Inclusion body myositis (IBM) is a slowly progressive skeletal muscle disease with unique clinical and patho­logical features (including finger flexor and quadriceps weakness and the presence of infiltrating cytotoxic T cells in muscle). In patients with IBM, the onset of symptoms of muscle weakness typically occurs between 45 and 70 years of age, and progression is insidious. The combination of slow progression towards disability and the lack of any reliable treatment to reverse the disease course results in a substantial unmet medical need.

IBM lies within the category of inflammatory myop­athies. This category started with the single member, polymyositis, in 1887 (refs1,2) and has since undergone repeated subdivision (fig. 1). Dermatomyositis was recognized as a separate entity early in 1891 (refs3,4), but it took almost a century before the next refine­ment, IBM, was adequately recognized in 1978 (ref.5). Immune­ mediated necrotizing myopathy (IMNM) was distinguished in 1991 (ref.6). Advances continue to reduce the remaining category of polymyositis7, splitting off non­ specific myositis8 (or unclassified myositis9) and virtually eliminating the term polymyositis from what once constituted the entire category of inflammatory myopathies. The generally accepted scheme currently consists of five members (polymyositis, dermato­myositis, IBM, IMNM and non­ specific myositis)8,10 plus other rare entities (such as granulomatous myositis

and macrophagic myofasciitis). Further subdivision of dermatomyositis into distinct syndromes associated with specific autoantibodies is currently an active area of research11.

Many excellent general IBM reviews have been published over the past 5 years12–19, and some have focused specifically on the pathogenesis20,21. This Review discusses IBM generally, with a focus on some of the more confusing areas around nomenclature and clini­cal features, and addresses key questions regarding its pathogenesis.

History of IBMA historical perspective provides some insight into what has shaped our current understanding of IBM (fig. 1). It was first viewed as a form of polymyositis resulting from chronic viral infection of muscle in 1967 (ref.22), leading to an ongoing line of research directed towards the iden­tification of a persistent muscle viral infection23–26. The name inclusion body myositis is derived from a 1971 single case report entitled ‘Inclusion body myositis’27 that described a 26­year­ old patient with a limb­ girdle pat­tern of weakness and quadriceps sparing with onset at age 18 years (which is not the disease we now call IBM).

The first IBM clinical case series was published in 1978 and described patients with a distinct form of inflammatory myopathy characterized by prominent

Inclusion body myositis: clinical features and pathogenesisSteven A. Greenberg1,2,3

Abstract | Inclusion body myositis (IBM) is often viewed as an enigmatic disease with uncertain pathogenic mechanisms and confusion around diagnosis, classification and prospects for treatment. Its clinical features (finger flexor and quadriceps weakness) and pathological features (invasion of myofibres by cytotoxic T cells) are unique among muscle diseases. Although IBM T cell autoimmunity has long been recognized, enormous attention has been focused for decades on several biomarkers of myofibre protein aggregates, which are present in <1% of myofibres in patients with IBM. This focus has given rise, together with the relative treatment refractoriness of IBM, to a competing view that IBM is not an autoimmune disease. Findings from the past decade that implicate autoimmunity in IBM include the identification of a circulating autoantibody (anti-cN1A); the absence of any statistically significant genetic risk factor other than the common autoimmune disease 8.1 MHC haplotype in whole- genome sequencing studies; the presence of a marked cytotoxic T cell signature in gene expression studies; and the identification in muscle and blood of large populations of clonal highly differentiated cytotoxic CD8+ T cells that are resistant to many immunotherapies. Mounting evidence that IBM is an autoimmune T cell- mediated disease provides hope that future therapies directed towards depleting these cells could be effective.

1Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA.2Children’s Hospital Computational Health Informatics Program, Boston Children’s Hospital, Boston, MA, USA.3Harvard Medical School, Boston, MA, USA.

e- mail: sagreenberg@ bwh.harvard.edu

https://doi.org/10.1038/ s41584-019-0186-x

REVIEWS

Nature reviews | Rheumatology

quadriceps weakness and distal weakness (not specified as the wrist and finger flexor involvement now associ­ated with the disease)5; in hindsight, the authors mis­takenly used the term IBM for these patients, despite the differences in phenotype between these patients and the one in the original 1971 case report. Numerous retrospective case series studies followed in the 1980s and 1990s, emphasizing the unique distribution of IBM muscle weakness particularly in finger flexors, quadriceps and ankle dorsiflexors28–37. The past two decades have seen the publication of large amounts of cross­ sectional data38–40 addressing the clinical features of IBM, including detailed views of regional muscle involvement38,41,42. Some longitudinal data are currently available, such as paired measurements of outcome measures in 51 patients 1 year apart and in 13 patients 4 years apart41,43–47, but more data are needed.

A crucial discovery regarding IBM pathogenesis came around 1984–1988 with the identification of cytotoxic CD8+ T cells invading myofibres of patients with IBM through the application of a novel technology (mono­clonal antibody immunohistochemistry)48–51. These observations launched an ongoing line of research into IBM T cell clonality52–61, T cell differentiation phenotype (including the relationship to large granular lymphocytic leukaemia (LGLL)62–65) and therapies targeting T cells66–68.

Although the identification of unique circulating autoantibodies in polymyositis and dermatomyositis69 began in 1976 (refs70,71) and is still ongoing11,72, the rec­ognition that autoantibodies were also present in IBM was greatly delayed until 2011. The identification of molecular signatures associated with B cells and plasma cells in IBM muscle73 and the identification and char­acterization of intramuscular plasma cells74, including clonally related plasma cells (the presence of which implicates an underlying antigen­ driven process)75–77, in IBM then led to searches for circulating blood autoanti­bodies78 and the discovery of the target antigen of these antibodies, cytosolic 5′­nucleotidase 1A (cN1A; encoded by NT5C1A)79,80.

Further key events in IBM history, which are dis­cussed in more detail later, include the following: the identification of myofibre protein aggregates81 and

mitochondrial abnormalities in muscle biopsy samples of patients with IBM82, both of which seem to be second­ary to autoimmunity83–85; the recognition of the genetic linkage of IBM to the HLA region (like other auto­immune diseases)86, which was confirmed by many sub­sequent studies42,87–93 including whole­ genome studies94; the first blinded placebo­ controlled IBM therapeutic clinical trial95; studies of evidence that rimmed vacuoles are derived from myonuclei96 and their lack of necessity as biomarkers in the diagnosis of IBM9,97; and findings demonstrating the apparent ability of some sera from patients with IBM to induce muscle protein aggregation in passive transfer in vitro and in vivo animal models98.

