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Expert Opinion on Orphan Drugs

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Advances in inclusion body myositis: genetics,pathogenesis and clinical aspects

Merrilee Needham & Frank Mastaglia

To cite this article: Merrilee Needham & Frank Mastaglia (2017) Advances in inclusion bodymyositis: genetics, pathogenesis and clinical aspects, Expert Opinion on Orphan Drugs, 5:5,431-443, DOI: 10.1080/21678707.2017.1318056

To link to this article: https://doi.org/10.1080/21678707.2017.1318056

Accepted author version posted online: 24Apr 2017.Published online: 26 Apr 2017.

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REVIEW

Advances in inclusion body myositis: genetics, pathogenesis and clinical aspectsMerrilee Needhama,b and Frank Mastagliaa,b

aIIID Murdoch University, Murdoch, Australia; bPerron Institute for Neurological and Translational Research, Nedlands, Western Australia

ABSTRACTIntroduction: Inclusion body myositis is the most common acquired muscle disease affecting olderadults. It has an insidious onset with a very specific pattern of muscle involvement, but the aetiopatho-genesis is still unknown. Pathologically the combination of inflammatory changes, degenerativechanges as well as mitochondrial and nuclear changes are seen, and probably all contribute to theloss of muscle, however the primary abnormality remains a mystery. Treatment is currently supportive,but clinical trials are ongoing and are directed at new targets.Areas covered: Clinical profile, genetic susceptibility, pathogenesis and treatmentExpert opinion: Understanding the aetiopathogeneis is vital to identify future treatment targets. Inaddition, understanding the natural history and the roles of biomarkers including the anti-CN1a anti-body is vital for designing future clinical trials in IBM, to be properly designed and of sufficient durationto detect clinically significant changes.

ARTICLE HISTORYReceived 11 February 2017Accepted 7 April 2017

KEYWORDSClinical; diagnosis; genetics;inclusion body myositis(IBM); pathogenesis;sporadic inclusion bodymyositis (sIBM)

1. Introduction

Inclusion body myositis (IBM) is the most common myopathyaffecting individuals over the age of 50 years. While mostcases are sporadic, occasional familial cases have also beenreported. The condition has a distinctive clinical and patholo-gical phenotype, with a progressive course and poor responseto treatment, which helps distinguish it from other myopa-thies presenting in adult life. Pathologically it is characterizedby a combination of muscle inflammation and degeneration,with the accumulation of multi-protein aggregates in musclefibers. The pathogenesis of the disease is not fully understood,and there is still uncertainty as to whether it is primarily anautoimmune disease or a degenerative myopathy with a vig-orous secondary immune and inflammatory response [1–3].

The present review summarizes recent progress in ourunderstanding of the pathogenesis of IBM and the role ofgenetic susceptibility factors, as well as clinical advances andapproaches to the diagnosis and treatment of the disease.

2. Clinical profile of sporadic IBM

In the majority of cases of sporadic IBM (sIBM), there is a selectivepattern of muscle involvement, with slowly progressive atrophyand weakness which is most pronounced in the quadricepsfemoris and forearm finger flexors and is often more severe onthe nondominant side, while other muscle groups such as thewrist and finger extensors and the proximal upper limb andanterior tibial muscles tend to be spared until later in the courseof the disease. The basis for the greater susceptibility of certainmuscle groups at least in the earlier stages of the disease is still notunderstood. The differential patterns of involvement of the flexorsof the distal phalanges of the fingers and thumb in the early

stages, with sparing of the intrinsic hand muscles, are featureswhich are helpful inmaking the diagnosis of sIBM and distinguish-ing it from other neuromuscular disorders such as amyotrophiclateral sclerosis, polymyositis, and genetic forms of distal myopa-thy. Observations in a number of large sIBM patient cohorts haveshown that there is considerable individual variability in the clin-ical phenotype and disease severity at the time of presentation,and a number of longitudinal studies have helped to documentthe rate of decline of muscle strength and functional abilities asthe disease progresses [4–8]. A disease-specific functional ratingscale (the IBM functional rating scale [IBMFRS]) has been devel-oped for use in the clinic and to monitor disease severity andprogress in clinical trials [9].

Atypical phenotypes and clinical presentations have beenreported in as many as 24% of cases in some series [10] andinclude patients with quadriceps sparing or with a limb-girdlepattern of weakness, scapular winging, foot drop, and severeinvolvement of the pharyngeal or facial muscles. Weakness ofthe paraspinal muscles may also occur as the disease progresses,resulting in dropped head or camptocormia, and can be an earlyfeature in some cases [11,12]. Recent studies have shown thatsubclinical weakness of the respiratory muscles and obstructivesleep apnea due to dysfunction of the oropharyngeal muscles arecommon in sIBM, and it has been recommended that respiratoryfunction should be routinely assessed in the clinic [13,14].

3. Diagnostic criteria

In the majority of cases, the diagnosis of sIBM is relatively straight-forward and relies on recognition of the characteristic clinicalphenotype and how it evolves over time and on the demonstra-tion of the cardinal histopathological changes in the muscle

CONTACT Merrilee Needham Merrilee.Needham@health.wa.gov.au Murdoch University, 390 Discovery Way, Murdoch, WA 6150, Australia

EXPERT OPINION ON ORPHAN DRUGS, 2017VOL. 5, NO. 5, 431–443https://doi.org/10.1080/21678707.2017.1318056

© 2017 Informa UK Limited, trading as Taylor & Francis Group

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biopsy: i.e. a CD8+ T-cell-predominant endomysial inflammatoryinfiltrate with invasion of non-necrotic muscle fibers; rimmedvacuoles, congophilic inclusions, and multi-protein aggregates inmuscle fibers; and increased numbers of cytochrome oxidase c(COX)-/SDH+ fibers withmitochondrial abnormalities. However, insome patients, the diagnosis is challenging, particularly thosepresenting early in the course of the disease and with atypicalclinical phenotypes, or when some of the cardinal histopathologi-cal features are absent in the initial biopsy. When present serumantibodies against the cytosolic 5ʹ nucleotidase (cN1A) may beuseful diagnostically in the clinical context of slowly progressivemuscle weakness in the sIBM-specific pattern, but these antibo-dies are not as specific for sIBM as once thought, also being foundin some patientswith Sjogren’s disease and systemic lupus erythe-matosus (SLE) but without muscle involvement in these diseases,but rarely in polymyositis [15]. There have been small case seriesand a larger retrospective study suggesting that they correlatewithmore severe disease and a highermortality, withmore bulbarand respiratory involvement, but this requires confirmation inprospective studies [16,17]. Muscle MRI has been proposed to bea useful tool in some patients, with a high specificity for thepattern of muscle involvement in sIBM [18]. More detailed immu-nohistochemical studies looking for abnormal protein aggregates(e.g. ubiquitin, β-amyloid, SMI-31, TDP-43, and p62 protein) andmajor histocompatibility complex (MHC-I) andMHC-II [19] can alsoimprove the diagnostic yield of the muscle biopsy in suchcases [20].

Several sets of diagnostic criteria combining clinical andpathological characteristics have been proposed over thepast 20 years with the aim of standardizing the selection ofcases for inclusion in clinical trials and research studies [1,21–23], the most recent being the 2011 European NeuromuscularCentre (ENMC) criteria [24]. While the muscle biopsy remainsthe definitive diagnostic procedure, greater emphasis hasrecently been given to the importance of clinical findings,such as the characteristic selective pattern of weakness ofthe long finger flexors [24–27]. A recent evaluation of theENMC criteria in a large cohort of patients with sIBM andother neuromuscular disorders found that while some criteriahad a high sensitivity, others lacked sensitivity [27].

4. Genetic susceptibility

While most cases of sIBM are sporadic, in occasional casesthere is a history of other affected family members, andthere have been reports of occasional families with either anautosomal recessive or dominant pattern of inheritance. Thecausative gene/mutation has yet to be identified in any ofthese familial forms of the disease, which need to be distin-guished from monogenic forms of hereditary inclusion bodymyopathy (hIBM), such as those caused by mutations in theVCP, GNE, or MYHC2A genes, which share some of the patho-logical features of sIBM but usually lack muscle inflammation,and have recognizably different clinical phenotypes [28,29].

