Muscle involvement in juvenile idiopathic arthritis

H. Lindehammar and B. Lindvall1

Department of Neuroscience and Locomotion, Division of Clinical Neurophysiology and 1 Neuromuscular Unit, Department of Neuroscience and Locomotion, Division of Neurology, Faculty of Health Sciences, Linköping University, Sweden.

Correspondence to: H. Lindehammar, Department of Clinical Neurophysiology, University Hospital, SE- 581 85 Linköping, Sweden. E-mail: hans.lindehammar{at}lio.se


    Abstract
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Objective. An observational study of changes in muscle structure and the relation to muscle strength in juvenile idiopathic arthritis (JIA).

Methods. Fifteen children and teenagers (eight girls and seven boys) with JIA, aged 9–19 yr (mean age 16.1), were studied. Muscle biopsies were obtained from the anterior tibial muscle and were examined using histopathological and immunohistochemical methods. Muscle fibre types were classified and fibre areas measured. As markers of inflammation, the major histocompatibility complex (MHC) class I and class II and the membrane attack complex (MAC) were analysed. Results were compared with biopsies from the gastrocnemius muscle in 33 young (19–23 yr) healthy controls. Isometric and isokinetic muscle strengths were measured in ankle dorsiflexion. Strength was compared with reference values for healthy age-matched controls. Nerve conduction velocities were recorded in the peroneal and sural nerves.

Results. Four of the 15 muscle biopsies were morphologically normal. Eleven biopsies showed minor unspecific changes. Two of these also showed minor signs of inflammation. MHC class II expression was found in 4/15 patients, which was significantly more than in the healthy controls (P = 0.0143). The expression of MHC class I and MAC did not differ from that in the controls. The mean area of type I fibres was lower than that of type IIA fibres in 12/13 biopsies. Muscle strength was significantly reduced in the patient group. There was a significant positive correlation between muscle fibre area and muscle strength. Nerve conduction studies were normal in all cases.

Conclusions. Changes in leg muscle biopsies appear to be common in children and teenagers with JIA. The presence of inflammatory cells in the muscle and expression of MHC class II on muscle fibres may be a sign of inflammatory myopathy. There are no findings of type II muscle fibre hypotrophy or neuropathy, as in adults with RA.

KEY WORDS: Muscle, Strength, Muscle fibre, Biopsy, Juvenile idiopathic arthritis, Juvenile chronic arthritis, Juvenile rheumatoid arthritis, Nerve, Myositis


    Introduction
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
In adult rheumatoid arthritis (RA), neuromuscular complications such as neuropathy and myopathy are not uncommon [1]. Despite the absence of any overt neuromuscular disease, muscle weakness and hypotrophy may develop in some patients. Inactivity due to the disease can result in a generalized reduction in muscle volume and strength. Localized hypotrophy and weakness are sometimes apparent in muscles close to active synovitis, especially in the thigh muscle in knee arthritis [2–4]. This may be caused by disuse hypotrophy or reflex inhibition elicited by pain or effusion in the joint near to the weakened muscle [5, 6]. In one study of the relationship between muscle weakness and muscle wasting in RA, it was found that the weakness was more marked than the muscle hypotrophy [7]. This could be the effect of arthrogenous muscle inhibition or muscle dysfunction. Polymyositis and dermatomyositis occur in adults with RA. Muscle biopsies have shown inflammation and signs of muscle fibre degeneration [8–11]. Myopathy may also be a complication of treatment with steroids or antirheumatic drugs (chloroquine, D-penicillamine) [9, 12]. Vasculitic neuropathy, distal symmetrical neuropathy and compression neuropathies are also seen in chronic RA [13–17].

Muscle fibres have different structural and functional features. In normal human muscles they can be divided into three fibre types: I, IIA and IIB. Type I is slow-twitch, oxidative. Type IIA is fast-twitch, fatigue-resistant, oxidative/glycolytic. Type IIB is fast-twitch, fatigue sensitive, glycolytic. Usually these types occur in approximately equal proportions, but this may vary in different muscles. Sometimes immature muscle fibres, type IIC fibres, are seen in biopsies. The degree of physical activity influences the structure of the muscles. Immobilization results in reductions in muscle strength, muscle volume and muscle fibre area [18]. The relative frequencies of the different fibre types may also change in response to physical activity. In walking adults with chronic hemiplegia, the proportion of type II fibres was increased in the anterior tibial muscle of the weakened leg compared with the healthy leg [19]. This was probably caused by a transformation of type I muscle fibres to type II in response to different demands on the muscle. Exercise influences both muscle fibre composition and area. Muscle fibre areas, especially type II fibres, increase after exercise, but the responses are variable among different muscles and also depend on the type of exercise.