NomenclatureSeveral similar abbreviations of other diseases have cre­ated confusion regarding IBM. IBM is an abbreviation for ‘inclusion body myositis’ not ‘inclusion body myop­athy’. The abbreviation IBM refers unambiguously to the single disease IBM, not to a collection of disparate diseases that share the microscopic histological feature of rimmed vacuoles. The rimmed vacuole myopathies include IBM but also a set of genetic non­ immune dis­orders that have been arbitrarily split off into heredi­tary inclusion body myopathies (hIBMs) (for example, disorders due to mutations in GNE, VCP or MYH2), other inherited disorders that are not viewed as forms of hIBM (such as oculopharyngeal muscular dystrophy due to PABPN1 mutations) and yet others that have been classified as hIBM by some authors but not others (for example, myofibrillar myopathy due to desmin mutations, formerly called IBM1 in OMIM99). The hIBM diseases lack the two main characteristic features of IBM: its distinctive pattern of muscle weakness and the presence of muscle histological immune cell infil­tration. Many publications have used the abbreviation IBM to refer to both IBM and hIBM; the interpretation of laboratory models of hIBM as relevant to patients with IBM is a mistake arising from this practice100.

The term sporadic IBM (sIBM) was introduced to try and avoid confusion with hIBM by emphasizing its sporadic, or non­ inherited, occurrence. However, the use of this term might give the mistaken impression that the diseases sIBM and hIBM have similar clinical and patho­logical features, representing the same pathophysiological process that can either occur sporadically or be inherited. This misconception could impede IBM research.

Familial IBM (fIBM) refers to the occurrence of typi­cal IBM within families, almost always within a single generation of siblings101–103. This pattern is analogous to the familial occurrence of many other autoimmune diseases, such as myasthenia gravis and multiple scle­rosis, and probably results from the associated genetic risk from HLA variants present in IBM and common to many autoimmune diseases.

Clinical features of IBMEpidemiology and economic costsCalculations of the prevalence of IBM are probably underestimates because of the high rate of misdiag­nosis. In a rigorous meta­ analysis published in 2017, the pooled prevalence of IBM was 46 patients per million104.

Key points

•Inclusionbodymyositis(IBM)progressesslowlyandiscommonlymisdiagnosedinitiallyasarthritisorpolymyositis;IBMisassociatedwithcardiovascularcomplicationsandotherautoimmunediseasesandhasahigheconomiccost.

•IBMhasuniquephysicalexaminationfeatures(suchasfingerflexorandkneeextensorweakness)thatdistinguishitfrommostothermusclediseases.

•IBMhasagreaterrangeofautoimmuneT cellabnormalitiesthananyothermuscledisease;treatmentrefractorinesshasparadoxicallygivenrisetotheviewthatIBMisnotanautoimmunedisease.

•DegenerativeabnormalitiesthatcanoccurinIBMincludenumerousmyofibreproteinaggregatesassociatedwithendoplasmicreticulumstress.

•DegenerativeabnormalitiesmightoccurfollowingautoimmunityincellcultureandmousemodelsandfollowingimmunecelldysfunctioninpatientsinfectedwithHIVorhumanT celllymphotropicvirustype1.

•TreatmentrefractorinessprobablyreflectstheinabilityofcurrenttherapiestoinhibitordepletethehighlydifferentiatedpopulationofeffectormemoryandterminallydifferentiatedeffectorT cellspresentinIBM.

www.nature.com/nrrheum

R e v i e w s

The results of this study suggest a sharp increase in IBM prevalence over the past decade, probably owing to improved ascertainment105, with the first published estimate of IBM in 2000 (from a nationwide study in the Netherlands) being 5 per million106 and the most recent estimate in 2017 (from a population­ based study in Ireland) being 112 per million107.

Typical estimates of the mean age of IBM symp­tom onset range from 61 to 68 years39,105,108–110. IBM is often viewed as affecting people >50 years old; however, a substantial proportion (20%38) of patients develop symptoms in their forties. The reported male­ to­female gender ratio varies widely from 0.5 (ref.111) to 6.5 (ref.35) (mean of 1.6). IBM is initially misdiagnosed as another condition in 40–53% of patients42,110,112, and the mean duration from symptom onset to correct diagnosis is 4.6–5.8 years42,109,110,112,113.

Before 2010, no International Classification of Diseases, Ninth Revision, Clinical Modification (ICD­9CM) code existed for IBM, making estimates of the prevalence and health­ care costs from US medical pay­ment databases impossible. In 2018, the use of this code

to estimate US health­ care costs for patients with IBM and Medicare coverage suggests annual costs of 35,000 US dol­lars per year in excess of the costs of matched controls and a prevalence of 84 per million in people >65 years of age114.

Clinical featuresIBM typically presents in middle or late age with slowly progressive, painless difficulty walking or using the hands. Walking difficulties typically result from knee buckling, owing to knee extensor weakness, or tripping owing to ankle dorsiflexion weakness. Grip impairment results from finger flexor weakness. Symptoms are often initially attributed to age or arthritis; when a neuromus­cular disease is recognized, a diagnosis of polymyositis or, less often, motor neuron disease is more typical than an immediate recognition of IBM. Muscle pain is very uncommon in IBM42,97.