4.1. Association with HLA genes

However, the vast majority of sIBM cases are sporadic butgenetic factors are known to play an important role in deter-mining disease risk, as well as having modifying effects on theage at which the disease first manifests and the clinical phe-notype. The strongest association is with alleles in the centraland class II MHC region. A strong association with HLA-DR3and other alleles associated with the ‘8.1 ancestral haplotype’or ‘autoimmune haplotype’ (HLA-A1, B8, DR3) was firstreported by Garlepp et al. [30], and it has been proposedthat differences in population frequencies of these allelesmay account for the variation in the prevalence of sIBM indifferent racial and ethnic groups [20,31]. High-resolution gen-otyping studies have shown that the contribution of the ClassII MHC region is complex, the strongest association being withthe HLA-DRB1*03:01 allele, while a number of other alleles atthe highly polymorphic HLA-DRB1 locus appear to be protec-tive [31,32]. Moreover, carriage of either of the secondary DRBloci HLA-DRB4 or HLA-DRB5 has also been shown to be pro-tective [32]. The risk of sIBM has also been shown to beinfluenced by the complementary allele at the HLA-DRB1locus, the highest risk being associated with carriage of theHLA-DRB1*03:01/*01:01 combination, which is also associatedwith a more severe clinical phenotype and an earlier age ofclinical onset. Recombination mapping studies have localizedthe susceptibility region to a 172-kb segment in the Class IIMHC region, encompassing the HLA-DRA and HLA-DR3 lociwhich encode the α and β subunits of the peptide-presenting HLA-DR molecules [33]. This HLA association pro-vides support for the autoimmune hypothesis of sIBM, as itmay impact how the immune system presents and respondsto a particular antigen.

4.2. Association with non-HLA genes

The findings of a number of recent studies suggest that geneticsusceptibility to the disease is polygenic and that variants innon-HLA genes may also play a part. Although there is noapparent association between APOE alleles and sIBM [34], tworecent studies have shown that polymorphism in the TOMM 40gene, which is adjacent to and in linkage disequilibrium withAPOE on chromosome 19 and encodes an outer mitochondrialmembrane translocase, can influence the risk of developingsIBM as well as the age at onset of symptoms [35,36]. The

Article highlights

● Sporadic IBM is the most common acquired muscle disease of mid-and later life and is poorly responsive to conventional immunetherapies

● Genetic susceptibility is likely to be polygenic, being most stronglyassociated with the HLA-DRB1 locus and 8.1 MHC ancestral haplotype,but mitochondrial and protein degradation genes may also beinvolved

● Multiple interacting molecular and structural abnormalities co-exist insIBM muscle and contribute to muscle dysfunction and breakdown,but the primary abnormality is not yet known.

● Clearly elucidating the underlying pathogenetic pathways involvedwill be vital for identifying novel therapeutic targets

● Future clinical trial designs must take into account what is currentlyknown about the natural history of the disease and variability in therate of progression in order to be of sufficient power and duration todetect meaningful changes

This box summarizes key points contained in the article.

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original study in an Australian sIBM cohort showed that diseaserisk was lower in individuals with a very long (>30) poly-T tractin the rs10524523 intronic polymorphism of TOMM 40, as wellas a later age at onset which has since also been confirmed in alarger international patient cohort [36].

In a North American cohort of 79 sIBM patients, pathogenicmutations in VCP (valosin-containing protein) were found intwo patients who met the diagnostic criteria for sIBM, butnot in other hIBM genes [37]. A whole-exome sequencingstudy of a large international sIBM cohort comprising 181cases identified rare missense variants in the SQSTM 1(Sequestosome 1) and VCP genes, which have previouslybeen associated with neurodegenerative disorders, in 4% ofsIBM cases [38]. However, a study which screened for muta-tions in known hIBM and myofibrillar myopathy genes in agroup of 21 Japanese patients with IBM found no mutations inthe VCP or GNE (glucosamine) genes, but three patients had amutation in MYHC2A (myosin heavy chain 2a) which is asso-ciated with type 3 hIBM [39] and one patient in the ZASP gene(also known as LDB3 [LIM domain binding 3]) gene.

These findings point to a possible overlap in genetic sus-ceptibility between the sporadic and hereditary forms of IBMand between sIBM and other neurodegenerative disorders,which is also reflected in the underlying pathogenetic path-ways in these various disorders. It is therefore likely thatgenetic susceptibility for sIBM is polygenic and may perhapsalso require variations in genes affecting both immune func-tion and protein degradation systems in muscle.

5. Pathogenesis

The etiopathogenesis of sIBM is unknown, but it is likelymultifactorial. As indicated above, there is a definite geneticpredisposition associated with carriage of HLA-DRB1*03:01,which could leave the immune system susceptible to devel-oping autoimmunity against an as-yet-unidentified muscle-specific protein, perhaps after exposure to an environmen-tal trigger such as a viral infection. The closest associationwith viruses has been reported with HIV; sIBM becomesapparent at a younger age in HIV-positive than in non-HIVpatients. Because the HIV itself is absent from the skeletalmuscle cells, it is unlikely that the autoimmune manifesta-tions are directly due to immune targeting of the virus butare rather an indirect effect secondary to the antiviralimmune response. In addition, it is possible that other non-HLA-linked genetic variations or mutations could contributeto the myonuclear breakdown, abnormal RNA metabolism,and degenerative processes associated with impairedautophagy resulting in multi-protein accumulation andmuscle breakdown in muscle fibers. Evidence of acceleratedaging is seen in the accumulation of an excess of somaticmitochondrial DNA mutations which may result in the upre-gulation of reactive oxygen species, oxidative stress andendoplasmic reticulum (ER) stress, and further protein accu-mulation and muscle dysfunction. Such mutations couldtherefore be responsible for cellular alterations that mayinduce muscle cell death either directly or by driving animmune attack on muscle.

5.1. Immunopathogenesis

The evidence for the significant involvement of an autoim-mune attack in the etiopathogenesis of sIBM is overwhelming.On sIBM muscle biopsies, particularly when taken early in thedisease course, inflammatory changes including a prominentendomysial T-cell-predominant inflammatory infiltrate, inva-sion of non-necrotic fibers and myocytes behaving as antigen-presenting cells with sarcolemmal and sarcoplasmic upregula-tion of MHC-I and MHC-II in myocytes [19]. While the inflam-matory infiltrate was traditionally mainly considered to becomposed of clonally expanded antigen-stimulated CD8+T-cells which persist over time [40,41], it is known that CD4+T-cells, myeloid dendritic cells, and macrophages also invadenon-necrotic fibers [42–44]. In addition, a significant numberof transcriptionally active antigen-driven CD138+ plasma cellsare present [45,46], supporting a role for humoral immunity inthe pathogenesis of sIBM. Microarray studies have shown thatimmunoglobulin transcripts are expressed at high levels[47,48], and an association of IBM with monoclonal gammo-pathies has been reported [49]. Moreover self-reactive antibo-dies against the cN1A have been identified in a highproportion of sIBM patients [50–53]. This enzyme catalyzesthe hydrolysis of adenosine monophosphate to adenosineand inorganic phosphate and is involved in the physiologiccontrol of cell metabolism and replication. It is still not knownwhether these self-directed antibodies are pathogenic or anepiphenomenon or whether they share antigenic targets withthe T-cells. Many sIBM patients also have other antibodies,including antinuclear antibodies [54], and antibodies againstdesmin, an intermediate filament protein that regulates mus-cle sarcomere architecture, have also been reported in onepatient [50]. If antibodies are discovered against muscle-specific proteins or they are the target of the T-cell-mediatedattack, it may help explain the muscle specificity that is remi-niscent of inherited muscle disorders, where genetic muta-tions in particular muscle proteins cause a specific pattern ofmuscle weakness.

There are a large number of reports of sIBM arising in thecontext of other autoimmune diseases including Sjogren’ssyndrome [55,56], SLE [57], systemic sclerosis [58], rheumatoidarthritis, and autoimmune thyroiditis [59,60]. It can also beassociated with an impaired immune system including com-mon variable immunodeficiency [61], chronic lymphocytic leu-kemia [62], human T-cell leukemia virus (HTLV) [63,64], andHIV [65–67]. The association with HIV is of interest, as the CD8+ T-cells that surround muscle fibers in these patients are viralspecific, and therefore, it has been postulated that the viralantigens trigger viral-specific T-cell clones that may cross-reactwith muscle-specific antigens, causing sIBM. Moreover, therehas been an increasing interest in the association of sIBM andhepatitis C (HCV) infection. Uruha and colleagues [68] reporteda significant proportion of their sIBM patients harbored anti-bodies to HCV. Although a viral etiology has been postulatedfor many decades [69], no viruses have been isolated fromaffected muscle thus far. However, this does not preclude thepossibility of a viral infection initiating an immune response tomuscle antigens in susceptible patients via molecular mimicryas suggested above, or via the induction of muscle injury and

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presentation of autoantigens by MHC-expressing myofibers, orvia induction of the ER stress response [70,71]. Perhaps, peoplewith a particular HLA genotype (in Caucasians, the HLA-A1, B8,and DR3 haplotypes) or other genotype combinations makethis sequence of events more likely.

