Magnetic resonance imaging changes of thigh muscles in myopathy with antibodies to signal recognition particle

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1 RHEUMATOLOGY Rheumatology 2015;54: doi: /rheumatology/keu422 Advance Access publication 21 November 2014 Original article Magnetic resonance imaging changes of thigh muscles in myopathy with antibodies to signal recognition particle Yiming Zheng 1, Linlin Liu 1, Lu Wang 1, Jiangxi Xiao 2, Zhaoxia Wang 1,HeLv 1, Wei Zhang 1 and Yun Yuan 1 Abstract Objective. The aim of this study was to evaluate muscle MRI changes and the role of MRI in monitoring therapy in patients with myopathy associated with antibodies to signal recognition particle (anti-srp myopathy). Methods. We identified 12 patients with anti-srp myopathy [6 females and 6 males; mean age of onset 38.5 years (S.D. 12.4), mean duration 22.8 months (S.D. 20.6). The main symptoms were proximal limb muscle weakness. Mean serum creatine kinase levels were moderately increased. Muscle biopsies revealed necrotizing myopathy in all patients, with obvious connective tissue proliferation in five patients and a single focus of lymphocytic infiltration in the endomysium in one. The myositis disease activity assessment (MYOACT) visual analogue scales scores were assessed. Muscle MRI was performed through the thighs. All patients were treated with corticosteroids and other immunosuppressive drugs. Results. MRI revealed fatty infiltration and oedema in the thigh muscles of all 12 patients. Prominent fatty infiltration was present in 4 of the 12 patients. The hamstrings and adductor magnus were the most severely infiltrated and the quadriceps femoris the least. Obvious oedema was observed in 10 of the 12 patients, the most severely affected muscles being the vastus lateralis, rectus femoris, biceps femoris and adductor magnus, with relative sparing of the vastus intermedius. The degree of oedema was not correlated with creatine kinase levels or MYOACT scores. The four patients with striking fatty infiltration were refractory to therapy. Conclusion. MRI of the thigh muscles shows a distinct pattern of oedema and fatty infiltration and can be used to monitor the treatment of patients with anti-srp myopathy. Key words: myositis, MRI, muscles. Rheumatology key messages. We describe distinctive patterns of MRI changes in muscles of myopathy associated with antibodies to signal recognition particle (anti-srp myopathy).. Anti-SRP myopathy patients with obvious fatty infiltration have poor response to therapy.. MRI can help diagnosis and manage anti-srp myopathy. CLINICAL SCIENCE 1 Department of Neurology and 2 Department of Radiology, Peking University First Hospital, Peking, China Submitted 9 April 2014; revised version accepted 11 September 2014 Correspondence to: Yun Yuan, Department of Neurology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing , People s Republic of China. yuanyun2002@sohu.com Introduction There are five major types of idiopathic inflammatory myopathy: DM, PM, sporadic inclusion body myositis (sibm), autoimmune necrotizing myopathy and overlap myositis. Myopathy associated with antibodies to signal recognition! The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Yiming Zheng et al. particle (anti-srp myopathy) has recently been regarded as an autoimmune necrotizing myopathy. Clinically this disease is characterized by adult onset, proximal and symmetric limb weakness and markedly elevated serum creatine kinase (CK) levels. The typical pathological findings in muscle are necrotic myopathy without inflammatory cell infiltration [1 6]. The quite variable disease progression and neurological outcomes may lead to delayed or wrong diagnoses [7]. Most patients are refractory to corticosteroid therapy. MRI of skeletal muscles and detection of myositisspecific autoantibodies have recently become useful additions to diagnostic and management workups in patients with inflammatory myopathies. Moreover, muscle MRI adds important information about the activity of the myositis [8]. However, no detailed study concerning muscle MRI changes in patients with anti-srp myopathy have been published. Herein we evaluate MRI changes in 12 patients with anti-srp myopathy. Materials and methods Patients The study comprised 12 patients with myopathy with anti- SRP antibodies diagnosed in the Department of Neurology at Peking University First Hospital from January 2011 to January 