ReviewInclusion body myositis: A review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches
Introduction
The first description in the literature of the condition now referred to as inclusion body myositis (IBM) appears to have been that of Adams, Kakulas and Samaha in 1965 [1], although the name was not suggested until 1971 [2]. It is now recognised that sporadic inclusion body myositis (sIBM) is the most common primary myopathy presenting after the age of 40 years and the form of inflammatory myopathy most likely to be encountered in adult neurological practice. The prevalence of IBM varies, being highest in Caucasian northern European, North American and Australian populations in which prevalence figures of 4.9–14.9 per million have been reported [3], [4]. It is distinguished from other inflammatory myopathies by its insidious and progressive course and selective pattern of muscle involvement, and pathologically by the combination of inflammatory and myodegenerative features and abnormal protein aggregates in affected muscles. Because of this, and the fact that the condition is poorly responsive to conventional forms of immune therapy, there is still debate as to whether IBM is primarily autoimmune in origin or a degenerative myopathy with a secondary inflammatory/immune response.
Section snippets
Clinical aspects
Typically, the quadriceps femoris and long finger flexors are preferentially affected and there is progressive wasting of the thighs and forearms (Fig. 1). Other muscle groups such as the finger extensors, upper arm muscles and ankle dorsiflexors are often also affected to varying degrees in patients with more advanced disease, and some patients may also develop weakness of the paraspinal muscles resulting in dropped-head or camptocormia, and of the facial muscles (Fig. 2). Because of the
Immunological associations
In some cases sIBM is associated with another autoimmune disease such as Sjögren’s syndrome [14], systemic lupus erythematosus, scleroderma, rheumatoid arthritis or thrombocytopenic purpura [15]. In addition, the frequency of non-organ specific autoantibodies such as antinuclear antibody, anti-Ro 52/60 and anti-ribonucleoprotein, and monoclonal gammopathy is increased [16], [17]. sIBM has also been reported to occur in association with retroviral infections (human immunodeficiency virus or
Genetics
Most cases of IBM are sporadic, but there are rare reports of familial cases with a recessive or dominant pattern of inheritance [23], [24], [25], [26]. In Caucasian populations there is a strong association with the HLA-DRB1*0301 allele and 8.1 major histocompatibility complex (MHC) ancestral haplotype (HLA-A1, B8, DR3) in sporadic cases, and HLA-DRB1*0301 carriers have more severe muscle weakness [17], [27], [28], [29], [30]. It has been estimated that in Western Australia, carriers of
Electrophysiological studies
Electromyography (EMG) can provide a clue to the diagnosis of sIBM, and typically shows a mixture of low amplitude short duration and large longer duration motor unit potentials, as well as spontaneous fibrillations and positive sharp waves in affected muscles such as the flexor digitorum profundus [35]. In some patients these findings may lead to a mistaken diagnosis of a neurogenic disorder such as amyotrophic lateral sclerosis [36]. While large polyphasic potentials can also be seen in other
Muscle imaging
Muscle MRI can provide useful information that may help in the diagnosis of sIBM, particularly in cases in which the muscle biopsy is inconclusive, and allows recognition of the selective pattern of muscle involvement in the upper and lower limbs and degree of involvement of the paraspinal muscles. Proton-density weighted images demonstrate atrophy and signal change in the deep flexor muscles of the forearms and in the quadriceps femoris and calf muscles (Fig. 3, Fig. 4) [42] which are also
Muscle pathology
The major pathological features on which the diagnosis of sIBM is based are summarised in Table 1. The endomysial inflammatory infiltrate is mixed and comprises mainly CD8+ T cells, but also variable numbers of CD4+ T cells, myeloid dendritic cells, macrophages and plasma cells [48], [49]. CD8+ T cells surround and invade non-necrotic muscle fibres and are thought to cause perforin-mediated cytotoxic injury as a result of the interaction between antigen presenting MHC class I molecules on
Diagnostic approach
The approach to the diagnosis of sIBM has evolved over the past three decades, beginning with an emphasis on the presence of key pathological features on muscle biopsy (Table 1), [55] particularly the combination of a CD8+ T-cell lymphocytic endomysial infiltrate with invasion of non-necrotic fibres, MHC-I and II upregulation, together with rimmed vacuoles, congophilic inclusions and protein aggregates, and mitochondrial changes. More recently the importance and specificity of clinical criteria
Treatment
There have been many clinical trials of immunosuppressive and immunomodulatory drugs, but none have yet shown clear benefit for patients with sIBM. However, most trials have been underpowered and of relatively short duration, and it is possible that there are subgroups of patients with sIBM who may benefit from some of these medications. In particular, there has been some evidence that patients suffering with both sIBM and Sjögren’s syndrome may derive at least short-term benefit from
Concluding remarks
Further prospective studies of large cohorts of patients with sIBM are needed to more fully define the phenotypic spectrum and natural history of the disease, to refine and validate current diagnostic criteria, to identify disease biomarkers that can be useful diagnostically, and to monitor disease activity and response to therapy. In particular, further studies are needed to confirm the sensitivity and specificity of the anti-cN1A antibody in the diagnosis of sIBM. In addition, further genetic
Conflicts of Interest/Disclosures
Dr M. Needham has received a consultancy honorarium from Novartis. The authors declare that they have no other financial or other conflicts of interest in relation to this research and its publication.
Acknowledgements
We are grateful to Dr Vicki Fabian and Dr Rei Junckerstorff from the Section of Neuropathology (Department of Anatomical Pathology) at Royal Perth Hospital for providing a muscle biopsy service, for allowing access to muscle biopsies from our patients, and for preparation of some of the photomicrographic illustrations; to Professor Roger Pamphlett, Dr James Miller and Min Wan for providing some of the histopathological illustrations; and to Professor Lesley Cala for performing and providing
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