The type 1 T helper (Th1)-mediated inflammatory responseis thought to be the predominant immune response in sIBMand is known to be triggered by intracellular bacteria andsome viruses [72]. Multiple studies using immunohistochem-ical techniques, mRNA and gene profiling studies, in situ hybri-dization, and Western blotting have identified multiplecytokines and chemokines upregulated in sIBM muscle fibers,with strong expression of tumor necrosis factor-alpha (TNF-α),interferon-gamma (IFN-γ), interleukin (IL)-1β, and CXC-9 andCCL-3 & 4 [73,74]. Cytokines are cell-signaling proteins thatmodulate the immune system response and may also exertdirect effects on target cells while chemokines are responsiblefor the attraction, activation, and accumulation of immunecells at the site of antigenic challenge. Cytokines, althoughproduced by muscle fibers under inflammatory conditions, canbe directly toxic to muscle fibers, particularly IL-1β [75] andTNF-α [76]. In addition, it is important to keep in mind thatmany of the inflammatory aspects of sIBM are shared withpolymyositis even though there are important differences;most notably, alterations such as protein degradation, mito-chondrial changes, and even MHC-II upregulation on musclefibers are not seen at all or as frequently in polymyositis.Moreover, the inflammatory changes seen in polymyositis areoften at a lower intensity than is seen in sIBM and are mainlylocalized to myofibers near areas with a severe inflammatoryinfiltrate, whereas it is far more widespread in sIBM [73].Moreover, all idiopathic inflammatory myopathies displayupregulation of degeneration-associated molecules includingamyloid precursor protein (APP), ubiquitin, αβ-crystallin, anddesmin at the mRNA level, particularly in patients with morelong-standing disease, but protein deposition and vacuoliza-tion is not typically seen in either polymyositis or dermato-myositis. The factors and mechanisms behind thesedifferences are important to identify as they may provide animportant clue to the underlying cause of sIBM and point toimportant treatment targets.

5.2. Possible links between inflammation anddegeneration; cytokines, ER stress, and NF-κB

It is probable that the plethora of cytokines and chemokinesupregulated in sIBM may form an important link between theinflammatory and degenerative aspects of the disease as firstsuggested by Dalakas [77] and may in fact be driving much ofthe disease process. However, it is not clear whether theimmune recognition of self-antigens is primarily responsiblefor the cytokine production or whether the degenerativechanges that affect the muscle fibers result in immune activa-tion and cytokine release. It is well recognized that someforms of genetically induced muscle disease such as dysferli-nopathies are also associated with a vigorous inflammatoryresponse and cytokine production. Another example of dys-functional protein homeostasis causing cytokine imbalance (inthis case of TNF-α and epidermal growth factor) [78] is

mutations in VCP, suggesting that it is possible that a primarydegenerative process (such as β-amyloid deposition) drivesthe cytokine production and oxidative stress in sIBM as firstproposed by Askanas and Engel [79].

In sIBM, degenerative features are seen concurrently withthe inflammatory changes in muscle biopsies, with proteindeposition (including a large number of proteins such as p62and TDP43), the formation of rimmed vacuoles, and tubulofi-laments containing phosphorylated tau proteins [79,80].Amyloid deposition refers to the congophilic staining ofabnormal insoluble proteins in the β-pleated sheet conforma-tion and can refer to a number of different proteins. It is theend result of protein misfolding due to a variety of triggersincluding genetic mutations, an error in protein cleavage, oroverproduction [81]. APP and β-amyloid (1–42) depositionhave been proposed by Askanas and colleagues to be keyupstream events in sIBM [80,82], but this is disputed as it isnot specific to sIBM [83], as the APP mRNA transcript wasincreased not only in sIBM but also in polymyositis and ateven higher levels in dermatomyositis. However, β-amyloid(1–42) deposition has been shown to impair muscle functionby reducing the RYR-mediated calcium release and the forceof muscle contraction [84], as well as interacting with theimmune system via cytokines. It has been seen in vitro that β-amyloid (1–42) in combination with IL-8 led to the expressionof pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6), sug-gesting that it could be a possible driver of the inflammatoryresponse [85]. Alternatively, the immune activation may bedriving the β-amyloid deposition. Kitazawa and colleaguesdemonstrated that chronic inflammation induced by lipopoly-saccharides increased APP levels and the generation of β-amyloid, as well as enhancing tau phosphorylation via glyco-gen synthase kinase-3beta (GSK3β) [86]. In sIBM myofibers, IL-1β has been found to be co-localized with β-amyloid, andmyotubes exposed to IL-1β upregulated APP with subsequentβ-amyloid deposition. The presence of APP mRNA correlatedsignificantly with the degree of cellular inflammation as wellas mRNA levels of chemokines, IFN-γ and especially IL-1β [73].This has been postulated to occur via the upregulation ofinducible nitric oxide synthase (iNOS). A subsequent study bythe same group found that the combination of IFN-γ and IL-1βupregulated iNOS and nitric oxide, followed by accumulationof β-amyloid and myocyte necrosis [87]. This confirmed anearlier study by Baron and colleagues who reported that inC2C12 mouse muscle cells, both IFN-γ and amyloid-β (1–42)induce release of nitric oxide via the increase of iNOS mRNA[88]; this process was associated with DNA fragmentation insome cases. This suggests that a self-sustaining cycle of IL-1βproduction, β-amyloid (1–42) deposition, and iNOS in sIBM is apossible pathomechanism leading to myocyte death, althoughit appears that there is more evidence to indicate that inflam-mation and cytokines drives the APP upregulation, rather thanthe other way around.

Interestingly, Gotoh and Mori reported that nitric oxide andreactive oxygen species may be a trigger for ER stress [89]. TheER (called the sarcoplasmic reticulum in skeletal muscle) is anorganelle with important roles in protein synthesis, assembly,and modification. In muscle, it also has an important role as acalcium store to help control cellular energy and myofibrillar

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contraction and functions as a sensor within the cell to detectperturbations in the intracellular environment [90]. The linkbetween ER stress and inflammation is well established, butthe ER–mitochondrial and the ER–autophagy interplay is lesswell recognized [91]. The accumulation of unfolded or mis-folded proteins within the ER leads to the unfolded proteinresponse (UPR) and the ER overload response (EOR), which arecellular mechanisms to restore homeostasis. The UPR involveschanges in the transcription and translation of proteins (viaactivating transcription factor 6, inositol-requiring enzyme 1,and PKR-like eukaryotic initiating factor 2a kinase), with upre-gulation of chaperone protein gene expression to enhance theER protein folding capability, and with reduced translation ofother proteins to reduce the protein load. Evidence of ERstress and the subsequent UPR has been found in sIBM musclebiopsies [92,93]. The EOR involves the NF-κB and mitogen-activated protein kinase pathways and upregulation of MHC-I, the release of calcium, and initiation of the acute-phaseresponse [91]. High MHC-I expression on muscle fibers is anearly and consistent finding in immune-mediated myopathy[94]. MHC-I plays a critical role in presenting self-antigens toCD8+ T-cells, but also appears to be involved in muscle toxi-city in a T-cell-independent manner. A Class I MHC-transgenicmouse model demonstrated that overexpression of MHC-I wassufficient to cause a self-sustaining myopathy via the ER stressresponse and activation of NF-κB [94,95].

NF-κB is a central transcriptional regulator in eukaryotic cellswith a central role in controlling the expression of a largenumber of genes including cytokines, chemokines, adhesionmolecules, enzymes involved in protein degradation via theubiquitin–proteasome system, and others [96]. NF-κB is acti-vated by inflammatory stimuli (e.g. cytokines [TNF-α and IL-1]and viral and bacterial infections), as well as via noninflamma-tory pathways including ER stress, oxidative stress, and biome-chanical stress. NF-κB signaling is emerging as one of the mostimportant pathways associated with muscle loss, not only viainflammatory mechanisms, but also via degradation of specificmuscle proteins and by blocking the regeneration of myofibers[96]. It has been found that TNF-α, TWEAK (a TNF-α homologue),and IL-1β can block the terminal differentiation of myoblastsinto mature myotubes via NF-κB [97,98]. In addition, it has alsobeen found NF-κB can block myogenesis via destabilization of amajor myogenic transcription factor (MyoD) mRNA via the RNAstabilization protein HuR and iNOS pathway [99]. NF-κB hasbeen found to be increased in sIBM and may be significantlycontributing to the disease process [100].

