classification
The two characteristic features of myositis are muscle weakness and evidence of muscle inflammation. Using clinical, histological and immunopathological criteria, myositis can be divided into three major groups:
• Dermatomyositis: affects children and adults and is commoner in women. • Polymyositis: seen after the second decade of life.
• Sporadic inclusion-body myositis: more common in men over the age of 50.
Diagnostic criteria for myositis remain complex [1]. The most widely used criteria from Bohan and Peters [2] (Table 10.1) are of limited value as they were devised prior to current understanding of inclusion-body myositis. They also cannot differentiate myositis from some dystrophies.
A number of features should make the clinician reconsider whether myositis is the correct diagnosis. These include:
• disease onset before the age of 18;
• slow-onset myopathy that evolved over months to years;
• fatigue and myalgia, without muscle weakness, even if a transient rise in creatine kinase activity is seen; and
epidemioloGy
The annual incidence rate of polymyositis and dermatomyositis lies between 2 and 8 per million. One 20-year study from the USA found 6 per million between 1963 and 1982 [3]. Recent studies from Spain [4] also suggested an overall annual incidence of 8 per million. A study from North America focused on patients with myositis, rather than dermatomyositis, in Olmsted County, Minnesota, from 1981 to 2000 [5]. They found that for inclusion-body myositis the age- and sex-adjusted incidence rates were 8 per million and for polymyositis they were 4 per million. These were higher than previously reported. There are limited data on the prevalence of polymyositis and dermatomyositis. Retrospective studies from USA [6] and Japan [7] suggest that it is between 50 and 63 per million.
clinical presentation
Dermatomyositis is characterized by a rash which accompanies or precedes muscle weakness. The dermatological features include:
• heliotrope rash on the upper eyelids;
• erythematosus rash on the face, neck and anterior chest; • photosensitivity; and
• Gottron’s papules (raised violaceous papules on the knuckles).
Weakness varies from mild to severe; in some patients muscle strength seems normal (amyopathic dermatomyositis). Dermatomyositis may be associated with cancer and can overlap with other connective tissue disease.
Polymyositis is usually a subacute myopathy that develops over weeks or months; there is weakness of the proximal muscles. Often its onset is indistinct. Polymyositis is often difficult to distinguish from other muscle diseases. It is essentially a diagnosis of exclusion.
Inclusion-body myositis is the commonest inflammatory myositis in patients aged over 50. It is characterized by a slow onset and progression and early involvement of finger flexors. It also responds poorly to treatment with steroids. There are several subsets including familial form and a retrovirus-associated form.
Table 10.1 Bohan and Peters’ diagnostic criteria Features 1. Symmetrical proximal muscle weakness 2. Muscle biopsy evidence of myositis 3. Elevation in serum skeletal muscle enzymes 4. Characteristic electromyographic pattern of myositis 5. Typical rash of dermatomyositis Polymyositis Definite: all 1–4 Probable: any three of 1–4 Possible: any two of 1–4 Dermatomyositis Definite: 5 plus any three of 1–4 Probable: 5 plus any two of 1–4 Possible: 5 plus any one of 1–4
extramuscular manifestations
A number of extramuscular features are common in myositis. These include: • joint contractures, particularly in dermatomyositis;
• dysphagia, due to oropharyngeal muscles and upper oesophagus involvement; • cardiac disease (conduction defects, tachyarrhythmias and myocarditis);
• lung disease due to weakness of the thoracic muscles or interstitial lung disease; and • subcutaneous calcifications (only in dermatomyositis).
General symptoms include fever, malaise, weight loss and Raynaud’s phenomenon. investiGations
Three diverse investigations are needed to fully evaluate patients with a suspected inflammatory myositis. These comprise:
• muscle enzymes, particularly creatine kinase; • an electromyography; and
• muscle biopsy.
Each investigation has its limitations. Muscle enzymes are usually raised in active myositis, but they are very non-specific. Elevated levels also occur in dystrophies, cardiac disease and many other disorders. In addition, the normal range differs across racial groups and normal levels are often high in some African and Afro-Caribbean patients.
An electromyography (EMG) provides valuable information but is highly subjective and its value is related to the skill and expertise of the clinician involved. A characteristic finding is the presence of positive sharp waves and fibrillation potentials, seen in over 90% of patients with acute disease. Complex repetitive discharges and pseudomyotonic discharges may also be seen.
