Journal of Clinical Neuroscience · Review Inclusion body myositis: A review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches Frank L. Mastaglia⇑,

Journal of Clinical Neuroscience xxx (2014) xxx–xxx

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Journal of Clinical Neuroscience

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Review

Inclusion body myositis: A review of clinical and genetic aspects,diagnostic criteria and therapeutic approaches

http://dx.doi.org/10.1016/j.jocn.2014.09.0120967-5868/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author. Tel.: +61 8 9360 1350; fax: +61 8 9360 1388.E-mail address: [email protected] (F.L. Mastaglia).

Please cite this article in press as: Mastaglia FL, Needham M. Inclusion body myositis: A review of clinical and genetic aspects, diagnostic criteria anapeutic approaches. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.09.012

Frank L. Mastaglia ⇑, Merrilee NeedhamInstitute of Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, AustraliaWestern Australian Neuroscience Research Institute, Queen Elizabeth II Medical Centre, Verdun Street, Nedlands, WA 6009, Australia

a r t i c l e i n f o

Article history:Received 17 August 2014Accepted 14 September 2014Available online xxxx

Keywords:Clinical phenotypeDiagnostic criteriaGeneticsInclusion body myositisSporadic IBMTreatment

a b s t r a c t

Inclusion body myositis is the most common myopathy in patients over the age of 40 years encounteredin neurological practice. Although it is usually sporadic, there is increasing awareness of the influence ofgenetic factors on disease susceptibility and clinical phenotype. The diagnosis is based on recognitionof the distinctive pattern of muscle involvement and temporal profile of the disease, and the combinationof inflammatory and myodegenerative changes and protein deposits in the muscle biopsy. The diagnosticimportance of immunohistochemical staining for major histocompatibility complex I and II antigens, forthe p62 protein, and of the recently identified anti-cN1A autoantibody in the serum, are discussed. Thecondition is generally poorly responsive to conventional immune therapies but there have been relativelyfew randomised controlled trials and most of these have been under-powered and of short duration.There is an urgent need for further well-designed multicentre trials of existing and novel therapies thatmay alter the natural history of the disease.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction 2. Clinical aspects

The first description in the literature of the condition nowreferred to as inclusion body myositis (IBM) appears to have beenthat of Adams, Kakulas and Samaha in 1965 [1], although the namewas not suggested until 1971 [2]. It is now recognised that spo-radic inclusion body myositis (sIBM) is the most common primarymyopathy presenting after the age of 40 years and the form ofinflammatory myopathy most likely to be encountered in adultneurological practice. The prevalence of IBM varies, being highestin Caucasian northern European, North American and Australianpopulations in which prevalence figures of 4.9–14.9 per millionhave been reported [3,4]. It is distinguished from other inflamma-tory myopathies by its insidious and progressive course and selec-tive pattern of muscle involvement, and pathologically by thecombination of inflammatory and myodegenerative features andabnormal protein aggregates in affected muscles. Because of this,and the fact that the condition is poorly responsive to conventionalforms of immune therapy, there is still debate as to whether IBM isprimarily autoimmune in origin or a degenerative myopathy with asecondary inflammatory/immune response.

Typically, the quadriceps femoris and long finger flexors arepreferentially affected and there is progressive wasting of thethighs and forearms (Fig. 1). Other muscle groups such as the fin-ger extensors, upper arm muscles and ankle dorsiflexors are oftenalso affected to varying degrees in patients with more advanceddisease, and some patients may also develop weakness of theparaspinal muscles resulting in dropped-head or camptocormia,and of the facial muscles (Fig. 2). Because of the insidious natureof the disease and nonspecific initial symptoms many patients onlyseek medical attention once they start to have falls, and by then thedegree of weakness and atrophy of the quadriceps is already quiteadvanced. Early symptoms which should raise suspicion of thediagnosis include difficulty in climbing stairs or rising from a chairor squat, aching in the thighs and knees with exercise, weakness ofgrip and difficulty using spray cans or other utensils and tools. Dys-phagia is occasionally an early symptom but more often developslater in the course of the disease [5,6]. Obstructive sleep apnoeadue to weakness of the oropharyngeal muscles is also common[7]. Other clues to the diagnosis include the finding of selectiveweakness of the flexor digitorum profundus and flexor pollicis lon-gus in the early stages with sparing of the flexor digitorum super-ficialis and intrinsic hand muscles, and an asymmetric pattern ofmuscle involvement with the weakness usually being more severein the non-dominant arm and leg (Fig. 1).