5.3. Protein breakdown via ubiquitin–proteasomalpathway and autophagy and association with proteinaccumulation

Protein accumulation can be the result of either excess produc-tion or reduced breakdown. In sIBM, a large number of proteinshave been found to be deposited in the muscle fibers, and thishas been considered more likely to be posttranslational ratherthan due to a primary overproduction. Therefore, the focus thusfar has been onprotein degradation pathways. Abnormal solubleproteins are largely broken down by the 26S proteasomal

system, while degradation of insoluble proteins relies on autop-hagy. Autophagy is an important cellular process that deliverscytoplasmic proteins into lysosomal and endosomal compart-ments for degradation and possible recycling. Macroautophagyis the process whereby cytoplasmic proteins and organelles aresequestered inside a double-membrane vesicle called an autop-hagosome, which fuses with lysosomes. The cytoplasmic pro-teins are broken down and antigenic fragments are shuttled toMHC-II molecules to be presented to CD4+ T-cells. It has beenshown thatmarkers of autophagy, namely light chain 3 (LC3), areincreased in sIBM [101] and co-localize with APP/amyloid-β [102],but lysosomal enzymes cathepsins D and B have reduced pro-teolytic activity, thereby perhaps contributing to protein accu-mulation via reduced capacity for breakdown. Moreover inmuscle cultures, ER stress caused a similar increase in LC3 andreduced lysosomal activity, suggesting that ER stress may drivethe autophagic dysfunction in sIBM [101]. LC3+ autophago-somes containing β-amyloid/APP deposits are associated withMHC-I and MHC-II upregulation and CD4+ and CD8+ T-cell inva-sion within degenerating muscle fibers [102,103], perhaps sug-gesting that this protein degradation process could be driving atleast a component of the immune response. MHC-II is upregu-lated on the surface of myocytes in sIBM more than any otherinflammatory myopathy, suggesting that the impairment ofautophagy and presentation of self-antigens are more importantin sIBM than any other inflammatory myopathies [19].Interestingly TNF-α has been found to regulate the surfaceexpression of MHC-II molecules in IFN-γ-treated myoblasts, aswell as having an important role in inducing macroautophagy[104], so again cytokines appear to be an important link betweenthe inflammatory and degenerative aspects of this complex dis-ease. Failure of autophagy leads to the accumulation of proteinsand autophagic substrates including p62, a shuttle protein trans-porter for both the lysosmal and proteasomal degradation path-way, which is a well-recognized and key feature seen in sIBMbiopsies [105,106]. TDP43 on the other hand, a RNA-bindingprotein involved in mRNA splicing, stabilization, transport, andbiogenesis, is also seen to be accumulating in the sarcoplasm insIBM [107–109] and may suggest proteasomal dysfunction and/or myonuclear and RNA metabolism abnormalities.

Myonuclear abnormalities have been reported for 50 yearsin sIBM [110] with suggestions that myonuclear breakdowncontributes to the formation of rimmed vacuoles, further sub-stantiated more recently by findings that most rimmedvacuoles are lined with the nuclear proteins lamin A/C, emerin,and histone H1 [111,112]. TDP-43, which is normally located inthe nucleus and is commonly seen in neurodegenerative dis-eases (including amyotrophic lateral sclerosis and frontotem-poral dementia), is found in the sarcoplasm in sIBM myofibers,supporting the hypothesis of alterations in RNA metabolismplaying a role in the pathogenesis of these degenerative dis-orders as suggested by Salajegheh and colleagues [108]. AnRNA transcriptome study performed by Cortese et al. [113]supported this hypothesis by finding widespread sIBM-specificchanges (when compared with polymyositis) in the RNA meta-bolism pathways with differential expression of the MATR3and ZNF9 genes, as well as splicing changes in exon 6 inMAPT, and novel RNA binding proteins including hnRNPA2/

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B1 and hnRNPC1/C2. The exact mechanism by which theseabnormalities in mRNA metabolism could cause or contributeto myofiber loss in sIBM is not yet understood, but it could beby affecting the translation of specific proteins within themuscle, abnormal mRNA splicing,or possibly enhancing RNAdegradation.

5.4. Links with aging and mitochondrial defects

sIBM is a disease of aging, with no case reports in peopleunder 30 years of age. Aging in muscle is characterized byreduced capacity for regeneration, decreased muscle proteinsynthesis, and increased oxidative stress. Catabolic cytokinessuch as IL-1β, IL-6, and TNF-α, and NF-κB are all thought toplay a role in the sarcopenia of aging [114]. Indeed, many ofthe changes seen in sIBM muscle are those of acceleratedaging including telomere shortening and the accumulationof somatic mitochondrial DNA mutations. An increased num-ber of COX-negative fibers and ragged red fibers are a well-recognized and specific feature of sIBM biopsies and, in com-bination with the inflammatory changes, are very sensitive(100%) and quite specific (73%) for the histological diagnosisof sIBM [106]. These COX-deficient fibers are associated withdownregulated expression of complex I of the mitochondrialrespiratory chain and mitochondrial DNA (mtDNA) rearrange-ments and multiple acquired mtDNA deletions [115]. Lindgrenand colleagues [116] investigated whether variants in nucleargenes involved in mtDNA maintenance contribute to themtDNA deletions seen in sIBM muscle and found variants inPOLG and C10orf2. It is likely that these mitochondrialabnormalities translate into functional muscle impairmentcontributing to symptoms of fatigue and exertion-relatedsymptoms in sIBM patients. Joshi and colleagues found thatsIBM patients had significantly reduced oxygen desaturationand elevated peak serum lactate during exercise [117].Moreover, it has been found that there is a strong correlationbetween the degree of mitochondrial changes and number ofCOX-deficient fibers, severity of inflammation and number ofT-cells and macrophages, and muscle atrophy, suggesting apossible pathogenic link between these processes. It is knownthat mitochondrial changes play a major role in muscle degen-eration via dysregulation of mitochondrial permeability transi-tion pore opening and abnormal autophagy, in a largenumber of neuromuscular disorders including the congenitalmuscle disorders [118]. However, possible links between themitochondrial changes and protein accumulation have alsobeen reported. In the APP-transgenic mice, it has been foundthat structural and functional changes occur early in mito-chondria and precede other histopathological and clinicalfeatures [119].

Reduced capacity for muscle regeneration is a feature ofsIBM myoblasts in vitro, which with aging are found to accu-mulate congophilic deposits including β-amyloid (1–40) [120].In addition, sIBM mesoangioblasts are less able to undergomyogenic differentiation, possibly via TNF-like Weak Inducerof Apoptosis (TWEAK) [121]. This may help to explain theprogressive muscle atrophy and inability to improve musclestrength and bulk that is characteristic of sIBM, and better

understanding this pathway may lead to development ofnew therapeutic targets for the treatment of the disease.

6. Treatment

6.1. Pharmacotherapy

There are currently no effective curative treatments for patientswith sIBM. Over the last 20 years, multiple trials of immunosup-pressive and immunomodulatory drugs have been performed,including prednisone, intravenous and subcutaneous intravenousimmunoglobulin (IVIG) therapy, methotrexate, azathioprine, inte-feron-b-1A, etanercept, and infliximab without a significant posi-tive benefit (reviewed in Needham, Neurotherapeutics 2016). Apossible explanation for this was published by Zschuntzsch et al.[122] who found that although prednisolone and IVIG therapyreduced some inflammatory and degenerativemolecularmarkersin sIBM myofibers, cell stress mediators such as iNOS and othermyotoxic compounds including IL-1β andAβPPwere not affectedby these therapies. However, a pilot study was undertaken in foursIBM patients with anakinra, an IL-1 receptor antagonist, 100 mgsubcutaneously daily for a mean of 7.7 months, unfortunatelywith no improvement or stabilization of muscle strength beingobserved [123]. As IBM is thought to have a T-cell-driven compo-nent, including a CD8+ T-cell-predominant endomysial infiltratedemonstrating clonal expansion, a pilot study of T-cell depletionusing alemtuzumabwas carried out on a group of 13 IBM patients[124]. The patients demonstrated a lesser decline in strength thanwas seen in the natural history observational component of thestudy, but improvement in muscle strength occurred in only fourpatients. Alemtuzumab also had no effect on the mRNA expres-sion in the muscle of pro-inflammatory cytokines or chemokines(IFN-γ, TGF-β, IL-1β, CXCl-9, and CCL-4) or on degenerative mole-cules (APP or ubiquitin) [125]. Given the potential toxicity ofalemtuzumab, a larger placebo-controlled trial would need tobe performed before it could be recommended as a treatmentfor sIBM.

A small (n = 6) open-label trial of natalizumab [126] demon-strated near-complete elimination of inflammation in thebiopsy after 6 months, but no clinically significant improve-ment was seen. A current trial is in progress to address thepotential benefit of rapamycin, a compound that inhibitseffector T-cells and induces autophagy, thereby working ontwo possible pathogenic pathways in sIBM (NCT02481453); theresults should be available this year.