Dysphagia (difficult swallowing) is an underestimated component of IBM115 and is under­ reported as a present­ing symptom42,116 but is commonly present if sought by history or radiological studies116,117. Dysphagia becomes more evident as the disease progresses and might

1887 1891 1978 1991 2018

Name ‘IBM’ used in case report

First description of IBM pathology

Identification of cytotoxic CD8+ T cells using immunohisto-chemistry

First clinical andpathological case series description

Origin of β-amyloid theory

Identification of Congo red protein aggregates in 0.5% of myofibres

First blinded placebo controlled trial (IVIG)

Recognition of mitochondrial abnormalities

Recognition that rimmed vacuoles are commonly absent in IBM muscle

Identification of B cell role using microarray technology

Identification of a IBM-associated circulating autoantibody

Recognition of highly differentiated effector and effector memory CD8+ T cells in IBM muscle and blood overlapping with T-LGLL

Identification of the molecular target (cN1A; NT5C1A) of the IBM circulating autoantibody

Muscle protein aggregation is secondary to immune system MHC I upregulation in murine models

Genome-wide studies confirm linkage to common autoimmune disease haplotype

1887 1891 1967 1971 1978 1984 1991 1992 1993 1997 2002 2008 2010 2011 2013 2016 2017 2018

CD28+ (CD244–) highly differentiated cytotoxic CD8+ T cell identified

PMDM

PM

DM

IBM

PM

DM

IBM

IMNM

PM

DM

IBM

IMNM

Non-specific

PM

Fig. 1 | evolution of inflammatory myopathy classification and history of IBm. The upper timeline shows the key events in the history of inclusion body myositis (IBM). The lower timeline shows the progressive subdivision of the category polymyositis (PM) over time and current ongoing subcategorization of dermatomyositis (DM). IMNM, immune- mediated necrotizing myopathy ; IVIG, intravenous immunoglobulin; T- LGLL , T cell large granular lymphocytic leukaemia.

Nature reviews | Rheumatology

R e v i e w s

result in nutritional deficiency, weight loss and aspira­tion pneumonia, which is a major cause of mortality in IBM40,43,118. Cricopharyngeal sphincter dysfunction can be present116, and cricopharyngeal muscle biopsy sam­ples might show similar histological features to those of limb muscle biopsy samples119,120. Asymptomatic respiratory function impairment and sleep­ disordered breathing are common121.

IBM has unique physical examination features whose lack of recognition largely contributes to the high initial misdiagnosis rate (fig. 2a–e). The value of these physical examination features is sufficiently high that, when prop­erly appreciated, the additional value of muscle histo­pathology for a diagnosis of IBM is questioned122. There is preferential involvement of muscles controlling finger flexion, knee extension and ankle dorsiflexion with less involvement of the muscles that are typically affected in other acquired myopathies, such as those controlling proximal shoulder abduction, hip flexion and hip abduc­tion. This pattern of IBM is often referred to as distal, but this term might be confusing because truly distal hand muscles, such as the intrinsic muscles mediating finger abduction and adduction, are relatively spared in IBM.

A number of helpful physical examination findings greatly facilitate the diagnosis of IBM (fig. 3). These find­ings include the following: orbicularis oculi weakness (41% in one series)38; greater weakness of elbow flex­ion (controlled by the biceps) than shoulder abduction (controlled by the deltoids); greater weakness of flexor digitorum profundi than flexor digitorum superficialis (the muscles of the forearm that control finger flexing) and greater weakness of digit five (little finger) than digit

two (index finger)36; preservation of the adductor pollicis (the muscle that controls opposition of the thumb to index finger in the plane of the hand); and preservation of hip abduction42 and adduction even in patients with complete loss of knee extensor muscles. Complete paraly­sis of all deep and superficial finger flexors with preser­vation of the adductor pollicis and lumbricals (muscles of the hands that flex the metacarpophalangeal joints)38 results in the common end­ stage IBM hand appear­ance, allowing patients to grasp objects through thumb adduction and finger flexion at the metacarpophalan­geal joints (fig. 2b). Ventral forearm atrophy (fig. 2c), although striking in later disease stages, is often hard to recognize during the early stages of disease. Knee exten­sor weakness often requires functional testing, such as deep knee bends, hopping on one leg or climbing stairs, to detect. Among the quadriceps, the vastus medialis (and vastus lateralis) is affected considerably sooner than the rectus femoris (fig. 2d); thus, direct palpation of the medial thigh during attempted knee extension against resistance is an extremely helpful technique to detect its involvement.

Beyond physical examination, MRI can reveal charac­teristic regional muscle involvement37,123–128. For example, in patients with remarkable quadriceps muscle atrophy but only mild knee extensor weakness owing largely to the relative preservation of the rectus femoris in the early stages of disease, muscle loss is still detectable by MRI (fig. 2e). Ultrasonography might show similar regional muscle involvement129–132. Videofluoroscopy and real­ time MRI frequently show abnormalities related to dysphagia115,116,118,133.

Normal

IBM

a

c d e

b

Fig. 2 | IBm physical examination and imaging features. a,b | Weakness of finger flexion in patients attempting hand grip with partial involvement (part a) and end- stage (part b) inclusion body myositis (IBM). Relative preservation of lumbricals enables flexion at metacarpophalangeal but not interphalangeal joints. Subtle finger flexion weakness is often present at earlier stages of disease. c | Ventral forearm flexor muscle atrophy (arrows). d | Medial thigh atrophy (arrows). e | Thigh axial proton density fast spin echo MRI, with abnormal muscle signal due to fibrosis, highlighted in vastus medialis (arrows). Panels a–d reprinted with permission from the Inclusion Body Myositis Foundation.

www.nature.com/nrrheum

R e v i e w s

Abnormal laboratory test results typically include modest increases in serum levels of creatine phospho­kinase in most patients and a monoclonal immuno­globulin population (by serum immunofixation) in ~15% of patients97,134. Antinuclear antibodies, anti­ Ro or anti­ La antibodies, and rheumatoid factor positiv­ity might also be evident97. Testing for anti­ cN1A (also called anti­ NT5C1A) autoantibodies is helpful. Testing for HIV and human T cell lymphotropic virus type 1 (HTLV­1) might be considered in particular circum­stances, such as young age of IBM onset or the pres­ence of factors that suggest an underlying increased risk of being infected with HIV or HTLV­1. Additional blood biomarkers of highly differentiated CD8+ T cells (CD8+CD57+ T cells by flow cytometry, a reduced CD4:CD8 blood ratio and lymphocytosis evident on complete blood count differential)64 are the most common of all blood abnormalities in IBM but await further studies of their clinical utility.

