Departments of Rheumatology and
1 Radiology, St George's Healthcare NHS Trust, Blackshaw Road, London SW17 0QT, UK
We present four case histories from a series of 78 patients with idiopathic inflammatory muscle disease at St George's Healthcare NHS Trust. These cases illustrate some of the complexities in the presentation and natural history of inflammatory muscle disease, which may present pitfalls to the unsuspecting clinician. The cases illustrate the benefits of intensive therapy with standard immunosuppression, intravenous immunoglobulins (i.v. Ig) and prolonged airway protection in certain situations. We also describe the role of muscle magnetic resonance imaging (MRI) in the diagnosis and management of inflammatory muscle disease.
Case 1
Diagnosis: Dermatomyositis with dysphagia.
Treatment: Prednisolone, cyclosporin, i.v. Ig, percutaneous endoscopic gastrostomy (PEG) tube.
A 68-yr-old Asian man was admitted with a 3-month history of a rash on the face, ears, neck, arms and legs, with itchy puffy eyes. He had also noticed weakness with difficulty getting out of bed and climbing stairs. In the last month he had developed difficulty speaking and swallowing, and described 1 week of choking and coughing with pooling of saliva when eating. Examination revealed a thin ill man with dysphonic speech, puffy eyes, an erythematous rash, nail-fold lesions, splinter haemorrhages, proximal muscle weakness and wasting.
The full blood count was normal, erythrocyte sedimentation rate (ESR) 115 mm/h, C-reactive protein (CRP) <4 mg/l, creatine kinase (CK) 44 000 U/l (normal range: 30210 U/l), autoantibodies including antinuclear antibodies (ANA) and Jo-1 were not present and blood gases were normal. Electromyography (EMG) showed complex low-amplitude polyphasic potentials, with unstable units, jitter and blocking in keeping with a myopathic process. Muscle MRI showed patchy increased signal intensity on inversion recovery images in the anterior aspect of the thigh, with relative sparing of the posterior compartment muscles, suggestive of acute inflammation (see Discussion). Muscle biopsy from the anterior thigh showed a few degenerate muscle fibres with central nucleation but no inflammatory infiltrate. On barium swallow there was disordered peristalsis and incoordination with extensive aspiration. Laryngoscopy, chest radiography and echocardiography were normal. The features were characteristic of dermatomyositis with severe dysphagia and dysphonia.
A nasogastric tube was inserted and oral feeding stopped. He received i.v. methylprednisolone at 1 g daily for 5 days, followed by oral prednisolone at 60 mg daily. Dysphagia did not improve and so he received i.v. Ig at 2 g/kg over 5 days and cyclosporin was started. Skeletal muscle strength improved slowly, but a PEG tube was required as there was no immediate improvement in dysphagia. The ESR and serum CK normalized and he was discharged, feeding himself through the PEG. Prednisolone was slowly reduced and cyclosporin increased.
He was readmitted 1 month later with septicaemia, related to the PEG insertion site. He recovered after taking antibiotics, but remained unable to swallow. He therefore received a second course of i.v. Ig (2 g/kg) over 3 days. This resulted in a rapid improvement and over the next 4 months he gained 15 kg in weight; videofluoroscopy confirmed normal swallowing and the PEG was removed.
Comment
This case illustrates a discrepancy between the raised ESR and normal CRP. This pattern is found frequently in patients with inflammatory muscle disease as well as in other connective tissue disorders such as systemic lupus erythematosus. In this case we feel that the ESR reflects the underlying severity of muscle disease, which was also reflected by the very high CK. However, the ESR is not always a reliable marker of disease activity in inflammatory muscle disease, and indeed in our series was not elevated in approximately 50% of cases at presentation.
Severe myositis, as evidenced by the CK, does not necessarily imply diffuse myositis, as demonstrated in this case by the MRI. Indeed a patchy distribution on MRI is characteristic of these diseases, and explains why a normal muscle biopsy is not incompatible with severe disease. The lack of inflammatory cells in the muscle biopsy in this case may also be due to the vasculitic basis of dermatomyositis, leading to ischaemic muscle necrosis [13]. In other situations a normal biopsy may result from steroid treatment. However, in this case, central nucleation is a feature of regenerating muscle fibres, and therefore demonstrates an active pathological state.
In our series of 78 patients, 23 (29%) had pharyngeal or oesophageal involvement. Intravenous Ig was used to treat dysphagia in the four most severe cases, with complete recovery occurring in all, including the case described. Cyclosporin was used in this case rather than azathioprine as it is available in liquid form and is therefore more convenient for long-term use in patients with a PEG tube. This case illustrates the point that patients may need two or more courses of i.v. Ig before they regain normal swallowing. The use of i.v. Ig is discussed in detail in the Discussion.
Case 2
Diagnosis: Dermatomyositis, calcinosis, cerebellar vasculitis.
Treatment: Prednisolone, azathioprine, i.v. Ig, diltiazem.
A 51-yr-old African woman presented with a 3-month history of facial swelling, tenderness and weakness of the upper arms and thighs, and difficulty swallowing. On examination there was periorbital oedema and considerable proximal muscle weakness. The serum total CK was 8585 U/l, ESR 35 mm/h and no autoantibodies including ANA and Jo-1 were present. An EMG showed patchy low-amplitude polyphasic potentials and a full interference pattern in keeping with a myopathic process. Muscle biopsy from the thigh was normal. Barium swallow and echocardiogram were normal. The features were characteristic of dermatomyositis.
Following initial treatment with prednisolone and azathioprine the weakness slowly improved and the serum CK fell to 98 U/l. Prednisolone was successfully tapered to a low dose and she remained well. Three years later she developed calcinosis in the tissues of her buttocks and upper arms and a skin biopsy revealed vasculitis (Fig. 1). A year later she relapsed, became weak, the ESR rose to 58 mm/h and the CK remained normal. An MRI of both thighs showed patchy increased signal on inversion recovery images, and muscle biopsy from the thigh revealed basophilic fibres with lymphocytic infiltration. At the same time she developed ataxia and dizziness, and an MRI of the brain revealed a left cerebellar hemisphere infarct (Fig. 2
), which was presumed to be due to vasculitis. She received two courses of i.v. Ig (2 g/kg) resulting in an improvement in muscle weakness; and dizziness resolved spontaneously. The calcinosis was treated with diltiazem, up to 360 mg daily, but did not diminish.
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Calcinosis is a feature of dermatomyositis that is more frequently recognized in children. We have one other adult case of dermatomyositis with calcinosis in our series, in which, in contrast to this report, the calcinosis improved considerably following treatment with the calcium channel blocker diltiazem [4].
The primary pathological process in dermatomyositis is vasculitis within skeletal muscle [13], and is demonstrated in this case in the skin biopsy. Systemic vasculitis is also reported, but involvement of the central nervous system (CNS) is rare and more classically described in children [5]. In this case the appearances on the MRI were of ischaemia, which, in the absence of risk factors for thromboembolic disease, we feel was most likely to be due to vasculitis. We have seven other cases of systemic vasculitis in our series (9%), and one other case of CNS vasculitis, all in patients with dermatomyositis.
Case 3
Diagnosis: Fulminating onset polymyositis with myoglobinuric renal failure.
Treatment: Prednisolone, cyclophosphamide, i.v. Ig, cyclosporin, tracheostomy, PEG tube.
A 22-yr-old Caucasian man was admitted with a short history of fever, sweats, loss of weight, muscle pains and weakness. Before admission he developed shortness of breath, difficulty swallowing and noticed that he was passing dark urine. There was no history of drug or excess alcohol consumption. Examination revealed moderately severe proximal muscle weakness and tenderness but normal reflexes and sensation. The cardiovascular, respiratory and abdominal systems were normal.
Serum CK was >45 000 U/l, full blood count, urea and electrolytes, ESR and CRP were normal. Autoantibodies including ANA and Jo-1 were negative. Urine contained myoglobin. EMG showed numerous, low-amplitude, high-frequency complex motor units with prominent fibrillation potentials and a full interference pattern on maximum volition indicating an active myopathic process. MRI showed extensive inflammatory change in the muscles of both thighs with relative sparing of semitendinosus, semimembranosus and biceps femoris muscles (Fig. 3). The features were characteristic of fulminant polymyositis with myoglobinuria.
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Over the next year improvement in muscle strength continued with low-dose oral prednisolone and azathioprine. The serum CK remained elevated between 200 and 600 U/l and renal function tests remained normal. Because of abdominal pain the azathioprine was changed to cyclosporin. He has remained well, back at full time work, and has no muscle weakness. Repeat MRI 18 months after the initial presentation shows no acute inflammation, but evidence of fatty change and mild atrophy (Fig. 4).
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In acute cases of inflammatory muscle disease, respiratory function must be monitored regularly as rapid deterioration can occur from respiratory muscle involvement or aspiration from oesophageal dysmotility. These patients should be admitted to the ITU early and treated aggressively to save life. Our patient made an excellent recovery.
This is another example of dysphagia responding to i.v. Ig treatment but, as in case 1, requiring more than one course before the PEG tube could be removed. This case also illustrates our comments following case 1 regarding the ESR in inflammatory muscle diseases; in this patient it was normal at presentation.
Case 4
Diagnosis: Sarcoidosisacute myositis, nodular myositis and interstitial lung disease.
Treatment: Prednisolone, azathioprine.
A 27-yr-old professional guitarist presented with swelling, tightness and weakness of the forearms and pectoral muscles of 1-month duration, and some shortness of breath for a week. Examination revealed swelling and thickening of the brachioradialis and pectoralis muscles bilaterally and of the right extensor digitorum brevis. There was no muscle weakness and reflexes and sensory examination were normal. In the chest there were fine inspiratory crepitations at both bases. There was no rash or lymphadenopathy.
The full blood count was normal, serum CK 532 U/l, angiotensin-converting enzyme (ACE) 105 IU/l (normal range: 1075), ESR 13 mm/h, ANA and Jo-1 negative. Chest radiography showed bulky hilar shadowing and reticular shadowing at the lung bases. An EMG showed myopathic potentials, and an MRI of forearm muscles showed multiple regions of increased signal intensity on inversion recovery images suggestive of inflammation (Fig. 5). Muscle biopsy of right brachioradialis revealed an interstitial inflammatory infiltrate of lymphocytes, histiocytes and multinucleated giant cells, with some muscle fibre degeneration and regeneration, but no vasculitis (Fig. 6
). These features were all in keeping with a diagnosis of acute sarcoid myositis with lung involvement.
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Four years later he developed two skin papules on his cheek and a palpable 2 cm nodule in the left triceps muscle without tenderness or weakness. Biopsy of the skin showed sarcoid-like granulomatous inflammation. The clinical appearances of the triceps were of nodular myositis. Treatment with azathioprine was continued and he remains under review.
Comment
Sarcoidosis is only rarely associated with symptomatic muscle disease, for example reported in four out of 800 patients [7] and in two out of 500 patients [8] in two series, and in isolated reports subsequently [911]. Silverstein [7] suggests that three patterns of symptomatic sarcoid muscle disease may exist, namely palpable muscle nodules, acute myositis and chronic myopathy, though states that considerably overlap may exist, as demonstrated in our case. Our patient's presentation with acute myositis is typical of other cases in that he was young, had a short history of muscle symptoms and was otherwise healthy with few other features of sarcoidosis, with the exception of the chest radiograph and serum ACE, which was increased. In this situation the muscle biopsy is crucial to the diagnosis in showing a granulomatous myositis with an inflammatory infiltrate and associated muscle necrosis and regeneration. In contrast in systemic sarcoidosis the finding of non-caseating granulomas in biopsies from asymptomatic muscle, with no evidence of myocyte damage, is common and is reported in 50 to 80% of cases [7]. We have two other cases of sarcoid myositis in our series, one of which illustrates the additional association of dermatomyositis with sarcoidosis, seemingly particularly prevalent in Japanese patients [12].
The delayed development of nodular sarcoid myositis in our case is interesting, and illustrates the overlap between forms of symptomatic sarcoid muscle disease over time. As an isolated presentation, nodular sarcoid myositis should be discriminated from focal myositis, which is also a very rare and usually self-limiting benign disease [13, 14].
This case illustrates that sarcoid muscle and lung disease often responds well to prednisolone [7, 9, 10, 15]. This is in contrast to the outcome of interstitial lung disease in association with idiopathic inflammatory myositis (±Jo-1 antibody) where the outcome is less certain, particularly if the CK is normal [16].
Discussion
These four cases illustrate some of the complexities and challenges in the management of inflammatory muscle diseases. We have a series of 78 patients, followed at St George's Hospital since diagnosis for up to 28 yr. This series comprises 29 with pure polymyositis, 17 with pure dermatomyositis, 14 with mixed connective tissue disease, seven with malignancies, four with juvenile disease, two with inclusion body myositis, seven with granulomatous myositis and one with focal myositis. At present 40 are in complete remission, of whom 12 are off all treatment. A further 25 are in partial remission, four have resistant progressive disease and nine have died. Further demographic details are shown in Table 1.
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In our series between one and seven courses of i.v. Ig have been used in 13 patients (17%). The indications were resistant skeletal or oesophageal disease. Six patients with dermatomyositis, including two children, and three patients with polymyositis were treated and all responded well. In contrast two cases of inclusion body myositis and one patient with dermatomyositis and HTLV1 (in whom the aetiology of myositis was unclear) responded poorly. In particular, all four patients with severe dysphagia responded dramatically to treatment, allowing removal of the PEG tube; but required between two and seven courses of treatment.
Intravenous Ig continues to be used in our unit in cases of aggressive disease with life-threatening oesophageal or respiratory involvement (e.g. cases 1 and 3) and in cases where there has been an inadequate response, or relapse, following standard immunosuppression with prednisolone and either azathioprine or cyclosporin (e.g. case 2). We have had no deaths since starting to use i.v. Ig, apart from in patients with inclusion body myositis who failed to respond to any treatment. Previously, the highest mortality was in those patients who had pharyngeal/oesophageal involvement with severe dysphagia, from aspiration pneumonia or inanition.
Muscle magnetic resonance imaging
MRI is extremely sensitive to changes in the water content of tissues, and therefore is well placed to assess inflammatory muscle disease where oedema is a pathological hallmark. It is essential to employ the correct pulse sequences for the detection of muscle changes on MRI. Oedema/water is seen as low signal on T1-weighted images and is of slightly lower signal intensity than muscle. In contrast oedema/water is of high signal intensity on T2-weighted images, inversion recovery images (in which fat is suppressed) and on fat-suppressed T2-weighted images. Fat is of high signal intensity on T1- and T2-weighted images, and low signal intensity on inversion recovery images and fat-suppressed T2-weighted images. Therefore T2-weighted images cannot distinguish between oedema and fatty infiltration as both appear as high signal intensity. A comparison of T1-weighted images with inversion recovery or fat-suppressed T2-weighted images most effectively enables differentiation between oedema and fatty change (see Figs 35) and these are therefore important sequences to obtain in the assessment of muscle weakness (see Table 2
). In general terms axial images are more useful than coronal images for assessing muscle changes.
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In our series, MR images in persistently weak patients often demonstrate a mixed picture with areas of atrophy and fat replacement and also areas of oedema. In this situation the presence of oedema is important as this indicates that ongoing weakness may at least in part be due to ongoing inflammation that may be attenuated with increased immunosuppression. The images can therefore be very valuable to treatment decisions regarding escalation, change or withdrawal of immunosuppression.
In general it is not possible to differentiate between polymyositis and dermatomyositis with MRI. Both conditions characteristically demonstrate bilateral symmetrical oedema in the muscles of the lower pelvis and thighs [2634]. However, there are certain features which may favour a particular diagnosis. In polymyositis, oedema is generally only seen in muscle. In dermatomyositis, oedema may be seen in soft tissues as well as in muscle, and one report has suggested that the rectus femoris and biceps femoris muscles may be relatively spared [27].
Management algorithm
In our unit, at presentation all patients have serum CK and autoantibodies, including Jo-1, measured, an EMG, MRI of thighs (or weak area) and a muscle biopsy, which is often guided by the MRI. Occult malignancy is sought with a chest radiogram, mammogram, abdominal ultrasound and serum tumour markers. Muscle strength is assessed with serial reproducible objective measurements using a strain gauge dynamometer, which provides a more sensitive measure of change than the more rigid MRC power scale. The treatment of myositis has recently been reviewed [35]. In our unit first-line treatment for uncomplicated symptomatic polymyositis and dermatomyositis includes oral prednisolone starting with 4060 mg daily, reducing to 510 mg over 3 months. We use azathioprine at 50 mg increasing to 200 mg as a first-line steroid-sparing agent in view of its low toxicity (e.g. case 2). We also use cyclosporin at 100 mg increasing to 2.53 mg/kg per day or weekly methotrexate at 7.520 mg as alternative steroid-sparing agents, chosen on an individual patient basis, usually when azathioprine has been ineffective or poorly tolerated. In cases where the response to this standard induction immunosuppressive regime is poor, we feel it is important to reassess the diagnosis and confirm that there is still active inflammation, possibly repeating the MRI and muscle biopsy before escalating treatment with i.v. Ig and finally intravenous cyclophosphamide. It is especially important not to miss inclusion body myositis (by performing electron microscopy of muscle biopsy) and late-onset dystrophies, which are both currently untreatable and, as such, these patients should be spared toxic therapies. Patients with occult malignancy may also fail to respond well to initial treatment and a review or repeat of the investigations aimed at detecting tumours at the time of diagnosis should be undertaken.
In fulminant or life-threatening disease, we use pulses of i.v. methylprednisolone, i.v. Ig or cyclophosphamide early because of their fast mode of action (e.g. cases 1 and 3). In general we favour i.v. Ig over cyclophosphamide because it is less toxic, and we use i.v. Ig as the drug of choice for dysphagia. Intensive monitoring of respiratory function including blood gases on air and early transfer to ITU saves lives. Myoglobinuria is a feature of acute fulminating muscle disease with very high serum CK levels, and urine should be tested in such cases early at presentation (see case 3). Cases with myoglobinuria are medical emergencies where close monitoring of renal function and prompt and intensive treatment is necessary to prevent renal failure and ensure a good outcome.
Notes
Correspondence to: P. D. W. Kiely. E-mail: patrick.kiely{at}stgeorges.nhs.uk
References
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