In children, muscle volume increases during growth. This occurs by an increase in muscle fibre area; the number of muscle fibres does not increase. During child growth the proportion of type I fibres decreases and the proportion of type II fibres increases by transformation of type I fibres to type II fibres [20]. In healthy young people (16–27 yr of age) there were small changes in fibre type frequencies but no significant differences in muscle fibre area attributable to age [21]. Males usually have larger fibre areas than females. In healthy adults, type II fibres have slightly larger areas than type I fibres, especially in men [19, 21, 22]. In studies of adult RA, hypotrophy of muscle fibres, predominantly type II fibres, has been found [8–10, 23]. This seems to be more pronounced in patients treated with steroids. It is difficult to know whether this is caused by the medicine or whether patients treated with steroids often have a more severe disease [12].

The expressions of major histocompatibility complex (MHC) class I and class II and membrane attack complex (MAC) in muscle tissue are used as markers of inflammation [24]. MHC class I molecules are normally expressed on nucleated cells, including endothelial cells, but not or only very weakly on muscle cells. MHC class II molecules are normally not or only weakly expressed on endothelial cells and muscle cells. MAC (C5b-9) is formed as a result of complement activation. It is not expressed in normal muscles. MHC class I and class II are strongly expressed in inflammatory myopathies, independently of inflammatory infiltrates [25–28]. MHC class I, class II and MAC are also expressed in primary Sjögren's syndrome with signs of subclinical myositis [29]. MHC class I and class II have also been found in muscle biopsies from patients with RA [30]. MAC has been found in muscles in juvenile dermatomyositis [31]. These markers are rarely expressed in significant amounts in muscle biopsies from healthy persons [32].

Muscle weakness is also known to occur in juvenile idiopathic arthritis (JIA) [33, 34]. This has been much less studied than in adults, but the mechanisms are probably the same [35–37]. We are not aware of any study on muscle structure in children with JIA. In the present study, muscle biopsies in children and teenagers with JIA were examined and the findings correlated to muscle strength. The results were compared with those for control groups of healthy persons. The aim of the study was to analyse if there are signs of muscle inflammation, vasculitis, type II muscle fibre hypotrophy, or neuropathy in JIA, as have been found in adult RA.


    Material and methods
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Patients
Patients were selected from a county in Sweden with 400 000 inhabitants. All children and teenagers with diagnosed active JIA between 7 and 18 yr of age (n = 26) were asked to participate in the study, and 15 of them gave informed consent. Eight were girls and seven were boys. Their ages ranged between 9.5 and 19 yr (mean age 16.1 yr). Eight had oligoarthritis, six polyarthritis and one monoarthritis. Individual data are given in Table 1.


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TABLE 1. Basic data of the patients with JIA

 
Control groups
As a reference for muscle biopsies, samples taken from the gastrocnemius muscle in 33 healthy young volunteers (30 women and three men) aged 18–23 yr (mean age 21.8 yr) were used. This group was first examined to serve as controls in a different, hitherto unpublished study. All were physiotherapy students. For ethical reasons it was not considered appropriate to take biopsies from age-matched healthy children.

For the strength measurements, we used age-related reference values from healthy children and young adults aged 7–30 yr for isometric strength (n = 196) [38, 39] and aged 9–34 yr for isokinetic strength (n = 120) [40, 41].

Muscle biopsy
Biopsies were obtained from the anterior tibial muscle using local anaesthesia and the semi-open conchotome biopsy technique [42]. 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.

Routine staining was 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.

Immunohistochemical stainings were made on 6 µm thick frozen sections for analysis of cell surface markers with monoclonal antibodies. Mouse monoclonal antibodies from Dako (Glostrup, Denmark) were used: MHC class I (HLA-ABC M736, IgG2a, 1:100), 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 (on muscle fibres): expression involving the total circumference of the muscle fibre membrane in parts of the biopsy. MHC class II (on capillaries): 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 [29, 43]. The scales were validated in muscle biopsies from normal controls [32].