2013, including six previously reported cases [9]. The study was approved by the ethics committee of Peking University First Hospital and all patients gave informed consent. Relevant clinical data for these 12 patients, 6 female and 6 male subjects with a mean age of 39.9 years (S.D. 12.7; range years), are shown in Table 1. The mean age of onset was 38.5 years (S.D. 12.4; range years) and the mean duration was 22.8 months (S.D. 20.6; 2 72 months). The main symptoms were proximal limb muscle weakness in all patients, myalgia in two and dysphagia in three. No patients had a history of malignancy or treatment with statins. Physical examination at the time of diagnosis showed mostly symmetrical weakness involving all limbs, especially the proximal muscles, in all patients. Medical Research Council (MRC) grades (0 5) ranged from 3 to 5 in the proximal muscles of upper limbs and from 2 to 4 in those of the lower limbs. The distal muscles of all limbs were normal. Sensation was normal. Subjects were also scored on the modified Gardner-Medwin and Walton (G-M&W) scale (1 9; ranging from all activities normal to unable to sit without assistance) [10]; the mean G-M&W score was 4 (S.D. 2; range 1 9). All patients were also assessed with the myositis disease activity assessment (MYOACT) visual analogue scales (VASs), with the score comprising the sum of the 10 cm VAS scores for each of six individual extramuscular organ systems and the muscle system and ranging from 0 to 70 [11]. The mean MYOACT score was 15.1 (S.D. 6.3; range 8 29). Results of other investigations prior to treatment were as follows: mean serum CK level 5200 IU/l (S.D. 3314; range ; normal ), no ANAs detected in any patients, ESR normal in all patients, electromyographic findings consistent with a myopathic pattern in all patients and anti-srp antibodies detected in all patients by Euroimmun (Lübeck, Germany) immunoblots according to the standard methods (Euroline Myositis Profile 3 immunoline blot; Euroimmun) [9]. Muscle biopsies were performed during the initial diagnostic evaluation and showed myopathic features consistent with necrotizing myopathy, including prominent necrotic or regenerative fibres without perimysial or perivascular accumulations of lymphocytes. Prominently increased endomysial connective tissue was a feature in 5 of 12 patients (Fig. 1). One biopsy showed a single focus of lymphocytic infiltration in the endomysium. None of the biopsies showed a perifascicular distribution of atrophic changes or rimmed vacuoles in the muscle fibres. Methods Muscle MRI Muscle MRI examinations at 1.5 T (GE 1.5 Sigma Twin Speed; GE Healthcare, Waukesha, WI, USA) were performed at the thigh level in all patients before treatment. The following sequences were used: (i) axial T1-weighted spin echo series with 450/12 (repetition time, ms/echo time, ms) and (ii) axial short TI inversion recovery series with 5000/90 (repetition time, ms/echo time, ms). T1-weighted MRIs were used to evaluate the degree of fatty infiltration according to the modified Mercuri scale (0 5 scale; from normal appearance to complete fatty infiltration) [12]. Short TI inversion recovery sequences were used to assess the degree of oedema (0 5 scale; from normal to moderate intrafascicular global oedema changes) [13]. The MRI scans were examined by two musculoskeletal radiologists who looked for abnormal muscle bulk and signal intensity within the different muscles and blinded to all clinical data, including the diagnoses and clinical characteristics. Follow-up All patients were treated with oral corticosteroids and at least one other immunosuppressant, including MTX, AZA, ciclosporin, tacrolimus and CYC. Eleven patients were followed up for 3 72 months. To provide a general assessment of therapeutic effect, the following scale was used: 0, no improvement in muscle strength or G-M&W score; 1, partial improvement defined as muscle strength or G-M&W score improved at least one level; 2, almost complete improvement with muscle strength 5 and G-M&W scores 0 1. Statistics analysis The Shapiro Wilk test was used to assess whether the measured variables in our 12 patients were normally distributed. Descriptive statistics are presented as mean (S.D.; min max), unless otherwise stated. Correlations between MRI changes and various clinical parameters were calculated using the Spearman rank test and P < 0.05 was considered to be statistically significant