IVIG therapy continues to be controversial. A recent follow-up study of 16 sIBM patients treated with IVIG for a mean of23 months was found to have short-term benefit on musclestrength and dysphagia in some patients, but this was notsustained over time [127]. However, there may be an excep-tion with regard to treating dysphagia, and it has been sug-gested that the pharyngeal muscles may be more responsivethan the limb muscles to IVIG. This outcome may even applywith the use of subcutaneous immunoglobulin [128,129].Since the existence of regional differences in response toIVIG was questioned, and that persistent case reports chal-lenge the efficacy of IVIG in sIBM [130,131], further studieswill be required.

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However, many of these studies often included only smallpatient numbers and were of short duration and withoutconsistent outcome measures. Therefore, the possibilityremains that some of these medications may efficiently slowthe disease progression or that subgroups of patients maybenefit from some of these medications. There has beensome suggestion that patients with coexisting sIBM andSjogren’s syndrome [55], or other autoimmune diseases[59],may respond, even over the short term to immunotherapy.However, a long-term observational study of sIBM patientssuggested that patients who had been on immunosuppres-sion had a more rapid rate of decline [7].

Other compounds that affect the immune system have alsobeen tried. For example, due to the anti-inflammatory effect ofstatins on the immune response, a pilot study was carried outwith 40 mg daily of simvastatin over 12 months in 14 IBMpatients[132]; none of the 10 patients who completed thestudy had any improvement of muscle strength. The failureof various immunosuppressant and immunomodulatoryagents over decades, in addition to new pathogeneticinsights, has led to new directions for treatment.

Arimoclomol is an orally administered agent that amplifiesexpression of heat shock proteins which are thought to becytoprotective against the detrimental aspects of both inflam-mation and myodegeneration. A phase 2a proof-of-conceptstudy was undertaken in 24 sIBM patients over 4 months,including 16 patients with active treatment and 8 whoreceived placebo [133]. Overall, the drug was safe and welltolerated, and at 8 months, a trend was seen for a slowerdecline in the treatment group on the IBMFRS and right-hand grip maximum isometric contraction strength. A furtherstudy is underway to investigate efficacy in sIBM [134].

Bimagrumab is a fully humanized monoclonal antibody thatblocks the activin IIA and IIB receptors (ActRII) that bind myos-tatin and other ligands, thereby allowing uninhibited musclegrowth. An initial phase 2a trial in 14 IBM patients, where 11received a single infusion of bimagrumab and 3 received pla-cebo, demonstrated an increased thigh muscle volume andimproved performance with the 6-minute walk test [135].However, a multicenter, international, phase 2b/3, double-blinded, placebo-controlled, randomized controlled trial (RCT)has recently been completed, but unfortunately it did not meetits primary outcome measure which was improvement in the6-minute walk test. A gene therapy approach using follistatin toinhibit myostatin expression is also being tested using anadeno-associated virus vector and direct intramuscular injectioninto the quadriceps muscle (clinical trials identifier:NCT01519349) [136]. This approach has the potential advantagethat it may provide a long-term suppression of myostatin withinthe injected muscle. However, inhibiting myostatin or its path-way is unlikely per se to be a cure for sIBM unless the under-lying disease process can be suppressed.

Lithium is known to inhibit GSK3β which is involved in thephosphorylation of AβPP and phosphorylated tau. In culturedmuscle fibers, treatment with lithium decreased GSK3β activityand total AβPP and improved proteasomal function [137].However, an open-label trial (clinical trials identifier:NCT00917956) involving 15 IBM patients did not demonstrateany significant change in muscle strength [138].

6.2. Treatment of dysphagia

Treatments that have been suggested to manage dysphagia inIBM other than IVIG include cricopharyngeal myotomy, upperesophageal dilatation, or botulinum toxin injections. In addi-tion, isometric lingual strengthening exercises have been usedto help maintain swallowing function [139]. A retrospectivereview of 26 IBM patients with dysphagia was published by Ohet al. in 2008 [140], and in this series, cricopharyngeal muscledysfunction was a common finding, and symptomaticimprovement was more common with cricopharyngeal myot-omy than pharyngoesophageal dilatation. In addition, thepresence of dysphagia was associated with aspiration, pneu-monia, and even death in this series. Given the potentialimpact of dysphagia on quality, and possibly quantity of life,a large early prospective trial of noninvasive techniques suchas isometric lingual exercises and the Mendelsohn manoeuverwould be worthwhile, but would need to be long term to yieldsignificant results. An observational study may even suffice.

6.3. Exercise and other therapies

Exercise therapies have been shown to be safe in sIBM and arecurrently recommended as part of the treatment of sIBM [141–144]. While larger trials are required to prove benefit not onlyin terms of strength, but in terms of function and quality oflife, these smaller studies suggest that exercise programs canlead to short-term improvement or maintenance of musclestrength, aerobic capacity, and improved quality of life.Recent studies have also suggested that exercise itself maymodify the disease process by reducing the expression ofgenes related to inflammation and fibrosis and improvingmitochondrial capacity [145,146]. In addition, ischemic resis-tance training has been suggested as a possible variation onstandard exercise therapy for IBM patients on the basis of asingle case study, but will need to be trialed in larger numbersof patients [147,148]. Improvement after hyperbaric oxygentreatment has also been reported in a patient with sIBM [149].

Dealing with the psychological aspects of suffering withthis chronic progressive incurable disease is vital to improvingpatients’ quality of life. There is a study underway investigat-ing the effectiveness of acceptance and commitment therapy(a form of cognitive behavioral therapy) at the King’s CollegeHospital in London (NCT02810028).

6.4. Experimental and future considerations

Cultured human muscle fibers with impaired autophagydemonstrate vacuolization, reduced lysosomal activity, andincreased amyloid-β42 oligomers. When these cultured fiberswere treated with sodium phenylbutyrate by Nogalska andcolleagues [150], lysosomal activity improved, vacuolizationwas virtually prevented, and amyloid-β42 was decreased.This suggests that treatments directed towards improvinglysosomal dysfunction, and autophagy may be successful inreversing some of the pathological features seen in IBM.Whether this translates into clinically meaningful outcomes isyet to be seen, but may be a useful future direction for

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therapy, perhaps combined with treatments directed towardsmodifying the immune response.

There is increasing evidence that natural polyphenols, suchas oleuropein aglycone (OLE), which is found in extra-virginolive oil, may prevent the deposition of toxic amyloid. In atransgenic Caenorhabditis elegans model, OLE-fed worms dis-played reduced amyloid-β plaque formation, less paralysis,and increased lifespan compared with untreated worms[151]. Although this is clearly an imperfect model of sIBM,these findings suggest that dietary habits should be takeninto account when evaluating and following sIBM patients inthe clinic in the event that a dietary modification may enhancequality of life.

For example, high-fat, low-carbohydrate ketogenic diets areuseful in the treatment of some childhood epilepsies. A keto-genic diet was trialed for 1 month in an APP/PS1 knock-inmouse, and levels of AβPP and amyloid-β were assessed inboth the brain and skeletal muscles [152]. Although there wasno change in the levels of amyloid or nitrotyrosine (a productof oxidative stress), there was improved performance on theRota-rod apparatus, suggesting a possible role for a ketogenicdiet in improving muscle function, albeit not via reducingamyloid deposition. Nonsteroidal anti-inflammatory drugs(NSAIDs) have also been trialed in transgenic mice that over-express AβPP for a period of 6 months. Ibuprofen was the onlyNSAID that reduced amyloid-β in muscle, but there was nocorresponding improvement in phenotype, suggesting thatamyloid-β per se cannot explain the skeletal muscle dysfunc-tion [153]. In contrast, active immunization of a transgenicmouse model of sIBM inducing anti-amyloid-β antibodiesreduced amyloid-β deposition in myocytes and attenuatedthe motor impairment, suggesting that amyloid-β does infact contribute to muscle weakness [154].

7. Conclusions

The etiopathogenesis of sIBM remains enigmatic, and there arestill outstanding questions regarding the earliest pathological andmolecular changes and the interaction between the inflamma-tory and degenerative components of the disease that requirefurther investigation. Genetic susceptibility is now well estab-lished and appears to be polygenic and cumulative as in thecase of other neurodegenerative diseases. It is likely that poly-morphisms and structural variants in other as-yet-unidentifiedgenes are also involved and may contribute to disease suscept-ibility. Further genetic studies of sporadic and familial casesincluding sequencing of both exonic and noncoding regions ofthe genome are likely to be helpful in identifying newpolymorph-isms and structural variants that influence disease susceptibilityand may play a role in the pathogenesis of the disease.