Similarly, muscle biopsies require specific expertise in their interpretation, and are relatively subjective assessments. In addition, in many patients the disease is patchy and normal biopsies can be obtained from patients with overall serious disease. Frequent findings in dermatomyositis include decrease in the number of endomysial capillaries and perivascular inflammation in the perimysium. In polymyositis inflammation is primarily in the endomysium. The inflammatory response in inclusion body myositis is similar to that of polymyositis but there may also be rimmed vacuoles and an increase in ragged red fibres. Electron microscopy shows cytoplasmic and intranuclear tubulofilaments. Although rimmed vacuoles and tubulofilaments are fairly specific for inclusion-body myositis, they are sometimes absent in otherwise typical cases and so their absence does not exclude this diagnosis.
autoantibodies
In common with other connective tissue diseases, inflammatory myositis is associated with the development of a range of autoantibodies to cellular constituents. Some are found specifically in patients with polymyositis and dermatomyositis; these are termed myositis- specific autoantibodies. Others are found in patients with a myositis overlap syndrome and are termed myositis-associated autoantibodies. The most recent classification is shown in Table 10.2, based on a review by Mimori et al. [8]. Recently identified autoantibodies include those linked to amyopathic dermatomyositis (anti-CADM-140 antibody) and malignancy- associated myositis (anti-p155 and anti-p155/p140 antibodies).
imaGinG
Inflamed muscles can be assessed by a variety of imaging methods, particularly magnetic resonance imaging and ultrasound [9]. These indicate the extent of muscle disease and can be useful in identifying the optimal sites for muscle biopsy and for evaluating responses to treatment. Their use is limited at present as they are relatively non-specific.
assessments
As myositis affects not only the muscles, causing weakness, but also often damages many extramuscular components, there has been considerable interest in capturing the clinical effects of these disorders using standardized assessment methods. These include the Myositis Intention To Treat Index (MITAX) and the Myositis Disease Activity Assessment (MYOACT) visual analogue scale [10]. They have the ability to accurately and reproducibly assess patients; their use may be limited by both their relative complexity and the rarity of these diseases.
Table 10.2 Autoantibodies in myositis
antibody antigen frequency
Myositis-specific autoantibodies AntiJo1 HistidyltRNA synthetase 15–20% AntiPL7 ThreonyltRNA synthetase 5–10% AntiPL12 AlanyltRNA synthetase < 5% AntiEL GlcyltRNA synthetase 5–10% AntiOJ IsoleucyltRNA synthetase < 5% AntiKS AsparaginyltRNA synthetase < 5% AntiZo PhenylalaninetRNA synthetase < 1% AntiYRS TyrosyltRNA synthetase < 1% AntiSRP Signal recognition particle 5–10% AntiMi2 218/240kDa helicase family proteins 5–10%
AntiCADM140 Unknown 140kDa protein 50% (CADM)
Antip155 Transcriptional intermediary factor 1g 20% (dermatomyositis)
AntiMJ Unknown 140kDa protein < 5% AntiPMS DNA repair mismatch enzyme < 5% Myositis-associated autoantibodies AntiU1RNP U1 small nuclear RNP 10% AntiKu 70/80kDa DNAPK regulatory subunit 20–30% AntiOMScl Nuclear protein complex of 11–16 proteins 8–10% CADM, clinically amyopathic dermatomyositis.
TREATMENTS
Glucocorticosteroids
Glucocorticosteroids are the standard treatment for inflammatory myositis, although their effectiveness has not been subject to evaluation in a clinical trial [11]. There is an overwhelming consensus in favour of starting treatment with glucocorticosteroids in myositis [12]. The optimal dose remains uncertain; some physicians recommend a high initial dose such as prednisolone 60 mg/day. However, there is evidence that lower doses are equally effective and may limit adverse events [13]. For the foreseeable future, glucocorticosteroids will remain the mainstay of drug treatment.
immunosuppressants
There is strong empirical evidence that immunosuppressive agents, especially azathioprine, methotrexate and ciclosporin, are beneficial in patients with polymyositis and dermatomyositis who are refractory to treatment with steroids. This is almost entirely based on clinical experience rather than randomized controlled trials (RCTs) [14].
Clinical experience based on retrospective reviews of treated cases suggested that up to 75% show a good response in retrospective reviews when treated with immunosuppressants [15]. A retrospective review of over 100 patients at a single centre suggested methotrexate may be superior to azathioprine or further steroid treatment in patients who do not respond completely to initial therapy with prednisolone [16]. Other immunosuppressive agents that are sometimes used include ciclosporin, cyclophosphamide and mycophenolate mofetil. intravenous immunoGlobulins
Intravenous immunoglobulin has multiple mechanisms of actions and is the only treatment whose value is proven in RCTs (see below). The improvement with this treatment is noticeable by about 15 days. Repeated infusions may be required every 6–12 weeks to maintain improvement. As most patients with dermatomyositis respond to steroids, intravenous immunoglobulin is best reserved for steroid-resistant patients as a second-line therapy [17]. evidence-based immunosuppressive treatments
As inflammatory myositis is both rare and includes a spectrum of diseases, there have been few RCTs that have defined effective treatment. A recent Cochrane review [18] identified seven potentially relevant RCTs of immunosuppressants. One of these was excluded because it was a reported follow-up data from an earlier RCT.
Three RCTs compared immunosuppressant with placebo control. These comprised trials of:
• High-dose intravenous immunoglobulin [19]: showing treatment was effective. • Azathioprine [20]: showing no benefits of treatment.
• Plasma exchange and leucapheresis [21]: showing no benefits of treatment. Three RCTs involved comparisons of different treatments, which comprised: • Methotrexate and azathioprine [22]: showing no differences between groups. • Ciclosporin and methotrexate [23]: showing no differences between groups.
• Intravenous methotrexate and oral methotrexate plus azathioprine [24]: showing no differences between groups.
Key outcome data for the trials of intravenous immunoglobulin and azathioprine are shown in Figure 10.1. In all studies immunosuppressant therapy was associated with significant side-effects. Overall, there was minimal evidence that immunosuppressants are effective, mainly due to the relative dearth of RCTs.
tumour necrosis factor inhibitors
There is substantial evidence from studies of myositis pathogenesis that tumour necrosis factor (TNF) is involved and that inhibiting it might be effective [25]. However, in clinical practice its value appears questionable. A number of studies have now been reported, including two observational studies and an early RCT, and these give little indication of efficacy. The studies are as follows:
• A retrospective study of eight patients with dermatomyositis or polymyositis refractory to glucocorticosteroids and immunosuppressives were treated with TNF inhibitors between 1998 and 2004 [26]. Six patients were treated with etanercept alone, one with infliximab and one sequentially with both agents. Of the eight patients, six showed a favourable response with improved motor strength and decreased fatigue after 12 months. This study suggested potential benefit.
• An observational study of five patients with active dermatomyositis with lack of
response to glucocorticosteroid and cytotoxic therapy were given etanercept for at least 3 months [27]. All patients experienced an exacerbation of disease, with increase of muscle weakness, elevation of muscle enzyme levels and unchanged rash.
• A multicentre open-label controlled trial [28] of infliximab in myositis was terminated prematurely because of a low inclusion rate and a high dropout rate due to disease progression. Although infliximab combined with weekly methotrexate might be safe and well tolerated in a small subgroup of patients with drug-naive recent-onset myositis, its use was not advocated because of the uncertainty about treatment response.
The balance of evidence from these studies is that TNF inhibition is not effective in myositis.
Azathioprine
WMD muscle str
ength
WMD: weighted mean difference IVIg 30 25 20 15 10 5 0 –5 –10 –15 Figure 10.1 Comparison of active treatments with placebo from Cochrane review. WMD, weighted mean differ ence.
rituximab
A number of open-label trials have reported experience in treating myositis with rituximab, the biological that targets B cells. Three of these open-label pilot trials are particularly interesting, and all suggest a potential effect from targeting B cells. They are as follows: • A study of seven adult patients with dermatomyositis reported that all six evaluable
patients had major clinical improvements, with muscle strength increasing over baseline by 36–113% [29].
• A study of eight adult patients with dermatomyositis reported that three patients (38%) achieved partial remission by 6 months with improvements in muscle strength [30]. • A study of three patients with long-standing polymyositis or dermatomyositis poorly
responsive to prednisone combined with immunosuppressants reported muscle strength improved in all, with strength returning to normal in two [31].
Rituximab infusions were invariably well tolerated, with no serious infection complications. The results are generally positive, but there is some uncertainty in their interpretation. The key need is for them to be confirmed in a definitive RCT; this will take some time to come to fruition.
druG treatment of inclusion-body myositis
Unlike polymyositis, which it closely mirrors, inclusion-body myositis invariably fails to respond to immunosuppressive treatment. Intravenous immunoglobulins have been of some benefit in occasional patients. However, glucocorticosteroids, immunosuppressants and biologicals all appear universally ineffective.
Performance time
Exercise Exercise and
creatine +20 +10 0 –10 –20 Figure 10.2 Improvements in performance time for four functional tasks in patients treated with creatine and exercise over 6 months.
exercise
Until recently, patients with inflammatory myositis were discouraged from active exercise to avoid increasing muscle inflammation and were recommended to rest. Over the last two decades, a series of studies have shown that disability is reduced in patients with chronic polymyositis and dermatomyositis following resistive mild or intensive muscular training without signs of increased muscle inflammation. Patients with active, recent-onset disease also benefit from mild to moderate exercise without increased muscle inflammation [32].
A recent systematic review of exercise in a range of neuromuscular diseases identified seven trials that studied aerobic exercises for patients with muscle disorders [33]. Aerobic capacity benefited most; there were also improvements in muscle strength. A further three trials studied the combination of muscle strengthening and aerobic exercises and also showed evidence of benefit. Overall, this review concluded that strengthening exercises combined with aerobic exercises have positive effects on activities and participation in patients with muscle disorders and should be encouraged.
There is evidence that combining exercise with simple additional treatment to improve muscle strength increases performance. This has been shown in a recent RCT of creatine supplements, which increased performance in patients with myositis that had been treated with glucocorticosteroids and immunosuppressants [34]; all the patients had exercise but only those who had added creatine showed significant improvements. The extent of this improvement on an aggregated measure of performance (better performance reduces time involved) is shown in Figure 10.2.
outcomes
Myositis had a poor prognosis in the presteroid era. After glucocorticosteroids became available in the 1950s, outcomes improved considerably. A UK study from Sultan and colleagues [35] assessed long-term outcome in 46 patients with idiopathic myositis diagnosed from 1978 to 1999 by assessing cumulative survival probability over 20 years. During the course of the disease, seven patients (15%) went into full remission, eight (17%) had monophasic illness, nine (20%) had a relapsing–remitting course, 16 (35%) had chronic progressive illness and six (13%) died. The 5-year survival rate was 95% and the 10-year survival rate was 84%. A similar study from Finland [36] evaluated 176 patients with polymyositis and 72 patients with dermatomyositis diagnosed from 1969 to 1985. Their 5-year survival rate for polymyositis was 75% and for dermatomyositis was 63%; respective 10-year survival rates were 55% and 53%.
The most recent overall outcome data come from Bronner and colleagues [37]. They reviewed the clinical data and muscle biopsy specimens at presentation of 268 adult patients with ‘myositis’ or ‘possible myositis’ diagnosed from 1977 to 1998. Over 100 patients were excluded because of diagnostic uncertainty, leaving 165 considered to have definite myositis; these were followed for a mean of 5 years. During this time, 157 patients (95%) were treated with glucocorticosteroids and 94 (57%) were subsequently treated with one immunosuppressive or immunomodulating drug. Thirty-four (21%) patients died; in 18 patients death was related to their myositis. These associated deaths included cancer (in seven patients), pulmonary complications (in four patients) and adverse reactions to drugs (in four patients). Subsequently, 110 of 131 surviving patients (84%) were re-examined after 5 years’ follow-up. This showed 24% had considerable disability and 25% of the patients had muscle weakness (MRC sum score < 128); 41% were using prednisone or immunosuppressive treatment at follow-up. The relation of outcome to autoantibody categorization is shown in Figure 10.3.
The relation between myositis and malignancy is complex. A study from Hungary by András et al. [38] evaluated 309 patients with myositis; 37 of these had a malignancy. Thirty
patients had dermatomyositis and seven had polymyositis. In 65% the malignancy and myositis appeared within 1 year. The overall survival rate was 92% at 5 years and 89% at 10 years; it was considerably worse in patients with malignancy and myositis, and 32% of these patients died.
CONCLUSION
Most patients with dermatomyositis and polymyositis respond to treatment with glucocorticosteroids; the optimal dose is uncertain, but the benefits of high doses are probably overstated. Added immunosuppressants such as methotrexate or azathioprine will help most patients who show an incomplete response to steroids. Intravenous immunoglobulins should be reserved for patients who show an incomplete response to these approaches. Biologicals such as rituximab are likely to be more widely used in the future and have the potential to be highly effective. All patients will benefit from exercise. There is a need to increase the inclusion of patients with rare diseases of this sort in large RCTs and mechanisms need to be found to achieve this so that there is a firm evidence base for treatment.
REFERENCES
1. Dalakas MC. The future prospects in the classification, diagnosis and therapies of inflammatory myopathies: a view to the future from the ‘bench-to-bedside’. J Neurol 2004; 251:651–657.
MRC score high MRC score low No treatment at follow-up Treatment at follow-up (a) No MSA (n=56) SRP (n=3) Mi-2 (n=20) Synthetase (n=6) Jo-1 (n=14) 0 20 40 60 80 (b) No MSA (n=56) SRP (n=3) Mi-2 (n=20) Synthetase (n=6) Jo-1 (n=14) 0 20 40 60 80 Figure 10.3 Muscle strength and treatment needs by antibody subtype in myositis patients. (a) Muscle strength. (b) Treatment at followup. MRC, Medical Research Council; SRP, signal recognition particle [37].
2. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med 1975; 292:344–347.
3. Oddis CV, Conte CG, Steen VD, Medsger TA Jr. Incidence of polymyositis–dermatomyositis: a 20-year study of hospital diagnosed cases in Allegheny County, PA 1963–1982. J Rheumatol 1990; 17:1329–1334. 4. Vargas-Leguás H, Selva-O’Callaghan A, Campins-Martí M, Hermosilla Pérez E, Grau-Junyent JM,
Martínez Gómez X, Vaqué Rafart J. Polymyositis–dermatomyositis: incidence in Spain (1997–2004).
Med Clin (Barc) 2007; 129:721–724.
5. Wilson FC, Ytterberg SR, St Sauver JL, Reed AM. Epidemiology of sporadic inclusion body myositis and polymyositis in Olmsted County, Minnesota. J Rheumatol 2008; 35:445–447.
6. Kurland LT, Hauser WA, Ferguson RH, Holley KE. Epidemiologic features of diffuse connective tissue disorders in Rochester, Minn., 1951 through 1967, with special reference to systemic lupus erythemato- sus. Mayo Clin Proc 1969; 44:649–663.
7. Koh ET, Seow A, Ong B, Ratnagopal P, Tija H, Chang HH. Adult onset polymyositis/dermatomyositis: clinical and laboratory features and treatment response in 75 patients. Ann Rheum Dis 1993; 52:857–861. 8. Mimori T, Imura Y, Nakashima R, Yoshifuji H. Autoantibodies in idiopathic inflammatory myopathy:
an update on clinical and pathophysiological significance. Curr Opin Rheumatol 2007; 19:523–529. 9. Scott DL, Kingsley GH. Use of imaging to assess patients with muscle disease. Curr Opin Rheumatol
2004; 16:678–683.
10. Isenberg DA, Allen E, Farewell V, Ehrenstein MR, Hanna MG, Lundberg IE et al.; International Myositis and Clinical Studies Group (IMACS). 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 (Oxford) 2004; 43:49–54.
11. Dalakas MC. Current treatment of the inflammatory myopathies. Curr Opin Rheumatol 1994; 6:595–601. 12. Oddis CV. Therapy for myositis. Curr Opin Rheumatol 1993; 5:742–748.
13. Nzeusseu A, Brion F, Lefebvre C, Knoops P, Devogelaer JP, Houssiau FA. Functional outcome of myositis patients: can a low-dose glucocorticoid regimen achieve good functional results? Clin Exp
Rheumatol 1999; 17:441–446.
14. Dalakas MC. Inflammatory disorders of muscle: progress in polymyositis, dermatomyositis and inclu- sion body myositis. Curr Opin Neurol 2004; 17:561–567.
15. Ramirez G, Asherson RA, Khamashta MA, Cervera R, D’Cruz D, Hughes GR. Adult-onset polymyo-