3 Thigh muscle MRI changes in anti-srp myopathy TABLE 1 Clinical data in 12 patients with anti-signal recognition particle myopathy Patient Age, years Sex M F F M M M F F F M F M Disease duration, months MYOACT score (0 70) Before treatment Strength (0 5) CK, IU/l G-M&W (0 9) Muscle pathology Proliferation of connective tissue N Y N N N Y Y NA N Y Y N Inflammatory cell infiltration Y N N N N N N NA N N N N MRI scores Fatty (0 120) Oedema (0 120) After treatment Strength (0 5) NA CK (IU/l) WNL WNL WNL WNL WNL NA G-M&W (0 9) NA Improvement (0 2) (general assessment) NA General assessment scored on the following scales: 0, no improvement in muscle strength and G-M&W score; 1, partial improvement defined as muscle strength or G-M&W score improved at least one level; 2, almost complete improvement with muscle strength score 5 and G-M&W score 0 1. CK: creatine kinase; F: female; G-M&W: modified Gardner Medwin and Walton score; M: male; MYOACT: myositis disease activity assessment visual analogue scales; N: none; NA: not available; WNL: within normal limits; Y: yes

4 Yiming Zheng et al. FIG. 1Haematoxylin and eosin staining of muscle specimens from patients with anti-signal recognition particle myopathy (A) Muscle fibre necrosis and regeneration without connective tissue proliferation is evident. (B) Obvious connective tissue proliferation is evident. In neither case is there inflammatory cell infiltration. TABLE 2 Mean scores of MRI changes in 12 patients with anti-signal recognition particle myopathy Results MRI findings RF VL VI VM Sa Gr AL AM BF ST SM GM Fatty infiltration Oedema AL: adductor longus; AM: adductor magnus; BF: biceps femoris long head; GM: gluteus maximus; Gr: gracilis; RF: rectus femoris; Sa: sartorius; SM: semimembranosus; ST: semitendinosus; VI: vastus intermedius; VL: vastus lateralis; VM: vastus medialis. Fatty infiltration All patients had fatty infiltrations in their thigh muscles. The most seriously affected muscles were the adductor magnus, gluteus maximus, biceps femoris long head, semitendinosus and semimembranosus. Moderately affected muscles included the sartorius, gracilis and adductor longus. The least affected muscle was the quadriceps femoris (Table 2). Striking fatty infiltration was present in 4 of the 12 patients (33.3%), mainly in the hamstrings and adductor magnus, with a mean score 53. The other eight patients had mild fatty infiltration, the score for any individual muscle being 43 (Fig. 2A and B). Asymmetric fatty infiltration was present in three patients (25%), mostly in the adductor longus and hamstring muscles. Oedema All patients had oedema in their thigh muscles. Prominent oedema was present in 10 of the 12 patients (83.3%), the scores for some muscles being 53. The most obviously affected muscles were the vastus lateralis, rectus femoris, biceps femoris and adductor magnus. The gluteus maximus, semimembranosus, semitendinosus and vastus mesialis were moderately affected and the adductor longus, gracilis, sartorius and vastus intermedius were mildly affected (Table 2). Most intriguingly, the vastus lateralis muscle appeared to be more seriously affected compared with the vastus intermedius in 9 of the 12 patients (Fig. 2C and D). Asymmetric oedema was present in only one patient. Fig. 3 shows details of the severity and frequency of involvement of individual muscles. More muscle MRI scans are shown in the supplementary material, available at Rheumatology Online. Atrophy and hypertrophy Prominent atrophy was present in the hamstrings, with striking fatty infiltration in four patients. No hypertrophy was found in any thigh muscles. Correlations between MRI changes and clinical data There was a statistically significant correlation between the cumulative score of fatty infiltration of all muscles and disease duration (r = 0.683, P = 0.014). However, there was no correlation between fatty infiltration and CK levels (r = 0.519, P = 0.083) and MYOACT scores (r = 0.286, P = 0.368). No correlation was found between the cumulative score of oedema of all muscles and disease duration (r = 0.279, P = 0.380), CK levels (r = 0.432, P = 0.161) or MYOACT scores (r = 0.475, P = 0.118). There was also no correlation between muscle strength in the proximal muscles of the lower limbs and fatty infiltration (r = 0.147, P = 0.667) or oedema (r = 0.432, P = 0.185)

