There is a large and heterogeneous group of acquired disorders that have been grouped together collectively as inflammatory muscle diseases. Common clinical diagnoses are polymyositis, dermatomyositis and inclusion body myositis. An emerging group are myopathies without much evidence of inflammation but with autoimmune aetiology: immune-mediated necrotizing myopathy (IMNM) or necrotizing autoimmune myopathy (NAM). Muscle inflammation with non-specific features is also frequently encountered in other autoimmune disorders and is then frequently considered part of an overlap syndrome. The entire field is evolving not least depending on the discovery of an increasing number of autoantibodies associated with myositis, so-called myositis-specific autoantibodies ( , , ). These different autoantibodies are also to varying degrees associated with other features such as malignancy, interstitial lung disease, skin involvement or treatment resistance and may thus help in the evaluation of the patients. Presence of autoantibodies to aminoacyl transfer RNA (tRNA) synthetases is the basis for identification of a group of inflammatory myopathies referred to as antisynthetase syndrome. An emerging group of inflammatory myopathies are associated with immune therapy of cancer by usage of immune checkpoint inhibitors that block either the cytotoxic T-lymphocyte antigen-4 (CTLA4) or the programmed cell death protein-1 (PD-1/PD-L1) pathways. A variety of skeletal muscle complications have been reported including myasthenia gravis and various inflammatory and necrotizing myopathies ( ). In addition there is an inflammatory myopathy associated with sarcoidosis and also isolated granulomatous myositis. Classification of inflammatory myopathies is therefore evolving and may include clinical features, identified autoantibodies and muscle histopathology ( , ).
The histological features of inflammatory myopathies have in common the presence of various degenerative changes in the muscle fibres and usually, but not always, inflammatory cell infiltrates. In addition, appreciable levels of major histocompatibility class I antigens (MHC-I), which are confined to blood vessels in normal muscle, can be detected by immunohistochemistry on the sarcolemma of mature muscle fibres, or within fibres, irrespective of the presence of inflammatory cells ( , ). From a diagnostic point of view, it is important to note that infiltrates of inflammatory cells, particularly T cells and macrophages, are fairly commonly seen in the muscular dystrophies, not only in relation to necrotic fibres, and conversely the absence of any inflammatory infiltrates in a biopsy does not exclude an inflammatory myopathy, as for example in acute dermatomyositis in childhood. Up-regulation of MHC-I can also occur in some muscular dystrophies, such as Duchenne and limb-girdle muscular dystrophy 2B, caused by mutations in the gene encoding dysferlin, which may also show infiltration of inflammatory cells. Although cases of facioscapulohumeral muscular dystrophy may also show inflammatory cells, sarcolemmal MHC-I is not usually seen (see Ch. 14 ). The distinction between these disorders relies on the clinical presentation. In addition low levels of MHC-I may be seen in biopsies from neonates. The reason for this is unknown but the possibility of circulating cytokines has been put forward as an explanation.
For many years the papers of provided the basis and clinical criteria for the classification of polymyositis and dermatomyositis. With increasing knowledge these have been modified ( , , ). Polymyositis as a distinct entity is now questioned and at least considered very rare ( , ). In children polymyositis is not considered to be a disease entity. From a pathological point of view polymyositis was previously considered when there was an endomysial infiltration of T cells with invasion of non-necrotic muscle fibres but without features of inclusion body myositis ( ) ( Fig. 22.1a and b ).
During the past decade four major subgroups of idiopathic inflammatory myopathies have been recognized: dermatomyositis, antisynthetase syndrome, inclusion body myositis and immune-mediated necrotizing myopathy. In addition, myositis occurs as part of overlap syndromes with other autoimmune disorders.
Dermatomyositis
Clinical Features
The onset of dermatomyositis in adults is often associated with aching pains in the shoulders or hips or other sites, accompanied by some degree of weakness. The weakness may be proximal and symmetrical, as in limb-girdle dystrophy, or may be asymmetrical and have varying distribution. The weakness does not show the selectivity seen in the muscular dystrophies. It may be rapidly progressive, and may result in severe weakness, with the patient being confined to bed, or be relatively mild and chronic. There may be accompanying tenderness and swelling of muscle, but some 30–40% of patients may have no muscle pain, even in the presence of quite severe inflammatory disease.
In the most acute cases there may be profound generalized weakness developing over a few days, together with marked necrosis of muscle and associated gross elevation of creatine kinase (CK) and other serum enzymes. There may also be myoglobinuria, which may be severe enough to cause renal failure. Rhabdomyolysis and myoglobinuria, however, are relatively rare in dermatomyositis. The majority of cases tend to follow a more insidious subacute or chronic course.
The association with malignancy has been known for a long time ( , , ). The tumour and myopathy usually present within a short time of each other, but in occasional cases the myopathy may precede diagnosis of the tumour by months or even years.
Dysphagia may also be associated with the illness, and this can become severe enough to necessitate feeding by nasogastric tube. Some patients may also have respiratory symptoms, either from intercostal or bulbar weakness, or rarely because of direct involvement of the lung parenchyma.
In dermatomyositis, there are the additional changes in the skin. Frequently, there is a heliotrope or violaceous rash, particularly over the eyes and malar regions of the face. There is an erythema around the nail beds and over the knees and elbows. In severe cases, the skin changes become generalized and the entire skin becomes tight, shiny and reddened. In intractable cases, the development of ulcers over the pressure points may be a severe problem. In juvenile cases calcinosis is a particular feature.
Serum CK activity is frequently, but not invariably, elevated. A normal level does not exclude a diagnosis of myositis. Electromyography shows a fairly characteristic pattern, with a combination of spontaneous fibrillation potentials similar to those seen in denervation, and polyphasic, short-duration potentials on voluntary contraction as in myopathies.
Other laboratory investigations that may be helpful are a raised erythrocyte sedimentation rate (ESR). The ESR is raised in only a proportion of cases, however, and there is no correlation with weakness. Detection of serum autoantibodies is becoming increasingly important for diagnosis and management in both adults and children ( , ). Myositis-specific autoantibodies are biomarkers that help the diagnosis ( Table 22.1 ). Among the ones most often assessed are auto-antibodies to nuclear antigens such as anti-Mi-2, anti-TIF1γ, anti-NXP-2 and anti-SAE. Auto-antibodies to cytoplasmic antigens include anti-MDA5, anti-SRP, anti-HMGCR and anti-aminoacyl tRNA synthetase (ARS) antibodies ( , , , ). Autoantibodies are frequently seen in dermatomyositis: anti-Mi-2 is associated with typical skin lesions and mild to moderate myositis, which usually responds well to corticosteroid treatment; anti-TIF1γ is associated with malignancy in adults, anti-NXP-2 is associated with calcinosis in children and cancer in adults; anti-SAE is mainly seen in adults and associated with skin lesions and systemic involvement such as fever and weight loss. Anti-MDA5 antibodies are associated with a cutaneous-pulmonary syndrome with interstitial lung disease and severe skin manifestations with ulcerations and is frequently amyopathic. Anti-SRP and anti-HMGCR antibodies are associated with treatment-resistant immune-mediated necrotizing myopathy (see later).
| Antibody/Antigens | Disease | Special Clinical Features |
|---|---|---|
| Mi-2 | Dermatomyositis | Mild myositis, responds well to corticosteroids |
| TIF1γ | Frequently associated with malignancy | |
| NXP-2 | Dermatomyositis | Juvenile dermatomyositis, severe skin manifestations, malignancy in adults, calcinosis in children |
| SAE | Dermatomyositis | Early skin manifestations |
| MDA5 | Dermatomyositis | Amyopathic dermatomyositis, severe interstitial lung disease |
| Aminoacyl-tRNA synthetases: | ||
| Antisynthetase syndrome | |
| Antisynthetase syndrome | |
| Antisynthetase syndrome | |
| Antisynthetase syndrome | |
| Antisynthetase syndrome | |
| Antisynthetase syndrome | |
| Antisynthetase syndrome | |
| Antisynthetase syndrome | |
| SRP | Immune-mediated necrotizing myopathy | |
| HMGCR | Immune-mediated necrotizing myopathy | Sometimes associated with statin treatment |
| cN1A | Inclusion body myositis | |
Magnetic resonance imaging (MRI) of muscle shows a bright signal both on T2-weighted and short tau inversion recovery (STIR) sequences in relation to oedema and inflammatory changes ( ). The changes are not specific, however, but MRI may be useful for selecting the site of muscle biopsy or monitoring therapy.
There is considerable evidence that certain haplotypes are associated with myositic conditions. In Caucasians, alleles HLA-DRB1∗03:01 and HLA-B∗08:01 of the 8.1 ancestral haplotype are most strongly associated with idiopathic inflammatory myopathies, and associations with alleles outside the 8.1 ancestral haplotype reveal differences between different clinical subgroups of inflammatory myopathies indicating differences in pathogenesis ( ).
The majority of cases respond to steroid therapy, although recovery may at times be slow and incomplete. Azathioprine, cyclophosphamide, ciclosporin and methotrexate are also used in the treatment of these conditions. It can be extremely difficult in a case of chronic myositis, with apparent deterioration or lack of response to ‘adequate’ or often very high doses of steroids, to decide whether the persistent weakness is a reflection of a super-added steroid myopathy or continuing activity of the underlying myositis itself. Many cases diagnosed as polymyositis may later during the course turn out to have inclusion body myositis, explaining the therapy resistance. Certainly, in the childhood groups, some of the problems in chronic cases seem to reflect complications of the drug treatment, particularly over treatment with too high dosage of corticosteroids, or lack of supportive and rehabilitative care, rather than the underlying disease which has already become quiescent.
The childhood form of dermatomyositis, juvenile dermatomyositis, differs from the adult form in a number of respects. It is always an ‘idiopathic’ condition and is not associated with malignancy ( , ). Although muscle weakness is an invariable accompaniment of the condition, its degree may be extremely variable and, in some early cases, readily missed. Children with dermatomyositis usually have associated general symptoms, such as malaise, listlessness and lethargy, which may be the presenting features. As there are no other neuromuscular disorders which present with these general symptoms in addition to weakness, it is a useful rule of thumb in paediatric practice that ‘misery + muscle weakness = dermatomyositis’ until proved otherwise.
The associated skin manifestation may at times be florid and readily apparent over the face or other sites, but at times may be minimal and no more than a violaceous discoloration of the eyelids, or erythema or telangiectasia over the knuckles, malleoli of the ankle or other pressure points.
Calcinosis is another complication of childhood dermatomyositis and occurs particularly in the more chronic cases. The calcium is deposited in the subcutaneous tissue and in the supportive connective tissue within the muscle but not in the muscle fibres themselves. It may be extensive and not necessarily related to the degree of weakness. Recently, an association of anti-NXP-2 autoantibodies with calcinosis in juvenile dermatomyositis has been reported but the association in adults is less clear. Calcinosis in adults, however, is unusual ( ).
Pathology
Inflammatory changes are the hallmark of dermatomyositis, but the extent is variable, and some biopsies show no inflammatory infiltration. The inflammatory cells consist of lymphocytes, plasma cells and histiocytes, usually with a predominance of CD3 positive T cells and macrophages and they occur in the perimysial and endomysial regions and are often perivascular ( Fig. 22.1c and d ). Eosinophils are not a feature of dermatomyositis. Acid phosphatase activity is associated with the inflammatory cells and is also increased in the muscle fibres.
Abnormalities of fibre size are often present, but hypertrophy is less pronounced, or absent, compared with muscular dystrophies. Small or large group atrophy or fibre type grouping is not seen. Internal nuclei are common, and vesicular nuclei are present in almost all biopsies, particularly in basophilic fibres, when present Figs. 22.1c and 22.2 ). Moth-eaten fibres or fibres with core-like areas are also frequent ( Fig. 22.3 , and fibre splitting may occur. Some biopsies, however, may show very little change and no inflammation, and immunohistochemistry is then particularly useful.
Perifascicular atrophy is a particular feature of dermatomyositis (see Fig. 22.2 ). Histochemically these perifascicular fibres are of both types with staining for ATPase, but often show intense and aggregated NADH-TR activity (see Fig. 22.3 ) and frequently cytochrome c oxidase deficiency (see Fig. 18.28 ). Many of these small fibres express a number of proteins associated with immaturity, and differentiating them from regenerating fibres is then difficult. Some may represent attempts at regeneration rather than being atrophic but the presence of heat-shock proteins in these perifascicular fibres is also consistent with a stress response ( ).
Necrosis and regeneration are common, and there is a characteristic vacuolar degeneration, which can be extensive ( Figs. 22.4 and 22.5a ). Fibrosis is frequently seen and there may be a loose edematous separation of the muscle fibres with interspersed fibrous tissue (see Fig. 22.4 ). Some of the vacuolated, degenerate fibres may be unstained with most reactions and have been termed ‘ghost fibres’. Macrophages invade the fibre after it becomes necrotic. The necrosis may be segmental and may involve single muscle fibres or clusters of fibres. In dermatomyositis areas of infarction with groups of pale-staining fibres may be seen especially in cases with anti-NXP2 autoantibodies. There is frequently a granular change, which is basophilic with haematoxylin and eosin (H&E) stain and red on the trichrome. Basophilic regenerating fibres are also present, and necrotic fibres may show a peripheral basophilic regenerative cuff ( Fig. 22.6 ). These cuffs are rarely seen in the muscular dystrophies.
Blood vessels in dermatomyositis often have thickened walls, the capillaries may be enlarged, and with electron microscopy endothelial cells may show tubuloreticular inclusions (see Fig. 22.5d ). The number of capillaries is frequently reduced in dermatomyositis (see Fig 22.5b ), and necrotic capillaries can be identified (see Fig. 22.5c ).
Immunohistochemistry
The most important application of immunohistochemistry in the study of all inflammatory myopathies is the localization of MHC-I, and this has significantly increased the value of muscle biopsy in the assessment of inflammatory myopathies. In normal muscle MHC-I can only be detected on the blood vessels, but in all inflammatory myopathies there is appreciable expression on the sarcolemma and also internally in several fibres ( , ) ( Fig. 22.7 ). In the majority of cases all fibres show sarcolemmal MHC-I but occasionally some areas may be normal, for example, in adult cases of dermatomyositis, in which the perifascicular region usually is more intensely stained compared to the interior of the fascicles ( Fig. 22.7b ). It is also seen in the absence of cellular infiltrates and when the sample shows no, or minimal, pathology ( ).
Sarcolemmal MHC-I is not specific to inflammatory myopathies and can also be seen in various muscular dystrophies including Duchenne and Becker muscular dystrophy, limb-girdle dystrophy 2B, with a defect in the gene for dysferlin ( ) and some metabolic disorders such as acid maltase deficiency (see Fig. 17.6 ). Some expression may also occasionally be seen in neonates and in a variety of undefined conditions, but the reason is unknown. Regenerating fibres in all disorders show sarcolemmal and internal labelling of MHC-I, and it is important to distinguish this normal phenomenon from the abnormal labelling on mature fibres by the use of markers for immaturity, such as developmental myosins.
As MHC-I is present on all blood vessels it can be used to assess the number of capillaries but this is more easily seen with markers such as the lectin Ulex europaeus or laminin α5 as the capillaries are highlighted against the negative ( Ulex ) or weak (laminin α5) labelling of the sarcolemma. CD34 is a useful marker of endothelial cells (see Fig. 22.5 ). In normal adult muscle there is a capillary adjacent to every fibre, although in normal neonatal muscle the capillary network is less developed and fewer capillaries are seen. In both adult and juvenile dermatomyositis there is a depletion of capillaries, and this is an early feature that can be seen in the absence of other pathology (see Figs. 22.5 and 22.8 ).
Capillaries in adult and juvenile dermatomyositis frequently show deposits of immune complexes and the terminal component of the complement pathway, the membrane attack complex C5b-9 (MAC) ( Fig. 22.9 ), especially in cases with anti-TIF1γ or NXP2 autoantibodies. Complement and immune complexes, immunoglobulin G (IgG) and immunoglobulin M (IgM), are also seen in necrotic fibres ( Fig. 22.9b ). Human myxovirus resistance A (MxA), an interferon-α/β–inducible protein, has been demonstrated in capillaries and perifascicular fibres in adult cases of dermatomyositis and may relate to the capillary tubuloreticular inclusions seen with electron microscopy, which are an early feature of dermatomyositis ( ). MxA has also been revealed in some cases of juvenile dermatomyositis and may relate to specific autoantibodies ( ) but not in cases with antisynthetase syndrome ( ).