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Several studies have investigated the natural history of sIBM[8–12]. The rate of progression of weakness has been shown tobe around 4% per year and is more rapid in the lower limbs, butvaries from patient to patient. As the condition progresses, patientshave increasing difficulty with everyday activities such as hand-writing, cutting up food, dressing, personal hygiene and mobilityand become increasingly dependent. Most patients need to use awalking stick or walker after 5–10 years, but only a minoritybecome wheelchair-bound. A 10 point IBM functional rating scalehas been developed to quantify and monitor the severity of thesedisabilities over time [13].

3. Immunological associations

In some cases sIBM is associated with another autoimmune dis-ease such as Sjögren’s syndrome [14], systemic lupus erythemato-sus, scleroderma, rheumatoid arthritis or thrombocytopenicpurpura [15]. In addition, the frequency of non-organ specific auto-antibodies 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 withretroviral infections (human immunodeficiency virus or humanT-cell lymphotropic virus I), chronic lymphocytic leukaemia [18]and immunodeficiency states [19,20]. These findings are all sug-gestive of an underlying disturbance of immune control and sup-port the hypothesis of an immune basis for the myopathy. Therecent demonstration of serum antibodies to cytosolic 5-nucleotid-ase (anti-cN1A) with a high specificity for sIBM provides furtherevidence of an underlying immunological process and a possiblelink between the autoimmune and myodegenerative componentsof the disease [21,22].

4. Genetics

Most cases of IBM are sporadic, but there are rare reports offamilial cases with a recessive or dominant pattern of inheritance[23–26]. In Caucasian populations there is a strong associationwith the HLA-DRB1*0301 allele and 8.1 major histocompatibility

Fig. 1. Typical pattern of atrophy of the quadriceps femoris (A, B) and more severe impaiwith sporadic inclusion body myositis of different durations as shown.

Please cite this article in press as: Mastaglia FL, Needham M. Inclusion body myapeutic approaches. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.201

complex (MHC) ancestral haplotype (HLA-A1, B8, DR3) in sporadiccases, and HLA-DRB1*0301 carriers have more severe muscleweakness [17,27–30]. It has been estimated that in Western Aus-tralia, carriers of HLA-DRB1*0301 have a 10-fold higher risk ofdeveloping sIBM [3]. Carriers of the HLA-DRB1*0301/*0101 diplo-type were found to have the highest disease risk and more severemuscle weakness [30,31]. In contrast, carriage of the secondaryHLA-DRB loci DRB4 and DRB5 is protective and is associated witha reduced risk of developing IBM [32]. Although apolipoprotein E(APOE) alleles do not influence the risk of developing sIBM [33],the rs10524523 polymorphism in the TOMM40 gene, which is inlinkage disequilibrium with APOE and encodes an outer mitochon-drial membrane translocase, has recently been shown to be protec-tive and is associated with a reduced disease risk and a later age atthe onset of symptoms [34].

5. Electrophysiological studies

Electromyography (EMG) can provide a clue to the diagnosis ofsIBM, and typically shows a mixture of low amplitude short dura-tion and large longer duration motor unit potentials, as well asspontaneous fibrillations and positive sharp waves in affectedmuscles such as the flexor digitorum profundus [35]. In somepatients these findings may lead to a mistaken diagnosis of a neu-rogenic disorder such as amyotrophic lateral sclerosis [36]. Whilelarge polyphasic potentials can also be seen in other chronic myo-pathic conditions, this ‘‘mixed’’ EMG pattern with myopathic andneuropathic-appearing motor unit potentials is very typical ofsIBM. A neurogenic component has in fact been excluded by quan-titative EMG and single fibre EMG studies [37–39]. However, somepatients may develop a mild peripheral neuropathy and electro-physiological evidence of a subclinical neuropathy may be foundin some cases [40,41].

6. Muscle imaging

Muscle MRI can provide useful information that may help in thediagnosis of sIBM, particularly in cases in which the muscle biopsy is

rment of hand closure on the non-dominant left side (C, D) in right-handed patients

ositis: A review of clinical and genetic aspects, diagnostic criteria and ther-4.09.012


Fig. 2. Camptocormia due to weakness of the paraspinal muscles (A) and facial weakness (B, C) in three patients with longstanding sporadic inclusion body myositis.