Anti- cN1A autoantibodySerum anti­ cN1A antibodies are highly specific to IBM among the neuromuscular diseases and are seen in 90–95% of patients with IBM compared with 5–10% of patients with polymyositis, dermatomyositis or non­ immune neuromuscular diseases79,80,135–138. Accordingly, a positive test result in a patient with a muscle disease is highly predictive of IBM. However, the diagnostic sen­sitivity of anti­ cN1A antibody assays for IBM has varied widely79,80,135–140, ranging from 37%140 to 76%135, and is

probably the result of the varying methods of testing that have been used. Thus, a negative test should not be used to diminish confidence in the diagnosis of IBM. More controversial is the prevalence of anti­ cN1A antibodies in non­ neuromuscular autoimmune diseases, which will affect the diagnostic specificity of such assays for IBM. Different laboratories have found a widely varying preva­lence of these antibodies in systemic lupus erythematosus (0–20%) and Sjögren syndrome (0–36%)98,137,138,140–142.

Microscopic pathologyThe standard microscopic pathological findings in IBM are endomysial lymphocytic infiltration (fig. 4a), with lymphocytes surrounding and occasionally invading myofibres (fig. 4a,b). When phenotype is determined by immunohistochemistry, most lymphocytes are CD8+ T cells (fig. 4c). A small number of myofibres contain rimmed vacuoles (0.4–6.4%)81,96,143 (fig. 4d) and mitochondrial abnormalities, such as the pres­ence of COX−SDH+ and ragged red myofibres (fig. 4e). Haematoxylin and eosin staining and trichrome stain­ing show variation in fibre size, centralized nuclei and type 2 fibre atrophy and, occasionally, cytoplasmic inclusions. Electron microscopy or light microscopic examination of glutaraldehyde­ fixed, semithin sections often shows cytomembranous whorls and, less com­monly, tubulofilaments, within 2–6% of myonuclei144. Immunohistochemical stains for MHC class I and MHC class II show diffuse myofibre surface staining and, sometimes, punctate cytoplasmic staining, but MHC class I staining has been reported to be highly non­ specific (present in 93% of biopsy samples from patients with non­ inflammatory myopathies), with MHC class II staining being more specific to inflammatory myopa­thies145. Other special stains can demonstrate protein aggregates (such as TDP43, fig. 4 f).

A pathological diagnosis of IBM is often not made without the presence of rimmed vacuoles, although they are absent in 20% of patients with typical clinical features97,146. The clinical course for patients with and without rimmed vacuoles seems to be similar97, but one study has suggested a more aggressive course in patients with rimmed vacuoles147. Some authors have preferred to split IBM into two categories, classifying patients without rimmed vacuoles as having polymyositis with mitochondrial pathology (PM­ Mito), and view IBM and PM­ Mito as part of a broader category of inflammatory myopathy with vacuoles, aggregates and mitochondrial pathology (IM­ VAMP)148. The observation that patients with typical treatment­ responsive polymyositis might also have rimmed vacuoles has been little emphasized149.

Diagnostic criteriaVarious diagnostic criteria for IBM were proposed from 1987 to 2002 through individual author opin­ion31,150–152 and from 1995 to 2013 by consensus expert opinion106,153–157. Criteria based on expert opinion have been standard in the field, although studies evaluating their performance were lacking before 2013. Subsequent studies have disclosed major limitations in the diagnos­tic sensitivity of these criteria, with many patients with IBM failing to meet them122,158. In particular, the criteria

Front view Back view

Muscles preferentially affected in IBMMuscles preferentially affected in other inflammatory myopathiesMuscles commonly affected in both

Ankledorsiflexion

Hip abductionand extension

Wristflexion

Kneeextension

Shoulderabduction

Hipflexion

Fingerflexion

Elbowflexion

Elbowextension

Fig. 3 | Pattern of muscle involvement in IBm and other inflammatory myopathies. Weakness of finger flexion, knee extension and ankle dorsiflexion is characteristic of inclusion body myositis (IBM) with less involvement of muscles typically affected in other acquired myopathies, such as proximal shoulder abduction, hip flexion and hip abduction.

Nature reviews | Rheumatology

R e v i e w s

for the detection of rimmed vacuoles by microscopy, often referred to as biopsy­ proven IBM, can be restric­tive9,122,158. Criteria with sensitivity of 90% and speci­ficity of 96% were derived through machine learning approaches; these criteria included the presence of the following: finger flexor or quadriceps weakness, biopsy sample demonstrating endomysial inflammation and biopsy sample demonstrating invasion by T cells of non­ necrotic muscle fibres or rimmed vacuoles158. The use of blood testing for anti­ cN1A autoantibodies has not yet been incorporated into diagnostic criteria.

Associated disorders and comorbiditiesIBM is associated with another autoimmune disease in 13–24% of patients97,109,134, most commonly Sjögren syndrome (10–12%)91,109,159–161. A surprising number of patients with IBM (58% in one series) meet the diagno­stic criteria for LGLL, and a small number have overt leukaemia with cytopenias64.

IBM might develop from HIV162–165 and HTLV­1 (refs164,166) infection, resulting in a typical disease course except for a younger age of onset. HIV­ associated myositis has been categorized as either polymyositis or IBM. Patients with HIV­ associated myositis might show improved strength of proximal muscles as a result of treatment162,163, but in a study of 11 patients with HIV­ associated myositis, all subsequently developed treatment­ refractory IBM162.

The prevalence of some comorbidities, such as cardiovascular disease and diabetes mellitus, in IBM seemed to be high in a number of population­ based cohort and case series studies that lacked comparator groups (for example, 65% of patients had hypertension and 24% had diabetes mellitus in one study population of patients with IBM)109,167,168. A matched case–control

Medicare database study reported a higher preva­lence of comorbidities in patients with IBM than in matched patients without IBM114, with increased rates of hypertension (66% versus 22%), hyperlipidaemia (47% versus 18%), diabetes mellitus (34% versus 10%), myocardial infarction (13% versus 2%), congestive heart failure (17% versus 5%), pneumonia (11% ver­sus 2%; aspiration pneumonia, 6% versus 0.3%) and anaemia (32% versus 7%). These IBM comorbidities do not seem to be a consequence of complications of immunosuppressant therapy, such as corticoste­roids114, and are probably instead related to the systemic inflammatory environment resulting from autoimmun­ity, as in other forms of inflammatory myopathy168–173 and other autoimmune diseases174,175.

ProgressionIBM is a progressive disease, with mean or median loss of device­ free ambulation from symptom onset esti­mated at 7.5–10 years for a cane42,44 and 13–15 years for a wheelchair38,39,44. Hand impairment and dyspha­gia progression are less well quantified. Published longitudinal data regarding IBM progression are insuf­ficient41,43–47, and non­ uniform methods have been used to measure it. Furthermore, published annualized rates of progression of 4–28% per year41,43–47,53 are specific to the outcome measure used, such as quantitative muscle testing, and assume linearity over time. Some patients experience very little or no disease progression over periods of time ranging from 4 years45 to 12 years43.

Although IBM has been characterized as not fatal because statistical analyses of IBM populations have not detected a reduction in life expectancy39, it is a cause of premature mortality in some patients, most directly from aspiration pneumonia40,43,118.

12

20 µm 20 µm

20 µm 20 µm 10 µm

a b c

d e f

20 µm

Fig. 4 | IBm muscle pathology. a | Infiltration of muscle endomysium by immune cells (arrow) visualized by haematoxylin and eosin staining. b | Deep invasion of non- necrotic myofibre by immune cells (arrow) visualized by haematoxylin and eosin staining. c | Many invading immune cells are CD8+ cytotoxic T cells (arrow), as visualized by staining for CD8. d | Rimmed vacuoles (arrows) in trichrome stained sections. e | Ragged red fibre (a mitochondrial abnormality) (arrow) visualized by haematoxylin and eosin staining. f | TDP43 sarcoplasmic aggregates (red and arrow) visualized by immunofluorescence. The myofibre labelled 1 contains numerous sarcoplasmic aggregates; the myofibre labelled 2 has normal TDP43 localization to the myonuclei (blue). IBM, inclusion body myositis.

www.nature.com/nrrheum

R e v i e w s

IBM therapeuticsStandard of care for most patients with IBM involves strictly nonpharmacological management, includ­ing emotional support, physical therapy, education on fall precautions and exercise176–178, and dyspha­gia evaluation. Dysphagia can be treated transiently with pharyngoesophageal dilatation or cricopharyn­geal myotomy118. Few physicians routinely prescribe immunosuppressant therapies, with the belief that such therapies result in transient responses at best14,38,97.

Expert opinion and open- label trialsThe use of corticosteroids in IBM derives from expert opinion. Corticosteroids decrease serum levels of cre­atine phosphokinase, which is sometimes mistaken for a clinical response; however, the disease continues to progress in almost all patients32. Some patients with substantial proximal weakness, an atypical phenotype, do experience improvement in proximal strength32. A view that corticosteroids might even worsen IBM has been suggested on the basis of retrospective cross­ sectional data in which there were more patients with severe disease in a treated cohort than there were in an untreated cohort. However, this view is compli­cated by an uncontrolled confounder — the treated cohort also had substantially longer duration of disease diagnosis than the untreated cohort (50 months versus 18 months)39. The marked type 2 muscle fibre atrophy present in IBM179 is expected to worsen with cortico­steroid treatment and is another theoretical argument against its use.

Broad lymphocyte depletion strategies achieved statistical efficacy for strength measurements in two open­ label comparator group studies: antithymocyte globulin (ATG) with methotrexate compared with methotrexate alone (P = 0.02)66 and alemtuzumab67 compared with baseline (pretreatment; P < 0.002). Intravenous immunoglobulin (IVIG) or subcuta­neous immunoglobulin (SCIG) has been reported to be helpful specifically for patients with IBM­ associated dysphagia180–182. Results of an open­ label trial of three combined interventions (follistatin gene therapy, pred­nisone and exercise) were published as an interim analysis; somewhat controversially, the efficacy was attributed to follistatin gene therapy alone despite being tested only in combination183,184. An open­ label trial of exercise alone has demonstrated statistical efficacy for strength measurements178.

Blinded placebo- controlled trialsAlthough the literature is filled with the view that IBM is treatment refractory, high­ quality data on therapy for IBM are very limited, with published blinded placebo­ controlled clinical trials for only five FDA­ approved therapeutics (IVIG with and without prednisone95,185,186, methotrexate187, IFNβ188,189 and oxandrolone190) and two investigational therapeutic candidates (bimagrumab191 and arimoclomol100) (Table 1).

Oral methotrexate, 5–20 mg daily for 1 year, showed a directional trend towards benefit but no statistical efficacy187. Dysphagia was not assessed in this trial. Of three trials of IVIG of 3–6 months treatment duration,

one showed directional trends towards minor benefit in limb and swallowing muscles, with some statistical effi­cacy95, and the other two (one that included prednisone, which might have been counterproductive) showed no directional trend or statistical benefit in limb or swallow­ing muscles185,186. For such a slowly progressive disease, 3–6 months of therapy seems insufficient for a clinical trial efficacy end point. Preliminary results of a trial of rapamycin have been reported in an abstract68.

Trials of two muscle­ building therapies (oxandro­lone and bimagrumab), neither of which addresses the specific mechanism of myofibre injury, have shown some statistical benefits. Oxandrolone190 showed statis­tical efficacy for multiple end points. In a small study (n = 14)191, bimagrumab showed improvement in skeletal muscle mass. In a registration trial (n = 240)192 presented in abstract, bimagrumab again showed improvement in whole­ body skeletal muscle mass and in a patient­ reported secondary outcome measure, but no statis­tical efficacy in the primary outcome measure (the 6­minute walk distance). A trial of arimoclomol did not achieve proof of concept of the hypothesized mechanis­tic effect (increase in muscle levels of HSP70) or show clinical efficacy100.

Pathogenesis of IBMNo feature of IBM has generated more debate and speculation than the nature of its pathogenesis. IBM is often viewed as both a degenerative and an autoimmune disease. A number of perspectives have shaped these views and are addressed here.

Degenerative biomarkers and mechanismsVarious IBM muscle histochemical abnormalities have collectively been called degenerative (fig. 5). However, referring to IBM as a degenerative disease does not pro­vide information on the mechanisms by which the mus­cle is injured. The degenerative features of IBM include rimmed vacuoles and the related myonuclear degener­ation5,193, mitochondrial pathology82,194,195 and myofibre cytoplasmic protein aggregates.

The concept of protein aggregation has dominated mechanistic thought since the early 1990s, with inter­est initially focused on four muscle biomarkers (amy­loid detected by Congo red81, ubiquitin196, β­ amyloid197 and tau198). The number of distinct molecules reported as aggregated grew to >80 by 2010 (ref.199). A the­ory of β­ amyloid accumulation and myotoxicity has dominated144,200–202 and continues to be featured in con­ceptual models of IBM10. In hindsight, a published belief in this theory now seems to be out of proportion to the data supporting it. Indeed, citation distortions in its cita­tion network might have contributed to overvaluing the role of β­ amyloid deposition in IBM pathogenesis203,204. The supporting data were based on methods (immuno­histochemistry) and reagents (anti­ β­amyloid antibodies) that do not distinguish β­ amyloid from its precursor pro­tein203, the latter reported as non­ specifically expressed in regenerating myofibres in all muscle diseases205. Similar interest in tau protein deposits (using SMI­31 immuno­reactivity) also occurred206 and has similar limitations207. Focus on these biomarkers proceeded for decades despite

Nature reviews | Rheumatology

R e v i e w s

studies demonstrating their rarity or non­ existence in IBM muscle (for example, the presence of Congo red amyloid in 0.4% of myofibres208, ubiquitin in 0.7% of myofibres209 and β­ amyloid in 0% of myofibres210).

A second generation of muscle histochemical degen­erative biomarkers (p62, LC3 and TDP43 (refs211,212)) has evolved around the unfolded protein response and endo­plasmic reticulum (ER) stress213, altered autophagy214,215 and mislocalized myonuclear heterogeneous nuclear ribonucleoproteins (hnRNPs)216–218. Some of these studies have combined immunohistochemical results with western blots (TDP43 (refs217,218) and p62 (ref.219)). Furthermore, results have been reproduced by multiple independent laboratories, with quantitative data show­ing superior biomarker performance compared with Congo red amyloid, ubiquitin, β­ amyloid or SMI­31

immunoreactivity. For example, one comparative study found TDP43 aggregates in 23% of IBM myofibres compared with Congo red amyloid in 0.6%, SMI­31 in 0.8% and β­ amyloid in 0%218. Another study found both p62 and TDP43 aggregates in 12% of IBM myo­fibres compared with ubiquitin in 1.1% and β­ amyloid in 0.1%211. p62 and TPD43 aggregates are rarely seen in non­ IBM autoimmune muscle disease, suggesting that these second­ generation biomarkers have some value in the study of IBM.

Autoimmune biomarkers and mechanismsT cells. T cells, myeloid dendritic cells, macrophages and plasma cells all invade IBM muscle (fig. 5), but it is the infiltration of muscle by T cells that is the most obvi­ous histological feature of IBM muscle. The invasion of

Table 1 | IBm clinical trials

therapeutic year of clinical trial registration

year of publication

Number of patients

Duration of treatment (months)

outcome measures: primary (secondary)

Refs

Open- label studies

Azathioprine + methotrexate + intravenous methotrexate

NA 1993 11 3–6 MMT 296

IVIG NA 1993 4 2 Muscle strength 297

1994 9 1–3 MMT 298

Prednisone NA 1995 8 6–12 Muscle strength 299

Antithymocyte globulin + methotrexate versus methotrexate alone

NA 2003 11 12 QMT 66

Etanercept NA 2006 9 17 QMT 300

Anakinra NA 2013 4 5–12 MMT (Grip) 301

Alemtuzumab 2004 2009 13 12 QMT (MMT) 67,302

Lithium 2008 NA 20 6 QMT (MMT) 303

Follistatin gene therapy + prednisone + exercise

2012 2017 6 24 Safety (6MWD) 183,304

Natalizumab 2013 NA 6 6 Safety (Biopsy) 305

Bimagrumab 2014 NA 14 40 Safety (DEXA) 306

Blinded placebo- controlled studies

IVIG NA 1997 19 3 QMT (MMT) 95

2000 22 6 MMT (NSS) 185

IVIG + prednisone NA 2001 37 3 QMT (MMT) 186

Low- dose IFNβ1a NA 2001 30 6 QMT (MMT) 188

High- dose IFNβ1a NA 2004 30 6 QMT (MMT) 189

Oxandrolone NA 2002 19 6 QMT (MMT) 190

Methotrexate NA 2002 44 11 QMT (MMT) 187

Etanercept 2005 NA 20 12 QMT (MMT) 307

Arimoclomol 2008 2016 24 4 Safety (QMT) 100,308

Bimagrumab 2011 2014 14 6 MRI (QMT) 191,309

2013 NA 240 12 6MWD (sIFA) 310

Rapamycin 2015 NA 44 12 QMT (grip QMT) of quadriceps

311

Arimoclomol 2016 NA 150 20 IBMFRS (MMT) 312

6MWD, 6-minute walking distance; DEXA , dual- energy X- ray absorptiometry ; IBMFRS, inclusion body myositis functional rating scale; IVIG, intravenous immunoglobulin; MMT, manual muscle testing; NA , not applicable; NSS, neuromuscular symptom score; QMT, quantitative muscle testing; sIFA , sIBM functional assessment.

www.nature.com/nrrheum

R e v i e w s

myofibres by cytotoxic T cells is easily visible by micros­copy. IBM might be the only muscle disease involving cytotoxic T cell­ mediated myofibre injury; although polymyositis has been said to share this feature, con­siderable scepticism exists regarding this view9,220, in part because of the historical misdiagnosis of IBM as polymyositis or the evolution of patients with partially responsive polymyositis into treatment­ refractory IBM over time. In IBM, there is an estimated fivefold greater preponderance of endomysial CD8+ T cells than CD4+ T cells in muscle48–51. Numerous studies have reported clonal expansion of these T cells in the muscle and blood of patients with IBM52–61, indirectly providing evidence that T cells are targeting some unknown antigens, and studies of T cell phenotype have found that T cells in both the muscle and blood of patients with IBM have expanded repeatedly and have been driven into a highly differentiated state62–65.