5 Thigh muscle MRI changes in anti-srp myopathy FIG. 2Muscle MRIs of the upper legs (A and B) T1-weighted images showing fatty infiltration in the thigh muscles. The hamstrings and adductor magnus are the most seriously affected by fatty infiltration. (C and D) Short tau inversion recovery images showing oedema in the muscles of the upper legs, predominantly in the vastus lateralis and rectus femoris; the vastus intermedius is relatively spared. However, there was a significant negative correlation between the combined scores for fatty infiltration and oedema of all muscles and muscle strength (r = 0.614, P = 0.044). Follow-up Complete resolution of muscle weakness occurred in all limbs of 3 of the 11 patients after combined treatment and partial improvement in 4 of the 11 patients. The mean muscle strength was 4 in the proximal muscles of the lower limbs. G-M&W scores ranged from 1 to 5. There was no improvement after treatment in 4 of the 11 patients. The mean muscle strength in these patients was 2 4 and the mean G-M&W score was 3 9. The four patients with severe fatty infiltration in the hamstrings were all refractory to therapy, three experiencing no improvement and one partial remission. A statistically significant negative correlation was noted between fatty infiltration and therapeutic effect (r = 0.645, P = 0.032). No correlation between oedema and therapeutic effect was found (r = 0.479, P = 0.136). Discussion We demonstrated a distinct pattern of oedema and fatty infiltration changes in the thigh muscle MRIs of patients with anti-srp myopathy. The oedema pattern in the thighs characteristically affected the muscles in a decreasing order of severity, from vastus lateralis, rectus femoris, hamstrings, adductor longus, sartorius gracilis to vastus intermedius. The fatty infiltration pattern in thighs was characterized in a decreasing order of severity, from adductor magnus, hamstrings, gluteus maximus, sartorius, gracilis, adductor longus to quadriceps femoris. Overall, oedema was more pronounced than fatty infiltration in these patients, as has been reported for PM and DM [14 16]. The MRI changes in anti-srp myopathy differ from those found in other myopathies, including DM, PM, sibm and limb girdle muscular dystrophy. In DM, oedema is found along the fascia and subcutaneous fat and fatty infiltration is usually absent or mild [14, 17]. The quadriceps femoris tends to be more often and equally affected in DM patients [15]. Muscle oedema, most often in the adductors, as the sole abnormality is preferentially encountered in PM [15, 16]. Some PM patients have fatty infiltration, which is characteristically far less pronounced than in anti-srp myopathy [15]. Another difference is the pronounced oedema in the vastus lateralis, with relative sparing of the vastus intermedius that can occur in anti-srp myopathy; in contrast, in PM these muscles are reportedly almost equally affected [15, 16, 18]. Fatty infiltration and oedema are more obvious in patients with sibm. However, fatty infiltration occurs predominantly in the anterior compartment of the thighs in sibm, which is not the case for anti-srp myopathy [19]

6 Yiming Zheng et al. FIG. 3Severity and frequency (number of cases) of muscle fatty infiltration and oedema in the upper legs of patients with anti-signal recognition particle myopathy. AL: adductor longus; AM: adductor magnus; BF: biceps femoris long head; GM: gluteus maximus; Gr: gracilis; RF: rectus femoris; Sa: sartorius; SM: semimembranosus; ST: semitendinosus; VI: vastus intermedius; VL: vastus lateralis; VM: vastus medialis. Oedema can also occur in other neuromuscular disorders [20], particularly limb-girdle muscular dystrophy 2B (LGMD 2B). In this disorder, the posterior compartment of the thigh muscles is commonly invaded with fatty infiltration; the anterior compartment is also generally affected, in contrast to anti-srp myopathy [21]. Oedema is associated with disease activity in patients presenting with acute PM/DM [22, 23]. Both MYOACT scores and levels of CK have been used to assess disease activity in patients with inflammatory myopathies [11]. There is reportedly a striking correlation between CK and anti-srp autoantibody levels in patients receiving therapy [24]. However, we found no correlation between muscle oedema and CK levels or MYOACT scores. The findings are similar in other types of inflammatory myopathies [15, 23]. MYOACT scores reflect disease activity not only in muscles, but also including the constitutional, arterial, cardiac, pulmonary, gastrointestinal and cutaneous systems [11]. Since anti-srp myopathy usually causes muscle weakness without other organ involvement, MYOACT scores are not appropriate for evaluating disease activity in this condition. We suggest that muscle oedema is a more reliable and objective marker of myositis activity. Muscle oedema is thought to be related to infiltration of inflammatory cells in DM and PM [22, 23]. However, the mean severity of inflammatory infiltrates in MRI-affected muscles does not decrease significantly after treatment in patients with PM [20]. As we have previously reported [9] and found in the present study, there is no or minimal inflammatory cell infiltration in the thigh muscles of patients with anti-srp myopathy. These findings strongly suggest that, in this disease, muscle oedema is not induced by inflammatory cell infiltration. Similarly oedema is obvious in other neuromuscular disorders in which there is no inflammatory cell infiltration, such as LGMD 2B, facioscapulohumeral muscular dystrophy and Duchenne muscular dystrophy [25]. All these observations support the current view that various pathogenic mechanisms, not simply the presence of inflammatory infiltrates, may be responsible for muscle oedema in patients with myositis. High cytoplasmic Na + concentrations in muscle fibres result in oedema in Duchenne muscular dystrophy [25]. This suggests that such oedema is mainly of osmotic origin and may contribute to fibre necrosis in patients with anti-srp myopathy. We found a significant correlation between fatty infiltration and disease duration in anti-srp myopathy, similar to

7 Thigh muscle MRI changes in anti-srp myopathy correlations reported for other types of inflammatory myopathies [19]. We suggest that fatty infiltration occurs as a compensatory response to muscle lesions that occur in the chronic stage of these diseases. Muscle biopsies from patients with anti-srp myopathy often show connective tissue proliferation, which may be the pathological basis of fatty infiltration seen on muscle MRI, as is true in Duchenne muscular dystrophy [26]. We found that neither muscle fatty infiltration nor oedema alone correlated closely with measures of muscle strength. However, there was a negative correlation between muscle strength and combined scores for both muscle fatty infiltration and oedema. In the early stages of anti-srp myopathy, oedema may be the main cause of weakness. In DM there is reportedly a close correlation between the degree of oedema and muscle strength [27]. However, in the chronic stage of this disease, muscle fatty infiltration also contributes to symptoms. In sibm, a strong correlation has been found between the degree of fatty infiltration and both disease severity and disease duration, as we found in our study [19]. These findings match those of Tomasová Studynková et al. [23], who reported that persistent weakness after treatment is usually not purely related to oedema in patients with PM. In our study, most patients with severe oedema and mild fatty infiltration had good responses to combined therapy. However, patients with severe fatty infiltration responded poorly to therapy. In addition, there was a significant negative correlation between fatty infiltration and therapeutic effect. Muscle fatty infiltration, which represents the aftermath of damaged muscle in any muscle disease, is untreatable. We suggest that severe fatty infiltration in muscles is a marker of refractoriness to all immunosuppressive therapies in patients with anti-srp myopathy, as is true in other refractory inflammatory myopathies [28]. However, some patients with severe fatty infiltration also have only mild oedema, indicating little disease activity; this may also be responsible for poor responses to treatments. More patients and longer follow-up with assessments of muscle MRIs are required to clarify the underlying mechanism. In summary, although muscle MRI changes in individual anti-srp myopathy patients can be diverse, they show a distinct pattern that differs from those of other neuromuscular disorders. Our data also indicate that muscle MRIs can be useful for monitoring disease activity and predicting refractoriness to treatment in patients with anti-srp myopathy. Acknowledgements We gratefully acknowledge the participation of all patients. Funding: This work was supported by the Ministry of Science and Technology of China (grant number 2011ZX ). Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology Online. References 1 Targoff IN, Johnson AE, Miller FW et al. Antibody to signal recognition particle in polymyositis. Arthritis Rheum 1990; 33: Miller T, Al-Lozi MT, Lopate G et al. Myopathy with antibodies to the signal recognition particle: clinical and pathological features. J Neurol Neurosurg Psychiatry 2002;73: Kao AH, Lacomis D, Lucas M et al. Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy. Arthritis Rheum 2004; 50: Hengstman GJ, ter Laak HJ, Vree Egberts WT et al. Antisignal recognition particle autoantibodies: marker of a necrotising myopathy. Ann Rheum Dis 2006;65: Takada T, Hirakata M, Suwa A et al. Clinical and histopathological features of myopathies in Japanese patients with anti-srp autoantibodies. Mod Rheumatol 2009;19: Valiyil R, Casciola-Rosen L, Hong G, Mammen A, Christopher-Stine L. Rituximab therapy for myopathy associated with anti-signal recognition particle antibodies: a case series. Arthritis Care Res 2010;62: Suzuki S, Hayashi YK, Kuwana M et al. Myopathy associated with antibodies to signal recognition particle: disease progression and neurological outcome. Arch Neurol 2012;69: Del Grande F, Carrino JA, Del Grande M, Mammen AL, Christopher Stine L. Magnetic resonance imaging of inflammatory myopathies. Top Magn Reson Imaging 2011; 22: Wang L, Liu L, Hao H et al. Myopathy with anti-signal recognition particle antibodies: clinical and histopathological features in Chinese patients. Neuromuscul Disord 2014;24: Borsato C, Padoan R, Stramare R et al. Limb-girdle muscular dystrophies type 2A and 2B: clinical and radiological aspects. Basic Appl Myol 2006;16: Isenberg DA, Allen E, Farewell V et al. International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease. Rheumatology 2004;43: Mercuri E, Talim B, Moghadaszadeh B et al. Clinical and imaging findings in six cases of congenital muscular dystrophy with rigid spine syndrome linked to chromosome 1p (RSMD1). Neuromuscul Disord 2002;12: Stramare R, Beltrame V, Dal Borgo R et al. MRI in the assessment of muscular pathology: a comparison between limb-girdle muscular dystrophies, hyaline body myopathies and myotonic dystrophies. Radiol Med 2010; 115: Garcia J. MRI in inflammatory myopathies. Skeletal Radiol 2000;29:

8 Yiming Zheng et al. 15 Nishikai M, Akiya K. [Clinical significance of magnetic resonance imaging of skeletal muscles in idiopathic inflammatory myopathies of adults]. Ryumachi 2000;40: Dion E, Cherin P, Payan C et al. Magnetic resonance imaging criteria for distinguishing between inclusion body myositis and polymyositis. J Rheumatol 2002;29: Kimball AB, Summers RM, Turner M et al. Magnetic resonance imaging detection of occult skin and subcutaneous abnormalities in juvenile dermatomyositis. Implications for diagnosis and therapy. Arthritis Rheum 2000;43: Cantwell C, Ryan M, O Connell M et al. A comparison of inflammatory myopathies at whole-body turbo STIR MRI. Clin Radiol 2005;60: Cox FM, Reijnierse M, van Rijswijk CS et al. Magnetic resonance imaging of skeletal muscles in sporadic inclusion body myositis. Rheumatology 2011;50: Mercuri E, Pichiecchio A, Allsop J et al. Muscle MRI in inherited neuromuscular disorders: past, present, and future. J Magn Reson Imaging 2007;25: Paradas C, Llauger J, Diaz-Manera J et al. Redefining dysferlinopathy phenotypes based on clinical findings and muscle imaging studies. Neurology 2010;75: Davis WR, Halls JE, Offiah AC et al. Assessment of active inflammation in juvenile dermatomyositis: a novel magnetic resonance imaging-based scoring system. Rheumatology 2011;50: Tomasová Studynková J, Charvát F, Jarosová K et al. The role of MRI in the assessment of polymyositis and dermatomyositis. Rheumatology 2007;46: Benveniste O, Drouot L, Jouen F et al. Correlation of antisignal recognition particle autoantibody levels with creatine kinase activity in patients with necrotizing myopathy. Arthritis Rheum 2011;63: Poliachik SL, Friedman SD, Carter GT et al. Skeletal muscle edema in muscular dystrophy: clinical and diagnostic implications. Phys Med Rehabil Clin N Am 2012;23: Kinali M, Arechavala-Gomeza V, Cirak S et al. Muscle histology vs MRI in Duchenne muscular dystrophy. Neurology 2011;76: Maillard SM, Jones R, Owens C et al. Quantitative assessment of MRI T2 relaxation time of thigh muscles in juvenile dermatomyositis. Rheumatology 2004;43: Dastmalchi M, Grundtman C, Alexanderson H et al. A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies. Ann Rheum Dis 2008;67: