flexed 90 deg., arm supinated. Resistance applied on volar aspect offorearm, just above the wrist. Fixation: posterior aspect of upper arm,just above the elbow

Wrist dorsiflexors (isometric)Position: supineElbow extended, wrist in 90 deg.dorsiflexion.Resistance applied on dorsum of hand.Fixation: ventral aspect of lower arm.Handgrip strength Position: sittingElbow flexed 90 deg., arm supinated.Gripping the device as hard as possible.

Non-voluntary strength (electrical stimulation)Position: sittingElbow slightly flexed, arm supinated.Thumb abducted, arm and hand fixated in a specialdevice. Electrical stimulation of the ulnar nerve causing thethumb to adduct.

Muscle thicknessThe muscle bulk of the quadriceps muscle was measured by ultrasound imaging (ATL

Ultrasound, Advanced Technology Laboratories, Bothell, WA, USA). The thickness of the

30

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.

StainingRoutine 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 haematoxylin-

eosin 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.

ImmunohistochemistryImmunohistochemical stainings were made on 6 �m 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),

31

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 areasThe 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 studyNerve 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

32

(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 analysisStrength 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 designThis 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 considerationThe studies were approved by the ethics committee of the University Hospital, Linköping

(registration numbers 87110 and 97140).

33

Results and discussion

Paper IThe 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.

34

Figure 2. Isometric muscle strength in knee extensors

Knee extensors

0

100

200

stre

ngth

% o

f exp

ecte

d

rightleft

with local arthritis without local arthritis

Knee extensors

0

100

200

1 2 3 4 5 6 7 8 9 1011121314151617181920

patient and control number

stre

ngth

% o

f exp

ecte

d

patient rightpatient leftcontrol rightcontrol left

35

Table 5. Isometric muscle strength in knee extensors

Compared to reference values Compared to matchedcontrols

Isometricstrength Kneeextensors

Percentageof expectedvalue

Numberbelowexpectedvalue

Significance Percentageof controlgroup’svalue

Significance

Right 78 15/20 0.021 78 0.0034All patientsLeft 74 18/20 0.0007 75 0.0001Right 64 4/5 ns 64 0.043Patients

with localarthritis Left 65 6/6 0.016 66 0.028

Right 83 11/15 ns 82 0.044Patientswithoutlocalarthritis

Left 77 12/14 0.006 78 0.0012

36

Figure 3. Isometric muscle strength in ankle dorsiflexors

Ankle dorsiflexors

0

100

200

stre

ngth

% o

f exp

ecte

d

rightleft


Ankle dorsiflexors

0

100

200

1 2 3 4 5 6 7 8 9 1011121314151617181920


stre

ngth

% o

f exp

ecte

d


37

Table 6. Isometric muscle strength in ankle dorsiflexors


Isometricstrength Ankledorsiflexors




Significance

Right 94 15/20 0.021 89 0.012All patientsLeft 93 12/20 ns 96 nsRight 79 6/6 0.016 80 0.028Patients