The fibre types and fibre areas were measured with the Tema® system (CheckVision ApS, Hadsund, Denmark). ATPase staining at pH 4.3, 4.6 and 9.4 was used to differentiate between fibre types, and an antibody against the sarcolemmal protein merosin was used to delineate fibre areas. The numbers, percentages 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 the small amount of muscle tissue in the biopsy, the muscle fibre analysis could not be reliably performed for two patients.

All biopsies were prepared at the same laboratory, using the same methods for patients and controls. All evaluations of the muscle biopsies were made by an experienced muscle pathologist (BL) with the same criteria for patients and controls. The following findings were classified as minimal changes: the presence of some centrally positioned nuclei in muscle cells; the presence of some atrophic muscle fibres; and abnormal variation in fibre size (based on experience).

Muscle strength
The test procedures and positions were chosen to match reference values [38–41]. Maximal isometric muscle strength in ankle dorsiflexion was measured using a hand-held electronic dynamometer (Myometer; Penny and Giles, Christchurch, UK). The maximal voluntary strength was measured by the breaking force technique. The child sat with the knee in 90° flexion and the foot in neutral position. The transducer head was applied on the dorsal aspect of the foot proximal to the metatarsophalangeal joints. Force was applied until the resistance was lost. Three measurements were made and the peak value was used for presentation. The isokinetic muscle strength of ankle dorsiflexion was measured using a Cybex® II dynamometer. The position was the same as for isometric strength measurement. Maximal developed torque was measured at a constant angular velocity of 30°/s. Two measurements were made and the peak value was used. The strength measurements were made on the same leg as the biopsy and in all cases before the biopsy procedure.

Nerve conduction study
A nerve conduction study was carried out on 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.

Study design
This was a cross-sectional observational study.

Statistical methods
To compare the patient group with the control group, a non-paired, two-tailed t test was performed. To evaluate the relationship between muscle fibre variables and strength, a linear regression model was used. Qualitative data were analysed in 2 x 2 contingency tables using Fisher's exact test. A P value of less than 0.05 was considered significant.

The study was approved by the ethics committee of the University Hospital, Linköping (registration numbers 87110 and 97140).


    Results
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
Individual values for the patients and corresponding results for the control group are presented in Tables 2 and 3. Muscle strength in children is dependent on age and gender. Strength values were compared with the reference group and expressed as a percentage of the expected value (the mean of the reference group), for the appropriate age and sex, and in standard deviations from the mean.


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TABLE 2. Strength in absolute values and as a percentage of the mean of the reference group

 

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TABLE 3. Morphology and immunohistochemistry of muscle biopsies

 
Muscle biopsy
Structure
Out of the 15 biopsies, four were considered normal with no pathological changes on visual examination. Two biopsies showed signs of mild inflammation, with small perivascular infiltrates of inflammatory cells (Fig. 1). Eleven biopsies, including those with cell infiltrates, showed increased variability of the muscle fibre diameter or presence of some atrophic fibres or centrally placed nuclei. These findings were classified as non-specific minimal changes. In the healthy control group, none had perivascular infiltrates and 7/33 showed minimal changes.



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FIG. 1. Muscle biopsy from one of the patients showing perivascular inflammation. Haematoxylin–eosin staining.

 
Fibre type composition
The mean frequency of type I fibres in the patient group was 75%. The subgroup of patients with polyarthritis had a significantly lower percentage of type I fibres than the subgroup with mono/oligoarthritis (66 vs 80%, P = 0.0017).

Fibre type area
The mean area of type I fibres in the patient group was slightly but not significantly lower than that in the control group. The mean area of type IIA fibres in the patients was slightly but not significantly higher than in the control group (Figs 2 and 3). For 14 of 15 patients the mean area of type I fibres were lower than the mean area of type IIA fibres. The quotient of the mean areas of type I and type IIA fibres was significantly lower in the patient group compared with the control group (77 vs 99%, P = 0.0014). This difference was most pronounced for the older patients and especially in males. Only one patient had smaller type IIA fibres than type I fibres (case 2). Apart from this, there were no signs of type II fibre hypotrophy. The quotient of the mean areas of type IIA and IIB fibres was close to 100% in both patients and controls. Type IIC fibres were not found in any patient but were found in two of the healthy controls.