Further studies of large patient cohorts are needed torefine and validate the current diagnostic criteria for sIBMand identify novel biomarkers that can be used diagnosticallyand to monitor disease activity and response to therapy inclinical trials. In particular, the sensitivity and potential value ofanti-cN1A antibody assays and muscle imaging warrantfurther investigation. There is an urgent need to identify newtherapeutic targets and agents with the potential to modify

the natural history of the disease which can be tested inrandomized trials and to resolve the issue of whether somesubgroups of sIBM patients are more likely to respond todifferent immune therapies and whether the disease is morelikely to be responsive if treatment is commenced early andcontinued over longer periods.

8. Expert opinion

sIBM is a unique acquired myopathy of middle and later life inwhich genetic susceptibility factors associated with antigenpresentation to the immune system and with other neurode-generative disorders have been identified and which can rarelybe familial. Clinically, there is a highly specific pattern of muscleinvolvement which is more reminiscent of the large group ofinherited muscle diseases and differentiates sIBM from otherinflammatory myopathies such as polymyositis and dermato-myositis. Moreover, the poor response to traditional immuno-suppressant agents also distinguishes sIBM from otherimmune-mediated myopathies. Pathologically, a T-cell-dominant inflammatory infiltrate with muscle fiber invasion iscombined with myodegenerative changes including multi-protein aggregates and mitochondrial and myonuclearchanges, but the temporal relationship and interactionbetween these changes remains unclear. Identifying the earliestchanges in muscle remains a major challenge and will be vitalto developing a better understanding of the etiopathogenesisof the disease and identifying new therapeutic targets andtreatments to reverse or arrest the progression of the disease.

Overall, it is likely that the cardinal histopathological triadof changes seen in biopsies each contributes individually tothe muscle loss and weakness seen in sIBM, but the initiatingfactor is not known, and it remains unclear which of thesechanges is primary and which are secondary. While, on theone hand, sIBM has many features of a degenerative diseaseor a disease of accelerated aging, including the late age-at-onset, the lack of response to traditional immune therapies,the accumulation in myofibers of multiple somatic mtDNAmutations, myonuclear abnormalities, abnormal deposition ofproteins such as TDP-43, abnormal RNA metabolism, andabnormal autophagy, the degenerative changes in myofibersare seen to become more florid later in the disease course,perhaps suggesting that they are not primary, although theyclearly contribute to the ongoing progression of the dis-ease [155].

On the other hand, the association with the HLA-A1-B8-DR3, (autoimmune) haplotype, and HLA-DRB1 locus is oneof the strongest HLA–disease associations described and isconsistent with the co-occurrence of other autoimmunedisorders in sIBM. This suggests that susceptibility of theimmune system is a key underlying factor in the etiopatho-genesis of the disease. In addition, the strong upregulationof MHC Class I and II antigens on myofibers behaving asantigen-presenting cells for CD4+ and CD8+ T-cells is moreflorid than in any of the other forms of immune-mediatedmyositis, and a number of studies have provided evidencelinking the action of inflammatory cytokines/chemokines tothe development of cell stress, abnormal autophagy, mito-chondrial abnormalities, and myofiber degeneration.

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However, while these findings provide a plausible linkbetween the inflammatory and degenerative componentsof the disease, it is still unclear whether sIBM is a primarymuscle-specific autoimmune disease or a myodegenerativedisorder with a vigorous immune-inflammatory response ascan occur in a number of inherited myopathies.

Understanding the natural history of this enigmatic diseasemore fully and identifying the changes over time and the role(if any) of the anti-CN1a antibody and other biomarkers will beessential for designing future clinical trials of sufficient dura-tion with appropriate outcome measures to detect clinicallysignificant outcomes. Future progress will be greatly aided bythe establishment of disease registries and multicenter data-bases to assist in assembling and phenotyping patient cohortsof sufficient magnitude for further genetic and natural historystudies and RCTs of new therapies.

Acknowledgments

We acknowledge the valuable suggestions and contributions of Dr JeromeCoudert in his review of the manuscript and we acknowledge fundingsupport from the Perron Institute for Neurological and TranslationalResearch.

Funding

This paper was funded by Institute for Immunology & Infectious Diseases,Murdoch University.

Declaration of interest

M Needham has received honoraria for educational talks for Novartis andBristol-Myers-Squibb, for participation in advisory boards for Novartis andBayer, and travel grants by Novartis and Biogen-Idec. The authors have noother relevant affiliations or financial involvement with any organizationor entity with a financial interest in or financial conflict with the subjectmatter or materials discussed in the manuscript apart from thosedisclosed.

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58. Bielsa S, Madronero AB, Grau JM, et al. [Inclusion-body myositis asso-ciated with systemic sclerosis]. Miositis Con Cuerpos De InclusionAsociada a Esclerosis Sistemica. Med Clin (Barc). 2007;128:278.

59. Clerici AM, Bono G, Delodovici ML, et al. A rare association ofearly-onset inclusion body myositis, rheumatoid arthritis and auto-immune thyroiditis: a case report and literature review. FunctNeurol. 2013;28:127–132.

60. Hama K, Miwa H, Nishino I, et al. [Inclusion body myositis asso-ciated with chronic thyroiditis, Sjogren’s syndrome and autoim-mune cholangitis]. No to shinkei = Brain Nerve. 2004;56:503–507.

61. Dalakas MC, Illa I. Common variable immunodeficiency and inclu-sion body myositis: a distinct myopathy mediated by natural killercells. Ann Neurol. 1995;37:806–810.

62. Beck EH, Amato AA, Greenberg SA. Inclusion bodymyositis and chroniclymphocytic leukemia: a case series. Neurology. 2014;83:98–99.

63. Cupler EJ, Leon-Monzon M, Miller J, et al. Inclusion body myositis inHIV-1 and HTLV-1 infected patients. Brain. 1996;119(Pt 6):1887–1893.

64. Ozden S, Gessain A, Gout O, et al. Sporadic inclusion body myositisin a patient with human T cell leukemia virus type 1-associatedmyelopathy. Clin Infect Dis. 2001;32:510–514.

65. Dalakas MC, Rakocevic G, Shatunov A, et al. Inclusion body myositiswith human immunodeficiency virus infection: four cases withclonal expansion of viral-specific T cells. Ann Neurol.2007;61:466–475.

• This is an important case series emphasizing that immunedysregulation due to HIV with clonal expansion of T-cellsappears to be able to initiate sIBM.

66. Hiniker A, Daniels BH, Margeta M. T-cell-mediated inflammatorymyopathies in HIV-positive individuals: a histologic study of 19cases. J Neuropathol Exp Neurol. 2016;75:239–245.

67. Alverne ARSM, Marie SKN, Levy-Neto M, et al. [Inclusion bodymyositis: series of 30 cases from a Brazilian tertiary center].Miosite de corpos de inclusao: serie de 30 casos de um centroterciario brasileiro. Acta Reumatol Port. 2013;38:179–185.

68. Uruha A, Noguchi S, Hayashi YK, et al. Hepatitis C virus infection ininclusion body myositis: a case-control study. Neurology.2016;86:211–217.

69. Chou SM. Inclusion body myositis: a chronic persistent mumpsmyositis? Hum Pathol. 1986;17:765–777.

70. Christen U, Von Herrath MG. Initiation of autoimmunity. Curr OpinImmunol. 2004;16:759–767.

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71. Dalakas MC, Schmidt J. Viruses in IBM: hit-and-run, hide and persist,or irrelevant? Neurology. 2016;86:204–205.

72. de Paepe B, Creus KK, de Bleecker JL. Chemokine profile ofdifferent inflammatory myopathies reflects humoral versuscytotoxic immune responses. Ann N Y Acad Sci. 2007;1109:441–453.

73. Schmidt J, Barthel K, Wrede A, et al. Interrelation of inflammationand APP in sIBM: IL-1 beta induces accumulation of beta-amyloid inskeletal muscle. Brain. 2008;131:1228–1240.

•• This is an important article proposing a link between thedegenerative and inflammatory aspects of the disease.

74. de Paepe B, Zschuntzsch J. Scanning for therapeutic targets withinthe cytokine network of idiopathic inflammatory myopathies. Int JMol Sci. 2015;16:18683–18713.

75. Broussard SR, McCusker RH, Novakofski JE, et al. IL-1beta impairsinsulin-like growth factor i-induced differentiation and downstreamactivation signals of the insulin-like growth factor i receptor inmyoblasts. J Immunol. 2004;172:7713–7720.

76. Li YP, Chen Y, John J, et al. TNF-alpha acts via p38 MAPK tostimulate expression of the ubiquitin ligase atrogin1/MAFbx inskeletal muscle. Faseb J. 2005;19:362–370.

77. Dalakas MC. Molecular immunology and genetics of inflammatorymuscle diseases. Arch Neurol. 1998;55:1509–1512.

78. Dec E, Rana P, Katheria V, et al. Cytokine profiling in patients withVCP-associated disease. Clin Transl Sci. 2014;7:29–32.