Right 102 9/14 ns 93 nsPatientswithoutlocalarthritis

Left 103 5/13 ns 103 ns

38

Figure 4. Isometric muscle strength in elbow flexors

Elbow flexors

0

100

200

1 2 3 4 5 6 7 8 9 1011121314151617181920


stre

ngth

% o

f exp

ecte

d


Elbow flexors

0

100

200

stre

ngth

% o

f exp

ecte

d

rightleft


39

Table 7. Isometric muscle strength in elbow flexors


Isometricstrength Elbowflexors




Significance

Right 83 16/20 0.006 77 0.0001All patients

Left 86 18/20 0.0002 81 0.0013

Right 64 2/3 ns 68 nsPatientswith localarthritis Left 62 2/2 ns 66 ns

Right 86 14/17 0.006 78 0.0003Patientswithoutlocalarthritis

Left 89 16/18 0.0007 83 0.003

40

Figure 5. Isometric muscle strength in wrist dorsiflexors

Wrist dorsiflexors

0

100

200

1 2 3 4 5 6 7 8 9 1011121314151617181920


stre

ngth

% o

f exp

ecte

d


Wrist dorsiflexors

0

100

200

stre

ngth

% o

f exp

ecte

d

rightleft


41

Table 8. Isometric muscle strength in wrist dorsiflexors


Isometricstrength Wristdorsiflexors




Significance

Right 82 13/20 ns 75 0.002All patients

Left 74 16/20 0.006 76 0.002

Right 47 5/6 ns 43 0.046Patientswith localarthritis Left 43 6/6 0.016 45 0.028


Left 88 10/14 ns 89 0.04

42

Figure 6. Isokinetic muscle strength in ankle dorsiflexors

Isokinetic strength in ankle dorsiflexors

0

100

200

1 2 3 4 5 6 7 8 9 1011121314151617181920

patient number

stre

ngth

% o

f exp

ecte

d

patient rightpatient left

Isokinetic strength in ankle dorsiflexors

0

100

200

stre

ngth

% o

f exp

ecte

d

rightleft


43

Figure 7. Isokinetic muscle strength at different angular velocities

Table 9. Isokinetic muscle strength in ankle dorsiflexors

Compared to reference valuesIsokinetic strength Ankle dorsiflexorsAll velocities

Percentage ofexpected value

Number belowexpected value

Significance

Right 89 13/20 nsAll patients

Left 83 13/20 ns

Right 72 6/7 nsPatients withlocal arthritis Left 70 9/9 0.002

Right 100 7/13 nsPatients withoutlocal arthritis

Left 97 4/11 ns

Isokinetic strength ankle dorsiflexors

0

20

40

60

80

100

120

0 50 100 150 200 250

angular velocity (deg/sec)

stre

ngth

% o

f exp

ecte

d

all patientswith local arthritiswithout local arthritis

44

Figure 8. Handgrip strength

Handgrip strength

0

100

200

1 2 3 4 5 6 7 8 9 1011121314151617181920

patient number

stre

ngth

% o

f exp

ecte

d

patient right

Handgrip strength

0

100

200

stre

ngth

% o

f exp

ecte

d

right


45

Table 10. Handgrip strength

Compared to reference valuesHandgrip strength Percentage ofexpected value


Significance

All patients Right 80 17/20 0.002

Patients withlocal arthritis

Right 56 6/6 0.016

Patients withoutlocal arthritis

Right 89 11/14 0.029

46

Figure 9. Non-voluntary muscle strength

Non-voluntary strength

0

100

200

1 2 3 4 5 6 7 8 9 10 11 12 13 14 1516 17 18 19 20

patient number

stre

ngth

% o

f exp

ecte

d

right

Non-voluntary strength

0

100

200

stre

ngth

% o

f exp

ecte

d

right


47

Table 11. Non-voluntary muscle strength

Compared to reference valuesNon-voluntarystrength Percentage of

expected valueNumber belowexpected value

Significance

All patients Right 91 13/18 0.048

Patients withlocal arthritis

Right 85 8/8 0.004

Patients withoutlocal arthritis

Right 96 5/10 ns

48

Figure 10. Quadriceps muscle thickness

Muscle thickness

0

10

20

30

40

50

1 2 3 4 5 6 7 8 9 1011121314151617181920


mm


Muscle thickness

0

100

200

% o

f exp

ecte

d

rightleft


49

Table 12. Quadriceps muscle thickness


Quadricepsmusclethickness Percentage

of expectedvalue



Significance

Right 88 14/20 ns 88 0.003All patientsLeft 83 17/20 0.001 85 0.0009Right 73 5/5 0.031 77 nsPatients



Left 89 11/14 0.029 89 0.008

Table 13. Muscle strength in healthy controls compared with reference values

Compared with reference valuesControlsPercentage ofexpected value


Significance

Right 100 9/20 nsKnee extensorsLeft 99 10/20 nsRight 105 8/20 nsAnkle dorsiflexors

Left 97 8/20 ns

Right 109 6/20 nsElbow flexors

Left 106 9/20 ns

Right 110 4/20 0.006Wrist dorsiflexors

Left 98 11/20 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

50

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.

51

Paper IIPaper 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.

52

Figure 11. Relationship between muscle strength in knee extensors and local arthritis severityscore

Muscle strength and local articular disease severity score

0

20

40

60

80

100

120

0 1 2 3 4 5 6

local arthritis severity score (units)

stre

ngth

% o

f exp

ecte

d

53

For muscle thickness the relationship was not significant (Figure 12).

Figure 12. Relationship between thickness of quadriceps muscle and local arthritis severityscore

Muscle thickness and local articular disease severity score

0

20

40

60

80

100

120

140

0 1 2 3 4 5 6


% o

f exp

ecte

d

54

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. Onemean value for each patient.

Muscle thickness and muscle strength

0

20

40

60

80

100

120

0 20 40 60 80 100 120 140

muscle thickness % of expected

stre

ngth

% o

f exp

ecte

d

55

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 10patients with variation in arthritis severity score. The thick line is the mean of 10 patients.

Muscle strength and local articular disease severity score

0

20

40

60

80

100

120

0 2 4 6 8 10 12


stre

ngth

% o

f exp

ecte

d

56

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 10patients with variation in arthritis severity score. The thick line is the mean of 10 patients.

Muscle thickness and local articular disease severity score

0

20

40

60

80

100

120

0 2 4 6 8 10 12


% o

f exp

ecte

d

57

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).

58

Figure 16. Patient No. 4

0

5

10

15

20

25

30

35

40

12,5 13 13,5 14 14,5 15

muscle thickness (mm)

02468

101214161820

12,5 13 13,5 14 14,5 15

age (years)


0

50

100

150

200

250

300

350

400

12,5 13 13,5 14 14,5 15

strength (N)

59

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.

60


0

5

10

15

20

25

30

35

40

45

9,5 10 10,5 11 11,5 12 12,5


02468

101214161820

9,5 10 10,5 11 11,5 12 12,5

age (years)


0

50

100

150

200

250

300

9,5 10 10,5 11 11,5 12 12,5

strength (N)

61

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.

62


0

5

10

15

20

25

30

35

40

45

10,5 11 11,5 12 12,5 13 13,5

rightleft


0

2

4

6

8

10

12

10,5 11 11,5 12 12,5 13 13,5

age (years)

left


0

50

100

150

200

250

300

350

400

450

10,5 11 11,5 12 12,5 13 13,5

rightleft

strength (N)

63

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.

64


0

5

10

15

20

25

30

35

40

45

50

14 14,5 15 15,5 16

muscle thickness

0

2

4

6

8

10

12

14 14,5 15 15,5 16

age (years)


0

100

200

300

400

500

600

14 14,5 15 15,5 16

strength (N)

65

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.

66


0

5

10

15

20

25

30

35

40

45

50

16 16,5 17 17,5 18 18,5


02468

101214161820

16 16,5 17 17,5 18 18,5

age (years)


0

100

200

300

400

500

600

700

16 16,5 17 17,5 18 18,5

strength (N)

67

Figure 21. Ultrasound images from patient No. 19 and the matched healthy control

Patient No. 19Muscle thickness 22 mm

Age-matched control to patientNo. 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.

68


0

5

10

15

20

25

30

35

40

15,5 16 16,5 17 17,5 18


0

2

4

6

8

10

12

14

15,5 16 16,5 17 17,5 18

age (years)


0

100

200

300

400

500

600

15,5 16 16,5 17 17,5 18

strength (N)

69

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.

70

Paper IIIPaper 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.

71

Figure 23. Results from strength measurements in wrist dorsiflexors during two years

Wrist dorsiflexors

mean

+2SD

-2SD

Strength

start end

1

2

3

4

6 5

7

8

9

10 11

12

13

14

15

16 17

18

19

20

Patient nr

72

Figure 24. Results from measurement of handgrip strength during two years

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

Handgrip strength

mean

+2SD

-2SD

Strength

start end

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

Patient nr

73

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.