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FIG. 2. Muscle biopsy showing smaller area of type I fibres (light) compared with type II fibres (dark) stained for ATPase after preincubation at pH 9.4.

 


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FIG. 3. The same muscle biopsy as in Fig. 2 stained for ATPase at pH 4.6, showing type I fibres darkly stained and type II fibres lightly stained. Type I fibres are smaller than type II fibres.

 
Immunohistochemistry
Four of the 15 patients showed significant expression of MHC class II. This was significantly (P = 0.0143) more than in the control group (0/33). Two patients with cellular infiltrates did not have increased expression of MHC class II. For MHC class I and MAC the differences between patients and controls were not significant.

Muscle strength
For the patient group, both isometric (P = 0.018) and isokinetic (P = 0.008) strength were significantly reduced compared with the reference group. For three of the 15 patients, isometric strength was outside the normal range (±2 S.D.). For isokinetic strength, this was found in 1/15 patients.

Relationship between muscle strength and muscle structure
There was a significant positive correlation between mean areas of type I muscle fibres and isometric strength (P = 0.0315) and between the mean area of type IIA fibres and isometric (P = 0.0147) strength. There was no significant correlation between muscle strength and the proportion of type I fibres or strength and the quotient between areas of type I and type IIA fibres. Statistically, we found no significant correlation between strength and abnormal findings in the muscle biopsy, but 2/3 patients with muscle strength below normal limits (below –2 S.D.) had cellular infiltrates in the muscle biopsy. The disease subgroup or the presence of local arthritis did not have a significant effect on the muscle biopsy findings.

Nerve conduction study
One of the patients had a sural nerve conduction velocity just below the lower limit. This was not regarded as significant. The remaining results were normal.


    Discussion
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
In this study we found changes in the muscles of patients with JIA. The majority of the muscle biopsies showed minor changes, most commonly increased variation in muscle fibre diameter and the presence of some atrophic fibres. These are unspecific changes of unknown significance. We found no correlation between these small structural changes and muscle function or disease subgroup. Minimal biopsy changes are sometimes seen in healthy persons [22]. This was the case in 21% of our control group.

Perivascular cellular infiltrates are a sign of inflammation and are not a normal finding in muscle biopsies. This pathological result was found in biopsies from two patients. Both had reduced muscle strength. One of these patients had severe chronic polyarthritis with muscle weakness and hypotrophy. The other patient had moderately active oligoarthritis with reduced muscle strength. None of them showed other signs of vasculitis or myositis. In adult RA, both myositis and vasculitis are known to occur. Miro et al. [9] found myositis in 8/21 and vasculitis in muscle biopsies in 1/21 RA patients with muscle weakness. Halla et al. [10] found myositis in 13/31 RA patients, most frequently in systemic disease, and vasculitis in 2/31 patients. The expression of MHC class II in four of the patients in the JIA group in the present study may be a sign of inflammatory myopathy. This is further supported by the finding of perivascular cellular infiltration in two patients. The patients with cellular infiltrates were not the same as those who had positive MHC class II expression. This is in agreement with results from previous studies of inflammatory myopathies [25, 26, 29], in which muscle fibres express MHC class I and class II antigens independently of inflammatory infiltrates. The small cellular infiltrates were not examined for expression of inflammatory markers. Expression of MHC class I and class II is common near inflammatory infiltrates. The sections of the muscle biopsy specimen were not the same in the analysis of morphological changes and MHC expression. The four patients with positive expression of MHC class II antigens were young but no correlation with disease subgroup or muscle strength was found.