79. Askanas V, Engel WK. Sporadic inclusion-body myositis and itssimilarities to Alzheimer disease brain. Recent approaches to diag-nosis and pathogenesis, and relation to aging. Scand J Rheumatol.1998;27:389–405.

80. Askanas V, Engel WK. Sporadic inclusion-body myositis: conforma-tional multifactorial ageing-related degenerative muscle diseaseassociated with proteasomal and lysosomal inhibition, endoplas-mic reticulum stress, and accumulation of amyloid-beta42 oligo-mers and phosphorylated tau. Presse Med (Paris, France: 1983).2011;40:e219–35.

• A review summarizing the work of this group.81. Buxbaum JN. Treatment and prevention of the amyloidoses: can

the lessons learned be applied to sporadic inclusion-body myositis?Neurology. 2006;66:S110–3.

82. Sarkozi E, Askanas V, Johnson SA, et al. Beta-amyloid precursorprotein mRNA is increased in inclusion-body myositis muscle.Neuroreport. 1993;4:815–818.

83. Greenberg SA. Theories of the pathogenesis of inclusion bodymyositis. Curr Rheumatol Rep. 2010;12:221–228.

84. Shtifman A, Ward CW, Laver DR, et al. Amyloid-beta protein impairsCa2+ release and contractility in skeletal muscle. Neurobiol Aging.2010;31:2080–2090.

85. Franciosi S, Choi HB, Kim SU, et al. IL-8 enhancement ofamyloid-beta (Abeta 1-42)-induced expression and production ofpro-inflammatory cytokines and COX-2 in cultured humanmicroglia. J Neuroimmunol. 2005;159:66–74.

86. Kitazawa M, Trinh DN, LaFerla FM. Inflammation induces taupathology in inclusion body myositis model via glycogen synthasekinase-3beta. Ann Neurol. 2008;64:15–24.

87. Schmidt J, Barthel K, Zschuntzsch J, et al. Nitric oxide stress in sporadicinclusion body myositis muscle fibres: inhibition of inducible nitricoxide synthase prevents interleukin-1beta-induced accumulation ofbeta-amyloid and cell death. Brain. 2012;135:1102–1114.

• Important paper with a possible link between the inflamma-tion and degeneration.

88. Baron P, Galimberti D, Meda L, et al. Synergistic effect ofbeta-amyloid protein and interferon gamma on nitric oxideproduction by C2C12 muscle cells. Brain. 2000;123(Pt2):374–379.

89. Gotoh T, Mori M. Nitric oxide and endoplasmic reticulum stress.Arterioscler Thromb Vasc Biol. 2006;26:1439–1446.

90. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to theinflammatory response. Nature. 2008;454:455–462.

• Well-written article about ER stress and possible triggering ofinflammation.

91. Rayavarapu S, Coley W, Nagaraju K. Endoplasmic reticulum stress inskeletal muscle homeostasis and disease. Curr Rheumatol Rep.2012;14:238–243.

• Nice review on ER stress pathways in skeletal muscle andpossible link to mitochondrial changes.

92. Nogalska A, D’Agostino C, Engel WK, et al. Activation of theunfolded protein response in sporadic inclusion-body myositisbut not in hereditary GNE inclusion-body myopathy. JNeuropathol Exp Neurol. 2015;74:538–546.

93. Vattemi G, Engel WK, McFerrin J, et al. Endoplasmic reticulum stressand unfolded protein response in inclusion body myositis muscle.Am J Pathol. 2004;164:1–7.

94. Nagaraju K, Casciola-Rosen L, Lundberg I, et al. Activation of theendoplasmic reticulum stress response in autoimmune myositis:potential role in muscle fiber damage and dysfunction. ArthritisRheum. 2005;52:1824–1835.

• Interesting article exploring nonimmune mechanisms of mus-cle dysfunction in autoimmune myositis linking MHC-I upregu-lation to the ER stress response and NF-κB pathway.

95. Freret M, Drouot L, Obry A, et al. Overexpression of MHC class I inmuscle of lymphocyte-deficient mice causes a severe myopathywith induction of the unfolded protein response. Am J Pathol.2013;183:893–904.

96. Li H, Malhotra S, Kumar A. Nuclear factor-kappa B signaling inskeletal muscle atrophy. J Mol Med (Berl). 2008;86:1113–1126.

97. Dogra C, Changotra H, Mohan S, et al. Tumor necrosis factor-likeweak inducer of apoptosis inhibits skeletal myogenesis throughsustained activation of nuclear factor-kappaB and degradation ofMyoD protein. J Biol Chem. 2006;281:10327–10336.

98. Langen RC, Schols AM, Kelders MC, et al. Inflammatory cytokinesinhibit myogenic differentiation through activation of nuclearfactor-kappaB. Faseb J. 2001;15:1169–1180.

99. Di Marco S, Mazroui R, Dallaire P, et al. NF-kappa B-mediated MyoDdecay during muscle wasting requires nitric oxide synthase mRNAstabilization, HuR protein, and nitric oxide release. Mol Cell Biol.2005;25:6533–6545.

100. Nogalska A, Wojcik S, Engel WK, et al. Endoplasmic reticulum stressinduces myostatin precursor protein and NF-kappaB in culturedhuman muscle fibers: relevance to inclusion body myositis. ExpNeurol. 2007;204:610–618.

101. Nogalska A, D’Agostino C, Terracciano C, et al. Impaired autophagyin sporadic inclusion-body myositis and in endoplasmic reticulumstress-provoked cultured human muscle fibers. Am J Pathol.2010;177:1377–1387.

102. Lunemann JD, Schmidt J, Schmid D, et al. Beta-amyloid is a sub-strate of autophagy in sporadic inclusion body myositis. AnnNeurol. 2007;61:476–483.

103. Lunemann JD, Schmidt J, Dalakas MC, et al. Macroautophagy as apathomechanism in sporadic inclusion body myositis. Autophagy.2007;3:384–386.

104. Keller CW, Fokken C, Turville SG, et al. TNF-alpha induces macro-autophagy and regulates MHC class II expression in human skeletalmuscle cells. J Biol Chem. 2011;286:3970–3980.

105. Nogalska A, Terracciano C, D’Agostino C, et al. p62/SQSTM1 isoverexpressed and prominently accumulated in inclusions ofsporadic inclusion-body myositis muscle fibers, and can help differ-entiating it from polymyositis and dermatomyositis. ActaNeuropathol. 2009;118:407–413.

106. Brady S, Squier W, Sewry C, et al. A retrospective cohort studyidentifying the principal pathological features useful in the diag-nosis of inclusion body myositis. BMJ Open. 2014;4:e004552.

•• A very helpful histopathological analysis of sIBM.107. Dubourg O, Wanschitz J, Maisonobe T, et al. Diagnostic value of

markers of muscle degeneration in sporadic inclusion bodymyositis. Acta Myol. 2011;30:103–108.

108. Salajegheh M, Pinkus JL, Taylor JP, et al. Sarcoplasmic redistributionof nuclear TDP-43 in inclusion body myositis. Muscle Nerve.2009;40:19–31.

109. Weihl CC, Temiz P, Miller SE, et al. TDP-43 accumulation in inclusionbody myopathy muscle suggests a common pathogenic

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mechanism with frontotemporal dementia. J Neurol NeurosurgPsychiatry. 2008;79:1186–1189.

110. Chou SM. Myxovirus-like structures and accompanyingnuclear changes in chronic polymyositis. Arch Pathol. 1968;86:649–658.

111. Greenberg SA, Pinkus JL, Amato AA. Nuclear membrane proteinsare present within rimmed vacuoles in inclusion-body myositis.Muscle Nerve. 2006;34:406–416.

• Important paper looking at the possible role of the breakdownof myonuclei in the formation of rimmed vacuoles.

112. Nakano S, Shinde A, Fujita K, et al. Histone H1 is released frommyonuclei and present in rimmed vacuoles with DNA in inclusionbody myositis. Neuromuscul Disord. 2008;18:27–33.

113. Cortese A, Plagnol V, Brady S, et al. Widespread RNA metabolismimpairment in sporadic inclusion body myositisTDP43-proteinopathy. Neurobiol Aging. 2014;35:1491–1498.

• First study to describe widespread alterations of RNA meta-bolism in sIBM.

114. Bruunsgaard H, Pedersen BK. Age-related inflammatory cytokinesand disease. Immunol Allergy Clin North Am. 2003;23:15–39.

115. Rygiel KA, Miller J, Grady JP, et al. Mitochondrial and inflammatorychanges in sporadic inclusion body myositis. Neuropathol ApplNeurobiol. 2015;41:288–303.

• Interesting study which found that mitochondrial changes arecorrelated with inflammatory changes.

116. Lindgren U, Roos S, Hedberg Oldfors C, et al. Mitochondrial pathol-ogy in inclusion body myositis. NMD. 2015;25:281–288.

117. Joshi PR, Vetterke M, Hauburger A, et al. Functional relevance ofmitochondrial abnormalities in sporadic inclusion body myositis. JClin Neurosci. 2014;21:1959–1963.

118. Katsetos CD, Koutzaki S, Melvin JJ. Mitochondrial dysfunction inneuromuscular disorders. Semin Pediatr Neurol. 2013;20:202–215.

119. Boncompagni S, Moussa CEH, Levy E, et al. Mitochondrial dysfunc-tion in skeletal muscle of amyloid precursor protein-overexpressingmice. J Biol Chem. 2012;287:20534–20544.

120. Morosetti R, Broccolini A, Sancricca C, et al. Increased aging inprimary muscle cultures of sporadic inclusion-body myositis.Neurobiol Aging. 2010;31:1205–1214.

• Interesting study looking at the possible contribution of agingto the pathogenesis of sIBM.

121. Morosetti R, Gliubizzi C, Sancricca C, et al. TWEAK in inclusion-bodymyositis muscle: possible pathogenic role of a cytokine inhibitingmyogenesis. Am J Pathol. 2012;180:1603–1613.

122. Zschuntzsch J, Voss J, Creus K, et al. Provision of an explanation forthe inefficacy of immunotherapy in sporadic inclusion body myo-sitis: quantitative assessment of inflammation and beta-amyloid inthe muscle. Arthritis Rheum. 2012;64:4094–4103.

123. Kosmidis ML, Alexopoulos H, Tzioufas AG, et al. The effect ofanakinra, an IL1 receptor antagonist, in patients with sporadicinclusion body myositis (sIBM): a small pilot study. J Neurol Sci.2013;334:123–125.

124. Dalakas MC, Rakocevic G, Schmidt J, et al. Effect of alemtuzumab(CAMPATH 1-H) in patients with inclusion-body myositis. Brain.2009;132:1536–1544.

125. Schmidt K, Kleinschnitz K, Rakocevic G, et al. Molecular treatmenteffects of alemtuzumab in skeletal muscles of patients with IBM.BMC Neurol. 2016;16:48.

126. Saperstein DS, Levine TD. Interim analysis of a pilot trial of natali-zumab in inclusion body myositis. Neurology. 2015;86:161.

127. Dobloug C, Walle-Hansen R, Gran JT, et al. Long-term follow-up ofsporadic inclusion body myositis treated with intravenous immu-noglobulin: a retrospective study of 16 patients. Clin ExpRheumatol. 2012;30:838–842.

128. Pars K, Garde N, Skripuletz T, et al. Subcutaneous immunoglobulintreatment of inclusion-body myositis stabilizes dysphagia. MuscleNerve. 2013;48:838–839.

129. Cherin P, Delain J-C, de Jaeger C, et al. Subcutaneous immunoglo-bulin use in inclusion body myositis: a review of 6 cases. Case RepNeurol. 2015;7:227–232.

130. Recher M, Sahrbacher U, Bremer J, et al. Treatment of inclusionbody myositis: is low-dose intravenous immunoglobulin thesolution? Rheumatol Int. 2012;32:469–472.

131. Kierdaszuk B, Kaminska A. Inclusion body myositis: therapeuticapproaches. A case report. Neurologia I Neurochirurgia Polska.2011;45:68–73.

132. Sancricca C, Mora M, Ricci E, et al. Pilot trial of simvastatin in thetreatment of sporadic inclusion-body myositis. Neurol Sci.2011;32:841–847.

133. Machado P, Miller A, Herbelin L, et al. Safety and tolerability ofarimoclomol in patients with sporadic inclusion body myositis: arandomised, double-blind, placebo-controlled, phase IIA proof-of-concept trial. Ann Rheum Dis. 2013;72:164.

134. Ahmed M, Machado PM, Miller A, et al. Targeting protein home-ostasis in sporadic inclusion body myositis. Sci Transl Med.2016;8:331ra41.

• This was the pilot study and proof-of-principle study leadingto a larger randomized trial of arimoclomol in sIBM patients.

135. Amato AA, Sivakumar K, Goyal N, et al. Treatment of sporadicinclusion body myositis with bimagrumab. Neurology.2014;83:2239–2246.

• This was the pilot study and rationale for the multicenterinternational randomized trial.

136. Mendell JR, Rodino-Klapac L, Sahenk Z, et al. Gene therapy formuscular dystrophy: lessons learned and path forward. NeurosciLett. 2012;527:90–99.

137. Terracciano C, Nogalska A, Engel WK, et al. In AbetaPP-overexpressingcultured human muscle fibers proteasome inhibition enhances phos-phorylation of AbetaPP751 and GSK3beta activation: effects miti-gated by lithium and apparently relevant to sporadic inclusion-bodymyositis. J Neurochem. 2010;112:389–396.

138. Dimachkie MM, Barohn RJ. Inclusion body myositis. Neurol Clin.2014;32:629–46, vii.

139. Malandraki GA, Kaufman A, Hind J, et al. The effects of lingualintervention in a patient with inclusion body myositis andSjogren’s syndrome: a longitudinal case study. Arch Phys MedRehabil. 2012;93:1469–1475.

140. Oh TH, Brumfield KA, Hoskin TL, et al. Dysphagia in inclusion bodymyositis: clinical features, management, and clinical outcome. Am JPhys Med Rehabil. 2008;87:883–889.

141. Johnson LG, Edwards DJ, Walters S, et al. The effectiveness of anindividualized, home-based functional exercise program forpatients with sporadic inclusion body myositis. ClinNeuromuscular Dis. 2007;8:187–194.

142. Johnson LG, Collier KE, Edwards DJ, et al. Improvement in aerobiccapacity after an exercise program in sporadic inclusion bodymyositis. J Clin Neuromuscul Dis. 2009;10:178–184.

143. Alexanderson H. Exercise in inflammatory myopathies, includinginclusion body myositis. Curr Rheumatol Rep. 2012;14:244–251.

144. Alexanderson H, Lundberg IE. Exercise as a therapeutic modality inpatients with idiopathic inflammatory myopathies. Curr OpinRheumatol. 2012;24:201–207.

145. Alemo Munters L, Alexanderson H, Crofford LJ, et al. New insightsinto the benefits of exercise for muscle health in patients withidiopathic inflammatory myositis. Curr Rheumatol Rep. 2014;16:429.

146. Alexanderson H. Physical exercise as a treatment for adult andjuvenile myositis. J Intern Med. 2016;280:75–96.

147. Gualano B, Neves M Jr., Lima FR, et al. Resistance training withvascular occlusion in inclusion body myositis: a case study. Med SciSports Exerc. 2010;42:250–254.

148. Gualano B, Ugrinowitsch C, Neves M Jr., et al. Vascular occlusiontraining for inclusion body myositis: a novel therapeutic approach.J Vis Exp. 2010 Jun 5;(40). pii: 1894. doi: 10.3791/1894.

149. Pell M, Saththasivam P, Stephens PL, et al. Therapeutic effect ofhyperbaric oxygen on inclusion body myositis. Undersea HyperbMed. 2012;39:1111–1114.

150. Nogalska A, D’Agostino C, Engel WK, et al. Sodium phenylbutyratereverses lysosomal dysfunction and decreases amyloid-beta42 inan in vitro-model of inclusion-body myositis. Neurobiol Dis.2014;65:93–101.

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151. Diomede L, Rigacci S, Romeo M, et al. Oleuropein aglycone pro-tects transgenic C. elegans strains expressing Abeta42 by reducingplaque load and motor deficit. PLoS One. 2013;8:e58893.

152. Beckett TL, Studzinski CM, Keller JN, et al. A ketogenic dietimproves motor performance but does not affect beta-amyloidlevels in a mouse model of Alzheimer’s disease. Brain Res.2013;1505:61–67.

153. Beckett TL, Niedowicz DM, Studzinski CM, et al. Effects of nonster-oidal anti-inflammatory drugs on amyloid-beta pathology in mouseskeletal muscle. Neurobiol Dis. 2010;39:449–456.

154. Kitazawa M, Vasilevko V, Cribbs DH, et al. Immunization withamyloid-beta attenuates inclusion body myositis-like myopathol-ogy and motor impairment in a transgenic mouse model. JNeurosci. 2009;29:6132–6141.

155. Toepfer M, Fischer P, Muller-Felber W, et al. Correlation between thenumber of vacuolated amyloid-positive fibres and the duration andstage of disease in inclusion body myositis. Eur J Neurol. 1995;2:31.

• Interesting study indicating histopathologically the sequenceof changes. Further studies along this line would be interest-ing to define the earliest changes.

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