F.L. Mastaglia, M. Needham / Journal of Clinical Neuroscience xxx (2014) xxx–xxx 3

inconclusive, and allows recognition of the selective pattern of mus-cle involvement in the upper and lower limbs and degree of involve-ment of the paraspinal muscles. Proton-density weighted imagesdemonstrate atrophy and signal change in the deep flexor musclesof the forearms and in the quadriceps femoris and calf muscles(Fig. 3, 4) [42] which are also seen with T1- and T2-weighted andfat-suppressive short tau inversion recovery sequences. MRI alsodemonstrates the preferential involvement of the vasti with relativesparing of the rectus femoris, and of the medial head of gastrocne-mius and flexor digitorum profundus [42–45].

A recent ultrasound study of the forearm muscles has shownthat a contrasting pattern of echogenicity in the flexor digitorumprofundus and flexor carpi ulnaris muscles can be helpful diagnos-tically [46].

Preliminary studies using [11C] Pittsburgh Compound-B posi-tron emission tomography scanning to detect deposition of b-amy-loid in skeletal muscles have been carried out [47], but it remainsto be determined if this will be reliable enough to be of diagnosticvalue.

7. Muscle pathology

The major pathological features on which the diagnosis of sIBMis based are summarised in Table 1. The endomysial inflammatoryinfiltrate is mixed and comprises mainly CD8+ T cells, but alsovariable numbers of CD4+ T cells, myeloid dendritic cells, macro-phages and plasma cells [48,49]. CD8+ T cells surround and invadenon-necrotic muscle fibres and are thought to cause perforin-mediated cytotoxic injury as a result of the interaction betweenantigen presenting MHC class I molecules on muscle fibres andco-stimulatory molecules on the CD8+ cells. Serial T cell receptorspectratyping on muscle tissue has shown that the CD8+ T cellsare clonally expanded in situ and persist over time, suggesting anantigen-driven immune response [50,51], as does the finding ofupregulation of both MHC Class I and II antigens in muscle fibres[52] (Fig. 5).

In addition to the inflammatory infiltrate, degenerative changesare present in variable numbers of muscle fibres. These include


rimmed vacuoles, eosinophilic inclusions, and greater thanexpected numbers of cytochrome oxidase deficient (COX-negative)muscle fibres for the patient’s age, suggesting that there is anacceleration of the normal aging process in sIBM muscle (Fig. 6).The rimmed vacuoles represent areas of autophagic degenerationand are ubiquitin-positive. Amyloid-like inclusions can be identi-fied in sections stained with crystal violet (Fig. 5), or Congo redviewed with Texas red filters. Immunohistochemical staining tech-niques demonstrate pathological aggregates of a variety of proteinsin muscle fibres including b-amyloid, TDP-43, aB-crystallin, myoti-lin and p62 (Fig. 6) [53], suggesting that protein degradative mech-anisms in muscle fibres are dysfunctional [54].

Whilst the combination of inflammatory and myodegenerativechanges is characteristic of sIBM, not all of the histological changesare necessarily found together in all biopsies and the findings mayvary according to when the biopsy is performed. Thus, in the ear-lier stages inflammation tends to be more florid while rimmed vac-uoles and other changes may be inconspicuous or even absent andtend to become more prominent as the disease progresses.

8. Diagnostic approach

The approach to the diagnosis of sIBM has evolved over the pastthree decades, beginning with an emphasis on the presence of keypathological features on muscle biopsy (Table 1), [55] particularlythe combination of a CD8+ T-cell lymphocytic endomysial infiltratewith invasion of non-necrotic fibres, MHC-I and II upregulation,together with rimmed vacuoles, congophilic inclusions and proteinaggregates, and mitochondrial changes. More recently the impor-tance and specificity of clinical criteria such as the characteristicpattern of muscle involvement, with selective and severe weaknessof the long finger flexors and quadriceps, has been emphasised[56]. Over this period, more than 10 different sets of diagnostic cri-teria have been proposed [55,57–66]. These have recently beenevaluated by Lloyd et al. [67], and many have been found to lacksensitivity. There is no doubt that over time the diagnosis of sIBMbecomes clear by its slowly progressive clinical course with resis-tance to treatment, characteristic pattern of muscle weakness and



Fig. 3. Axial proton-density weighted MRI images of the thighs in three patients with sporadic inclusion body myositis of different duration (labelled) showing selectiveinvolvement of the vastus lateralis in (A) and increasing signal loss in the other components of the quadriceps in (B) and (C).