In IBM, CD4+ and CD8+ T cells are driven into highly differentiated effector cells in muscle62,64 and in blood62–64 (fig. 6). These highly differentiated populations of T cells have been reported in IBM using various overlapping markers, such as the loss of CD28 (CD28−; CD28 null) on CD4+ and CD8+ T cells62,63, the loss of CD62L on CD45RA+ T cells63 and the gain of CD244 (ref.62), CD57 (ref.64) and KLRG1 (S.A.G., unpublished observations) on CD8+ T cells. These subpopulations of cells are composed

of the effector memory T (TEM) cell and terminally differ­entiated effector memory T (TEMRA) cell populations and are sometimes characterized as senescent or of having a senescence­ associated secretory phenotype221, terms that obscure their aggressive cytokine secreting and cyto­toxic capacities222–225. CD8+CD28− T cells in IBM blood are major producers of IFNγ63. Highly differentiated CD4+ T cells that have lost CD28 expression are no longer helper T cells but instead have become cytotoxic killer cells226,227, and levels of these cells are known to be increased in other autoimmune diseases228–236. Highly dif­ferentiated CD8+ T cells express high levels of cytotoxic molecules (such as perforin and granzymes) and overlap phenotypically and functionally with natural killer cells. CD8+ T cell loss of CD5 expression and evolution into natural­ killer­like T cells that express CD16 or CD56 are common in IBM blood64 and suggest that, in IBM muscle, T cell cytotoxic injury to myofibres occurs independently of antigen recognition through CD3 or costimulation through CD28. These T cell phenotypic changes are also seen in T cell LGLL (T­ LGLL), a treatment­ refractory expansion of clonal highly differentiated effector CD8+ T cells237.

Plasma cells and autoantibodies. Circulating autoanti­bodies have been known to be present in polymyosi­tis and dermatomyositis for >40 years69–71. However, an autoantibody in IBM was recognized only in 2011 (ref.78). This delay was probably related to the early observations that, in IBM muscle, only sparse numbers of CD20+ endomysial B cells (0.5%) were present, com­pared with the large numbers of T cells (75%)48, com­bined with the popularity of the degenerative model of IBM. The application of newly invented gene expression microarray profiling to IBM muscle in 2002 provided an opportunity for non­ hypothesis­driven research — to examine IBM muscle globally without bias. These studies unexpectedly demonstrated robust production of immunoglobulin transcripts73, which could only be coming from intramuscular plasma cells74. The pau­city of CD20+ B cells in IBM muscle seems to be the result of an intense autoimmune environment causing antigen­ driven transformation of CD20+ B cells into CD19+ plasmablasts and clonal CD138+ plasma cells75–77. Recognition of this pathway facilitated the identifica­tion of circulating blood autoantibodies78 and the target antigen of these autoantibodies, cN1A (NT5C1A)79,80.

Genetics. Strong genetic linkage of IBM has been estab­lished exclusively to immune gene variants, specifi­cally to HLA­ DRB1*03:01 and HLA­ B*08:01, both of which are part of the common autoimmune disease 8.1 ancestral MHC haplotype42,86–93, and to the chemokine receptor CCR5 gene. A variant in TOMM40, encoding a mitochondrial protein, has been found to influence age of onset238,239 and perhaps disease risk238.

Chemokines and cytokines. IBM muscle is highly enriched with many secreted immune chemokines and cytokines that are difficult to measure at the protein level240,241 but whose transcripts can be detected through microarray experiments73. The marked elevation

• Rimmed vacuoles• Myonuclear degeneration• Mitochondrial pathology• Protein aggregates

Infiltrating cells• T cells (mainly CD8+ cytotoxic T cells)• Plasma cells• Macrophages• Myeloid dendritic cells

Autoimmune features Degenerative features

Healthy IBM

InfiltratingT cells

Proteinaggregate

Musclefascicle

Vacuole

Capillary

PerimysiumEndomysiumMuscle fibre

Fig. 5 | IBm muscle inflammation. Inclusion body myositis (IBM) shows features of an autoimmune disease with protein aggregates. Immune cells present in the endomysial region surround and invade myofibres; infrequent myofibres contain rimmed vacuoles (~1%) or p62 and TDP43 protein aggregates (~10%).

Nature reviews | Rheumatology

R e v i e w s

of levels of CXCL9 and CCL5 (ref.73) in the muscle strongly suggests upstream T cell activation and IFNγ production. The expression of genes encoding members of the IFNγ signalling cascade (the IFNγ signature) is higher in myofibres invaded by CD8+ T cells than in non­ invaded myofibres242.

Is IBM an autoimmune disease?IBM has sometimes been viewed as not being an auto­immune disease202, or the autoimmunity is viewed as being a secondary phenomenon. Some reviews have classified it as a non­ immune myopathy or excluded it from discussions of autoimmune myopathies243–245. Yet the magnitude of expression of numerous biomark­ers of T cell autoimmunity is far higher in IBM muscle than in any other muscle disease, including other forms of myositis. These markers include an abundance of T cells (particularly CD8+ cytotoxic T cells), the cytotoxic molecules granzymes and perforin and an abundance of T cell­ related chemokines and cytokines.

The invasion of non­ necrotic muscle fibres by cyto­toxic T cells has long been a diagnostic feature of IBM; invaded fibres were found to be approximately eight times more common than myofibres containing amyloid (detected by Congo red)208. By contrast, the harmful effect of protein aggregates on myofibres is speculative. Over the past 5 years, IBM has joined the ranks of other forms of myositis with autoantibody biomarkers through the iden­tification of a circulating IBM autoantibody (anti­ cN1A). As we are now in the era of whole­ genome sequencing, the lack of any causative gene mutation in patients with IBM has virtually eliminated the possibility that it is an unrecognized Mendelian genetic disorder and further­more has disclosed strong linkage to the HLA region, viewed by some as providing the strongest evidence to date that autoimmunity is causative in IBM246.

Evidence for causality in IBMAlthough IBM degenerative and autoimmune biomark­ers are associated, establishing causality will ultimately require human clinical trials of mechanistically unam­biguously specific interventions. Currently, the evidence suggests that causality flows from autoimmunity to degeneration, not the reverse (fig. 6).