In the present study of children and teenagers with JIA we did not find signs of type II muscle fibre hypotrophy, as might have been assumed from studies on adults with RA, which have revealed such hypotrophy. Halla et al. [10] found type II fibre hypotrophy in 12/16 RA patients without symptoms of myopathy. Miro et al. [9] found the same in 11/21 RA patients with symptoms of myopathy. The reduced quotient between the mean area of type I and type IIA in the patients compared with the control group may be a sign of relative type I fibre hypotrophy. The reason for this difference is not obvious. Selective type I fibre hypotrophy has previously been described in the quadriceps muscle after anterior cruciate ligament injuries [44], but is otherwise not a common finding. The selective fibre hypotrophy could not be solely due to immobilization, since other lesions to the knee do not cause this type of hypotrophy. The reason for this may be reflex inhibition. In the literature we have not found evidence for any difference in the relative areas of type I and type IIA fibres due to the age of children and adolescents [45, 46]. It is, however, possible that the difference in fibre area ratio between patients and controls is an effect of the relatively large type II fibres in the male patients. It is known that type II fibres are larger than type I fibres in adult healthy males, particularly in the anterior tibial muscle. Other studies in adults in which muscle fibre areas in the anterior tibial muscle have been measured reported a quotient between mean area of type I and type II fibres ranging from 49 to 67% [19, 22, 47]. Most of the persons in the control group in the current study were women and the biopsies were taken from another muscle. There were, however, no signs of selective hypotrophy of type II fibres in the JIA group.

In the present study, the patients with JIA had more type I fibres than the controls, probably because the biopsies were obtained from different muscles. The difference in fibre type composition could also be explained by the difference in age between the groups. Previous studies have indicated that in the anterior tibial muscle about 75% of the muscle fibres are of type I [22, 48]. The children with polyarthritis had a lower percentage of type I fibres than the other JIA patients. This could be an effect of less activity in children with polyarthritis. It is known that the distribution of fibre types and fibre area varies in different parts of the muscle [49, 50]. This may also explain the difference between patients and controls.

The patients’ muscle strength correlated to mean muscle fibre area. This is expected since muscle force is partly the effect of the amount of contractile myofilaments. In this study strength was reduced in proportion to mean muscle fibre area. This implies that part of the weakness is caused by a reduction in muscle fibre area. This is further supported by the fact that children with JIA also have reduced muscle thickness, related to muscle weakness in the knee extensor muscle [34].

The fibre area was not significantly affected by the presence of active local arthritis in the same leg, as could have been expected from reflex inhibition. The results could, however, have been confounded by the fact that all boys had arthritis in the examined leg, and older boys usually have larger muscle fibre areas than girls. Nor did we find any correlation between immunohistochemical changes in muscle biopsies and local arthritis. Of the two patients with cellular infiltrates, both had local arthritis. The material is too small to draw certain conclusions from.

The nerve conduction study did not show any obvious signs of sensory neuropathy or mononeuropathy in the leg, as have been found in adults with RA. One previous study also failed to reveal peripheral nerve involvement in JIA [51]. Consequently, nerve dysfunction is probably not responsible for the muscle dysfunction in JIA.

The main limitations of the present study are the small number of patients, the lack of a strictly age-matched control group for muscle biopsies, and the fact that the biopsies were not obtained from the same muscle in patients and controls. Muscle biopsies were not obtained from age-matched normal children and teenagers as this was considered unethical. The biopsy procedure is somewhat painful and not appreciated by younger children. The patients in the present study all volunteered; it was not possible to persuade all to participate. The 15 participants in the study are, however, a representative sample of children and teenagers with JIA. The biopsies from the control group were taken from a different muscle and were originally obtained for other studies (unpublished). This could explain the difference in fibre type composition and the difference in relative fibre type area between the groups. The presence of inflammatory cell infiltrates is not a normal finding. The occurrence of minimal changes and the expression of inflammatory markers are not supposed to be different in various muscles.

In conclusion, this study has shown that children and teenagers with JIA have reduced muscle strength and changes in muscle structure and muscle immunology, as in adult RA, with the difference that patients with JIA show no signs of neuropathy or selective type II muscle fibre hypotrophy.


    Acknowledgments
 
Special thanks to Professor Björn Gerdle for letting us use his muscle biopsies from healthy physiotherapy students, and to laboratory technicians Lisbeth Lindvall and Gunnvor Sjöö for their skilful work with the muscle biopsies. The study was supported by grants from The County Council of Östergötland, The Foundation Samariten, The Foundation Karlfeldts minne and The King Gustaf V Foundation.

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 

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Submitted 5 February 2004; revised version accepted 23 July 2004.



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