Fig. 4. Axial proton-density weighted MRI of the forearm in a patient withlongstanding sporadic inclusion body myositis showing signal change in the deepfinger flexor muscles (arrows).

Table 1Key pathological features of sporadic inclusion body myositis

d Endomysial inflammatory infiltrate (CD8+ T cell predominant)d Mononuclear cell invasion of non-necrotic myofibresd Up-regulation of major histocompatibility complex I and II antigens in

myofibresd Rimmed vacuoles and congophilic inclusions in myofibresd Protein aggregates in myofibres (amyloid, p62, TDP-43, ubiquitin)d Increased numbers of cytochrome oxidase-negative myofibres for age



wasting, and muscle biopsy changes that evolve over time, but notall of these features occur simultaneously or are present at the ini-tial presentation. The key is to be able to correctly diagnosepatients early to avoid the risks associated with unnecessaryimmunosuppression, and to enable eligibility for current andfuture clinical trials of new therapeutic agents.

In clinical practice the diagnosis of sIBM should be consideredwhen a patient over the age of 50 years (occasionally younger) pre-sents with slowly progressive weakness over a period of months toyears (compared with weeks to months for other inflammatory



Fig. 5. Histological findings in sporadic inclusion body myositis muscle biopsies: (A) Endomysial mononuclear cell infiltrate and invasion of non-necrotic muscle fibre (arrow)(haematoxylin and eosin, original magnification � 640). (B) Rimmed vacuoles in muscle fibres (arrows) (haematoxylin and eosin, original magnification � 400). (C) Amyloidprotein deposit in muscle fibre (arrow) (crystal violet stain, original magnification � 400). (D) Cytochrome oxidase stain with counterstaining for succinic dehydrogenaseshowing increased numbers of cytochrome oxidase deficient muscle fibres (blue).

Fig. 6. Immunohistochemical staining: (A) CD8+ T cells surrounding and invading muscle fibres (original magnification � 640). (B) Focal and more diffuse staining for p62protein in muscle fibres (original magnification � 400). (C) Diffuse sarcolemmal and sarcoplasmic staining for major histocompatibility complex (MHC) I (originalmagnification � 400). (D) Sarcolemmal and sarcoplasmic staining for MHC-II (original magnification � 400).


myopathies), with selective involvement of the long finger flexors(which is often more severe on the non-dominant side and easy tomiss unless specifically looked for), and of the quadriceps, anteriortibial, neck flexor and bulbar muscles. An MRI will confirm the


specific pattern of muscle involvement [42], and an EMG mayshow changes in keeping with an inflammatory myopathic process.The presence of anti-cN1A antibodies, which are 70% sensitive and92% specific at moderate reactivity [21], in the presence of the



Fig. 7. Proposed diagnostic algorithm for sporadic inclusion body myositis. Anti-cN1a Ab = antibody to cytosolic 50-nucleotidase, CK = serum creatine kinase level,COX = cytochrome oxidase, MHC = major histocompatibility complex, N = normal numbers, RV = rimmed vacuoles, sIBM = sporadic inclusion body myositis, ULN = upperlimit of normal, �ve = negative, +ve = positive. Derived in part from Brady et al. [56].


characteristic clinical findings may be diagnostic. However, in mostcases a muscle biopsy is still necessary for confirmation of thediagnosis.

The controversy surrounding the diagnostic criteria has oftenbeen related to cases in which one or more of the pathological fea-tures of sIBM are absent in the biopsy, making a definite patholog-ical diagnosis difficult. A recent retrospective study investigatedwhich pathological features were most sensitive and specific forthe diagnosis of sIBM [53], and found that in tissue sections thathad rimmed vacuoles, the morphology and distribution of p62aggregates in combination with the inflammatory changes was93% sensitive and 100% specific for the diagnosis of sIBM. Insections where rimmed vacuoles were absent, the combination ofinflammatory changes with mitochondrial changes was 100%sensitive and 73% specific for sIBM.

A proposed diagnostic algorithm based upon this clinicalapproach to a patient with suspected sIBM is shown in Figure 7.

9. Treatment

There have been many clinical trials of immunosuppressive andimmunomodulatory drugs, but none have yet shown clear benefitfor patients with sIBM. However, most trials have been underpow-ered and of relatively short duration, and it is possible that thereare subgroups of patients with sIBM who may benefit from someof these medications. In particular, there has been some evidencethat patients suffering with both sIBM and Sjögren’s syndromemay derive at least short-term benefit from immunosuppressivetherapy [14].

Medications that have been investigated include prednisone,intravenous immunoglobulin (IVIG), methotrexate, azathioprine,interferon-b-1A, etanercept, arimoclomol and alemtuzumab. To


further support the lack of clinical trial evidence for immunosup-pression, there was a suggestion in a long-term observationalstudy of sIBM that patients who had been tried on immunosup-pression had an accelerated degree of disability [10]. Only exercisetherapy has been shown in uncontrolled trials to not only be safe,but to result in improved muscle strength over a short period oftime [68–70]. Currently bimagrumab (BYM338), a monoclonalantibody which binds to activin-II receptors in muscle and blocksthe growth inhibitory effect of myostatin, is undergoing a multi-national multicentre Phase III clinical trial, including two Austra-lian centres. Whilst this will not be a cure for sIBM, it is hoped thatit will help maintain or build muscle strength and improve func-tion in affected individuals (ClinicalTrials.gov identifier:NCT01925209).

In clinical practice it is accepted that trials of immunosuppres-sion are not generally recommended, as the risks of such treatmentappear to outweigh any clinical benefit. However, it may be thatsome patients, such as those with a high degree of inflammationon the biopsy, those with another associated autoimmune disordersuch as Sjögren’s syndrome, or those with rapid clinical deteriora-tion or severe dysphagia may warrant a trial of prednisolone andan immunosuppressive agent such as methotrexate, or IVIG. IBMwith rapid progression or severe dysphagia has been an approvedindication for IVIG in Australia since July 2012 (National BloodAuthority, Australia).

There is a need for adequately powered randomised clinicaltrials to determine whether treatment with conventional or newerforms of immune therapy over sufficiently long periods (of at least12 months) can alter the natural history of the disease. Similarly,the possibility of developing therapies which target the abnormalprotein aggregation in the muscles, and the use of combined ther-apies, also warrant further investigation.




10. Concluding remarks

Further prospective studies of large cohorts of patients withsIBM are needed to more fully define the phenotypic spectrumand natural history of the disease, to refine and validate currentdiagnostic criteria, to identify disease biomarkers that can be use-ful diagnostically, and to monitor disease activity and response totherapy. In particular, further studies are needed to confirm thesensitivity and specificity of the anti-cN1A antibody in the diagno-sis of sIBM. In addition, further genetic studies in different ethnicand racial groups using exonic sequencing and genome wide asso-ciation studies are needed to confirm the importance of the knownHLA and non-HLA loci and to identify additional genetic loci thathave an association with disease susceptibility and pathogenesis.Large multicentre randomised control trials will also be necessaryto resolve the issue of whether subgroups of sIBM patients aremore responsive to immune therapies and whether the disease islikely to be more responsive if these therapies are commencedearly in the course of the disease and continued for prolongedperiods.

Conflicts of Interest/Disclosures

Dr M. Needham has received a consultancy honorarium fromNovartis. The authors declare that they have no other financial orother conflicts of interest in relation to this research and itspublication.

Acknowledgements

We are grateful to Dr Vicki Fabian and Dr Rei Junckerstorff fromthe Section of Neuropathology (Department of Anatomical Pathol-ogy) at Royal Perth Hospital for providing a muscle biopsy service,for allowing access to muscle biopsies from our patients, and forpreparation of some of the photomicrographic illustrations; toProfessor Roger Pamphlett, Dr James Miller and Min Wan for pro-viding some of the histopathological illustrations; and to ProfessorLesley Cala for performing and providing access to the MRI of ourpatients.

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Documents

Journal of Clinical Neuroscience · Review Inclusion body myositis: A review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches Frank L. Mastaglia⇑,