74

Paper IVIn 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 biopsiesMinimalmorphologicalchanges

Cell infiltrates MHC class I MHC class II MAC

Patients n = 15 11/15 2/15 1/15 4/15 2/15Controls n = 33 7/33 0/33 2/33 0/33 1/33p-value 0.046 ns 0.014 ns

75

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

76

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 areasType I fibres Type IIA fibres Type IIB fibres Mean

area typeI/IIA

% Meanarea µm²

% Meanarea µm²

% Meanarea µm²

%

Patientsn = 13

75 3158 20 4520 5 3483 77

Controlsn = 33

53 3620 33 3758 14 3681 99

p-value ns ns ns 0.0014

Figure 26. The mean area of different fibre types in patients and controls

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000area

mean area of type I fibres

mean area of type IIA fibres

mean area of type IIB fibres

patients controls patients controls patients controls

ns ns ns

77

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

0

20

40

60

80

100

120

140

160

180

200

type I/Type IIA area type IIA/Type IIB area

patients controlspatients controls

%

nsp=0.0014

78

Figure 28. Image from biopsy taken from patient 14 (in paper IV). Type I fibres are light andtype 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.

79

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 cross-

sectional 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.

81

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 twoyears

Patientnumber

Elbowflexors(isometric)

Wristdorsi-flexors(isometric)

Kneeextensors(isometric)

Ankledorsi-flexors(isometric)

Ankledorsi-flexors(isokinetic)

Handgripstrength

Non-voluntarystrength

Musclethickness(quadri-ceps)

1 N N N N N L Not done N2 N N N N N L N N3 N N N N N N N N4 L L L L L L N L5 N N N N N N N N6 N SL N N N N N N7 N N SL N N N N N8 SL SL SL N SL L N N9 N N N N N N N N10 N N N N N N N N11 SL N L N N N N N12 N N N N N N N N13 N N N N N N N N14 N N SL N N N N N15 N N N N N N N N16 L SL SL N N N N L17 N N N N N N N N18 L L N N N L N N19 L L L L L L N L20 SL L N SL L N N 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.

83

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

84

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

85

and from the anterior tibial muscle in patients. This may also explain some of the differences

between the groups.

87

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.

89

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.

91

References

References

1. Gare BA, Fasth A. Epidemiology of juvenile chronic arthritis in southwestern Sweden: a 5-yearprospective population study. Pediatrics 1992; 90:950-8.

2. Krumrey-Langkammerer M, Hafner R. Evaluation of the ILAR criteria for juvenile idiopathic arthritis.J Rheumatol 2001; 28:2544-7.

3. Gare BA, Fasth A. The natural history of juvenile chronic arthritis: a population based cohort study. I.Onset and disease process. J Rheumatol 1995; 22:295-307.

4. Koivuniemi R, Leirisalo-Repo M. Juvenile chronic arthritis in adult life: a study of long-term outcomein patients with juvenile chronic arthritis or adult rheumatoid arthritis. Clin Rheumatol 1999; 18:220-6.

5. Guillaume S, Prieur AM, Coste J, Job-Deslandre C. Long-term outcome and prognosis in oligoarticular-onset juvenile idiopathic arthritis. Arthritis Rheum 2000; 43:1858-65.

6. Lexell J, Sjostrom M, Nordlund AS, Taylor CC. Growth and development of human muscle: aquantitative morphological study of whole vastus lateralis from childhood to adult age. Muscle Nerve1992; 15:404-9.

7. Glenmark B, Hedberg G, Jansson E. Changes in muscle fibre type from adolescence to adulthood inwomen and men. Acta Physiol Scand 1992; 146:251-9.

8. Brooke MH, Engel WK. The histographic analysis of human muscle biopsies with regard to fiber types.4. Children's biopsies. Neurology 1969; 19:591-605.

9. Sandstedt P, Nordell LE, Henriksson KG. Quantitative analysis of muscle biopsies from volunteers andpatients with neuromuscular disorders. A comparison between estimation and measuring. Acta NeurolScand 1982; 66:130-44.

10. Jones, Stratton G. Muscle function assessment in children. Acta Paediatr 2000; 89:753-61.

11. Backman E, Odenrick P, Henriksson KG, Ledin T. Isometric muscle force and anthropometric values innormal children aged between 3.5 and 15 years. Scand J Rehabil Med 1989; 21:105-14.

12. Wessel J. Isometric strength measurements of knee extensors in women with osteoarthritis of the knee.J Rheumatol 1996; 23:328-31.

92

13. Slemenda C, Brandt KD, Heilman DK, et al. Quadriceps weakness and osteoarthritis of the knee. AnnIntern Med 1997; 127:97-104.

14. O'Reilly SC, Jones A, Muir KR, Doherty M. Quadriceps weakness in knee osteoarthritis: the effect onpain and disability. Ann Rheum Dis 1998; 57:588-94.

15. Halkjaer-Kristensen J, Ingemann-Hansen T. Wasting of the human quadriceps muscle after kneeligament injuries. Scand J Rehabil Med Suppl 1985; 13:5-55.

16. Ingemann-Hansen T, Halkjaer-Kristensen J. Computerized tomographic determination of human thighcomponents. The effects of immobilization in plaster and subsequent physical training. Scand J RehabilMed 1980; 12:27-31.

17. Nakamura T, Kurosawa H, Kawahara H, Watarai K, Miyashita H. Muscle fiber atrophy in thequadriceps in knee-joint disorders. Histochemical studies on 112 cases. Arch Orthop Trauma Surg1986; 105:163-9.

18. Berg HE, Larsson L, Tesch PA. Lower limb skeletal muscle function after 6 wk of bed rest. J ApplPhysiol 1997; 82:182-8.

19. Deandrade JR, Grant C, Dixon AS. Joint Distension and Reflex Muscle Inhibition in the Knee. J BoneJoint Surg Am 1965; 47:313-22.

20. Kennedy JC, Alexander IJ, Hayes KC. Nerve supply of the human knee and its functional importance.Am J Sports Med 1982; 10:329-35.

21. Geborek P, Moritz U, Wollheim FA. Joint capsular stiffness in knee arthritis. Relationship tointraarticular volume, hydrostatic pressures, and extensor muscle function. J Rheumatol 1989; 16:1351-8.

22. Fahrer H, Rentsch HU, Gerber NJ, Beyeler C, Hess CW, Grunig B. Knee effusion and reflex inhibitionof the quadriceps. A bar to effective retraining. J Bone Joint Surg Br 1988; 70:635-8.

23. Stokes M, Young A. The contribution of reflex inhibition to arthrogenous muscle weakness. Clin Sci(Lond) 1984; 67:7-14.

24. Herbison GJ, Jaweed MM, Ditunno JF. Muscle atrophy in rats following denervation, casting,inflammation, and tenotomy. Arch Phys Med Rehabil 1979; 60:401-4.

93

25. Robben SG, Lequin MH, Meradji M, Diepstraten AF, Hop WC. Atrophy of the quadriceps muscle inchildren with a painful hip. Clin Physiol 1999; 19:385-93.

26. Ekdahl C, Broman G. Muscle strength, endurance, and aerobic capacity in rheumatoid arthritis: acomparative study with healthy subjects. Ann Rheum Dis 1992; 51:35-40.

27. Hakkinen A, Hannonen P, Hakkinen K. Muscle strength in healthy people and in patients sufferingfrom recent-onset inflammatory arthritis. Br J Rheumatol 1995; 34:355-60.

28. Hsieh LF, Didenko B, Schumacher HR, Jr., Torg JS. Isokinetic and isometric testing of kneemusculature in patients with rheumatoid arthritis with mild knee involvement. Arch Phys Med Rehabil1987; 68:294-7.

29. Danneskiold-Samsoe B, Grimby G. Isokinetic and isometric muscle strength in patients withrheumatoid arthritis. The relationship to clinical parameters and the influence of corticosteroid. ClinRheumatol 1986; 5:459-67.

30. Helliwell PS, Jackson S. Relationship between weakness and muscle wasting in rheumatoid arthritis.Ann Rheum Dis 1994; 53:726-8.

31. Brooke MH, Kaplan H. Muscle pathology in rheumatoid arthritis, polymyalgia rheumatica, andpolymyositis: a histochemical study. Arch Pathol 1972; 94:101-18.

32. Miro O, Pedrol E, Casademont J, et al. Muscle involvement in rheumatoid arthritis: clinicopathologicalstudy of 21 symptomatic cases. Semin Arthritis Rheum 1996; 25:421-8.

33. Halla JT, Koopman WJ, Fallahi S, Oh SJ, Gay RE, Schrohenloher RE. Rheumatoid myositis. Clinicaland histologic features and possible pathogenesis. Arthritis Rheum 1984; 27:737-43.

34. de Palma L, Chillemi C, Albanelli S, Rapali S, Bertoni-Freddari C. Muscle involvement in rheumatoidarthritis: an ultrastructural study. Ultrastruct Pathol 2000; 24:151-6.

35. Bekkelund SI, Torbergsen T, Husby G, Mellgren SI. Myopathy and neuropathy in rheumatoid arthritis.A quantitative controlled electromyographic study. J Rheumatol 1999; 26:2348-51.

36. Lanzillo B, Pappone N, Crisci C, di Girolamo C, Massini R, Caruso G. Subclinical peripheral nerveinvolvement in patients with rheumatoid arthritis. Arthritis Rheum 1998; 41:1196-202.

37. Sivri A, Guler-Uysal F. The electroneurophysiological evaluation of rheumatoid arthritis patients. ClinRheumatol 1998; 17:416-8.

94

38. Lang AH, Kalliomaki JL, Puusa A, Halonen JP. Sensory neuropathy in rheumatoid arthritis: anelectroneurographic study. Scand J Rheumatol 1981; 10:81-4.

39. Danneskiold-Samsoe B, Grimby G. The relationship between the leg muscle strength and physicalcapacity in patients with rheumatoid arthritis, with reference to the influence of corticosteroids. ClinRheumatol 1986; 5:468-74.

40. Ekblom B, Lovgren O, Alderin M, Fridstrom M, Satterstrom G. Physical performance in patients withrheumatoid arthritis. Scand J Rheumatol 1974; 3:121-5.

41. Ekdahl C. Muscle function in rheumatoid arthritis. Assessment and training. Scand J Rheumatol Suppl1990; 86:9-61.

42. Stucki G, Bruhlmann P, Stucki S, Michel BA. Isometric muscle strength is an indicator of self-reportedphysical functional disability in patients with rheumatoid arthritis. Br J Rheumatol 1998; 37:643-8.

43. Vostrejs M, Hollister JR. Muscle atrophy and leg length discrepancies in pauciarticular juvenilerheumatoid arthritis. Am J Dis Child 1988; 142:343-5.

44. Wessel J, Kaup C, Fan J, et al. Isometric strength measurements in children with arthritis: reliability andrelation to function. Arthritis Care Res 1999; 12:238-46.

45. Giannini MJ, Protas EJ. Comparison of peak isometric knee extensor torque in children with andwithout juvenile rheumatoid arthritis. Arthritis Care Res 1993; 6:82-8.

46. Hedengren E, Knutson LM, Haglund-Akerlind Y, Hagelberg S. Lower extremity isometric joint torquein children with juvenile chronic arthritis. Scand J Rheumatol 2001; 30:69-76.

47. Henderson CJ, Lovell DJ, Specker BL, Campaigne BN. Physical activity in children with juvenilerheumatoid arthritis: quantification and evaluation. Arthritis Care Res 1995; 8:114-9.

48. Klepper SE, Darbee J, Effgen SK, Singsen BH. Physical fitness levels in children with polyarticularjuvenile rheumatoid arthritis. Arthritis Care Res 1992; 5:93-100.

49. Brostrom E, Haglund-Akerlind Y, Hagelberg S, Cresswell AG. Gait in children with juvenile chronicarthritis. Timing and force parameters. Scand J Rheumatol 2002; 31:317-23.

95

50. Dunn W. Grip strength of children aged 3 to 7 years using a modified sphygmomanometer: comparisonof typical children and children with rheumatic disorders. Am J Occup Ther 1993; 47:421-8.

51. Fan JS, Wessel J, Ellsworth J. The relationship between strength and function in females with juvenilerheumatoid arthritis. J Rheumatol 1998; 25:1399-405.

52. Englund P, Lindroos E, Nennesmo I, Klareskog L, Lundberg IE. Skeletal muscle fibers express majorhistocompatibility complex class II antigens independently of inflammatory infiltrates in inflammatorymyopathies. Am J Pathol 2001; 159:1263-73.

53. Englund P, Nennesmo I, Klareskog L, Lundberg IE. Interleukin-1alpha expression in capillaries andmajor histocompatibility complex class I expression in type II muscle fibers from polymyositis anddermatomyositis patients: important pathogenic features independent of inflammatory cell clusters inmuscle tissue. Arthritis Rheum 2002; 46:1044-55.

54. Turesson C, Englund P, Jacobsson LT, et al. Increased endothelial expression of HLA-DQ andinterleukin 1alpha in extra-articular rheumatoid arthritis. Results from immunohistochemical studies ofskeletal muscle. Rheumatology (Oxford) 2001; 40:1346-54.

55. Lindvall B, Bengtsson A, Ernerudh J, Eriksson P. Subclinical myositis is common in primary Sjogren'ssyndrome and is not related to muscle pain. J Rheumatol 2002; 29:717-25.

56. Goncalves FG, Chimelli L, Sallum AM, Marie SK, Kiss MH, Ferriani VP. Immunohistological analysisof CD59 and membrane attack complex of complement in muscle in juvenile dermatomyositis. JRheumatol 2002; 29:1301-7.

57. Backman E, Oberg B. Isokinetic muscle torque in the dorsiflexors of the ankle in children 6-15 years ofage. Normal values and evaluation of the method. Scand J Rehabil Med 1989; 21:97-103.

58. Backman E, Johansson V, Hager B, Sjoblom P, Henriksson KG. Isometric muscle strength andmuscular endurance in normal persons aged between 17 and 70 years. Scand J Rehabil Med 1995;27:109-17.

59. Backman E, Henriksson KG. Skeletal muscle characteristics in children 9-15 years old: force,relaxation rate and contraction time. Clin Physiol 1988; 8:521-7.

60. Oberg B, Bergman T, Tropp H. Testing of isokinetic muscle strength in the ankle. Med Sci SportsExerc 1987; 19:318-22.

61. Heckmatt JZ, Pier N, Dubowitz V. Measurement of quadriceps muscle thickness and subcutaneoustissue thickness in normal children by real-time ultrasound imaging. J Clin Ultrasound 1988; 16:171-6.

96

62. Backman E. Methods for measurement of muscle function. Methodological aspects, reference valuesfor children, and clinical applications. Scand J Rehabil Med Suppl 1988; 20:9-95.

63. Henriksson KG. "Semi-open" muscle biopsy technique. A simple outpatient procedure. Acta NeurolScand 1979; 59:317-23.

64. Lindvall B, Dahlbom K, Henriksson KG, Srinivas U, Ernerudh J. The expression of adhesion moleculesin muscle biopsies: the LFA-1/VLA-4 ratio in polymyositis. Acta Neurol Scand 2003; 107:134-41.

65. Brewer EJ, Jr., Giannini EH. Standard methodology for Segment I, II, and III Pediatric RheumatologyCollaborative Study Group studies. I. Design. J Rheumatol 1982; 9:109-13.

66. Giannini MJ, Protas EJ. Exercise response in children with and without juvenile rheumatoid arthritis: acase-comparison study. Phys Ther 1992; 72:365-72.

67. Nordesjo LO, Nordgren B, Wigren A, Kolstad K. Isometric strength and endurance in patients withsevere rheumatoid arthritis or osteoarthrosis in the knee joints. A comparative study in healthy men andwomen. Scand J Rheumatol 1983; 12:152-6.

68. Hakkinen A, Sokka T, Kotaniemi A, et al. Muscle strength characteristics and central bone mineraldensity in women with recent onset rheumatoid arthritis compared with healthy controls. Scand JRheumatol 1999; 28:145-51.

69. Freilich RJ, Kirsner RL, Byrne E. Isometric strength and thickness relationships in human quadricepsmuscle. Neuromuscul Disord 1995; 5:415-22.

70. Geborek P, Mansson B, Wollheim FA, Moritz U. Intraarticular corticosteroid injection into rheumatoidarthritis knees improves extensor muscles strength. Rheumatol Int 1990; 9:265-70.

71. Jones E, Hanly JG, Mooney R, et al. Strength and function in the normal and rheumatoid hand. JRheumatol 1991; 18:1313-8.

72. Ruperto N, Ravelli A, Levinson JE, et al. Long-term health outcomes and quality of life in Americanand Italian inception cohorts of patients with juvenile rheumatoid arthritis. II. Early predictors ofoutcome. J Rheumatol 1997; 24:952-8.

73. Puusa A, Lang HA, Makela AL. Nerve conduction velocity in juvenile rheumatoid arthritis. ActaNeurol Scand 1986; 73:145-50.

97

74. Henriksson-Larsen K. Distribution, number and size of different types of fibres in whole cross-sectionsof female m tibialis anterior. An enzyme histochemical study. Acta Physiol Scand 1985; 123:229-35.

75. Lexell J, Taylor CC. Variability in muscle fibre areas in whole human quadriceps muscle: how toreduce sampling errors in biopsy techniques. Clin Physiol 1989; 9:333-43.

76. Rosenbaum R. Neuromuscular complications of connective tissue diseases. Muscle Nerve 2001;24:154-69.

77. Danneskiold-Samsoe B, Grimby G. The influence of prednisone on the muscle morphology and muscleenzymes in patients with rheumatoid arthritis. Clin Sci (Lond) 1986; 71:693-701.

78. Chappel R, Willems J. D-penicillamine-induced myositis in rheumatoid arthritis. Clin Rheumatol 1996;15:86-7.

79. Halla JT, Fallahi S, Koopman WJ. Penicillamine-induced myositis. Observations and unique features intwo patients and review of the literature. Am J Med 1984; 77:719-22.

80. Bekkelund SI, Torbergsen T, Omdal R, Husby G, Mellgren SI. Nerve conduction studies in rheumatoidarthritis. Scand J Rheumatol 1996; 25:287-92.

81. Sivri A, Guler-Uysal F. The electroneurophysiological findings in rheumatoid arthritis patients.Electromyogr Clin Neurophysiol 1999; 39:387-91.

82. Edstrom L, Nordemar R. Differential changes in type I and type II muscle fibres in rheumatoid arthritis.A biopsy study. Scand J Rheumatol 1974; 3:155-60.

83. Larsson L, Li X, Berg HE, Frontera WR. Effects of removal of weight-bearing function on contractilityand myosin isoform composition in single human skeletal muscle cells. Pflugers Arch 1996; 432:320-8.

84. Helewa A, Goldsmith CH, Smythe HA. Measuring abdominal muscle weakness in patients with lowback pain and matched controls: a comparison of 3 devices. J Rheumatol 1993; 20:1539-43.

muscle function in juvenile idiopathic arthritis - diva...

Documents