First, genetic diseases with biomarkers of degener­ation do not result in autoimmunity. Although most of the >80 proteins that aggregate in IBM muscle have also been reported to aggregate in hIBM, these diseases do not manifest autoimmunity. Specifically, TDP43, p62 and ubiquitylated protein aggregates are prominent in biopsy samples from patients with genetic myotilinopathies and desminopathies247,248 and VCP­ mutation hIBM217 with­out autoimmunity. Vacuolar myopathy produced by colchicine or hydrochloroquine in patients is associated with ER stress and with p62 and LC3 aggregates249, but not autoimmunity. Some genetic muscular dystrophies, particularly facioscapulohumeral muscular dystrophy and dysferlinopathies, have inflammation, but only necrotic myofibres are invaded and only by macrophages (which are CD4+) and perhaps CD4+ T cells250,251. Many other genetic disorders have mouse models demon­strating impaired autophagy, with p62 and LC3 mouse

Endothelium

Blood Chronic stimulation

Clonal highlydifferentiatedcytotoxicT cells

Naive ormemoryT cells

TCR CD28

CD4+ T cell CD8+ T cell

IFNγ

Circulating T cellsmight lead to otherautoimmune features

• Treatment refractory• Leukaemia-like phenotype• Loss of CD28 expression• Gain of expression of CD57, CD244 and KLRG1

MHCclass I

Myofibre

• ER stress• Protein aggregation

↑ MHCclass I

Myofibre damage

Cytotoxicgranules

Fig. 6 | Proposed pathogenesis of IBM: highly differentiated cytotoxic T cells drive IBm myofibre injury. Chronic antigenic stimulation of T cells results over time in transformation of naive or early effector memory T cells (TEM1 and TEM2 cells) into a highly differentiated population of clonal cytotoxic CD8+ T cells (TEM3, TEM4 and terminally differentiated (TEMRA) cells), identified by CD8+CD28−, CD8+CD244+, CD8+CD57+ or CD8+KLRG1+) and CD4+ T cells (CD4+CD28−) present in inclusion body myositis (IBM) muscle and blood. These late stage T cells have the following features: they are highly cytotoxic and have escaped requirements for costimulation (for example, loss of CD28); they invade myofibres and injure them through release of cytotoxic granules (such as perforin and granzymes); and they produce abundant IFNγ, which results in upregulation of MHC class I on myofibres and causes endoplasmic reticulum (ER) stress and aggregation of proteins (including p62 and TDP43). These highly differentiated CD8+ T cells have similar features to those present in large granular lymphocytic leukaemia, including resistance to corticosteroids. Furthermore, some patients with IBM have features of disease other than just muscle manifestations, such as autoimmune features in bone marrow (cytopenias) or epithelial secretory tissue (Sjögren syndrome). TCR , T cell receptor.

www.nature.com/nrrheum

R e v i e w s

muscle aggregates without autoimmunity252. Similarly, the strong correlation between IBM muscle mitochon­drial patho logy (number of COX­ deficient myofibres) and auto immunity (number of invading T cells)85 sug­gests that the mitochondrial pathology results from autoimmunity, as muscle genetic mitochondrial myopa­thies do not produce autoimmunity. Dermatomyositis, which is also autoimmune, is similarly accompanied by mitochondrial abnormalities253,254.

Second, intervention studies show that manipulat­ing the immune system can produce skeletal muscle and other cellular protein aggregate biomarkers. Thus, in vitro treatment of cultured human myoblasts with cytokines (IL­1β and IFNγ) produces protein aggre­gates83, treatment of various mouse cells with IFNγ causes ubiquitylated inclusions255,256, and forced overex­pression of MHC class I in mouse muscle cells causes ER stress257. Inflammatory stimuli (lipopolysaccharide) cause in vitro cytoplasmic mislocalization of TDP43 in microglia and astrocytes258 and p62 accumulation in macrophages259. In vivo upregulation of muscle MHC class I (which is highly induced by IFNγ) alone is suffi­cient in mouse models to result in ER stress and a severe myopathy with rimmed vacuoles84. Third, a single study found that purified serum blood immunoglobulin frac­tions from patients positive for anti­ cN1A with IBM cause muscle degenerative p62 protein aggregation in cell culture and mouse models, although only in a small proportion of muscle cells or fibres98.

Finally, proof that causality flows from autoimmun­ity to degenerative muscle pathology in people comes from the existence of the clinical syndromes of HIV­ associated IBM and HTLV­1­associated IBM162–164,166,260. HIV and HTLV­1 infect T cells; their antigens are present in IBM endomysial T cells and macrophages but not myofibres164,166,260. These syndromes demon­strate that an external event that alters the function of the immune system can produce the full clinical and pathological picture of IBM including the degenera­tive biomarkers of rimmed vacuoles and p62, LC3 and TDP43 cytoplasmic aggregates163.

Why is IBM treatment refractory?The refractoriness of IBM might suggest that it is a non­ autoimmune degenerative disease. However, treat­ment refractoriness might instead suggest an autoim­mune process in which the immune system has escaped from typical checkpoints designed to restrain it, such as lymphocyte apoptosis and lymphocyte activation­ induced cell death261. The highly differentiated effec­tor memory and effector cytotoxic CD4+ and CD8+ T cells (loss of CD28 and gain of CD244, CD57 and KLRG1 expression, as discussed above) present in IBM are resistant to apoptosis and activation­ induced cell death229,262–264.

Unlike naive T cells, highly differentiated blood­ derived human T cells are resistant to corticosteroid inhibition ex vivo265–267. Individuals treated with cortico­steroids have reduced numbers of naive CD8+ T cells in their blood but increased numbers of highly differen­tiated effector memory CD8+ T cells268. In a cohort of patients with a diagnosis of polymyositis, defined using

criteria that classify all patients with IBM as having poly­myositis269, corticosteroids did not result in a reduction of invading CD28− T cells in the muscle266. In retrospec­tive comparisons, patients with IBM receiving long­ term immunosuppressive treatment (a mean of 35 mg daily of prednisone for a mean of 5.7 years) had the same number of invaded myofibres as patients with IBM not receiving treatment208. In prospective intervention trials, patients with IBM receiving corticosteroids or IVIG did not expe­rience substantial reduction in the total muscle­ invading T cell population54,186. Because of its close mechanistic pathogenesis, experience with T­ LGLL is informative for IBM. The T­ LGLL population of highly differenti­ated clonal T cells is resistant to apoptosis237,270 and is not reduced following treatment with corticosteroids271 or alemtuzumab272, the latter potentially owing to variable expression of CD52, its target, on these cells273.

Two other immune therapies have undergone open­ label IBM clinical trials and have shown trends towards efficacy: ATG66 and alemtuzumab67. ATG274 and alemtu­zumab275 rapidly deplete nearly 100% of blood CD4+ and CD8+ T cells, but the subsequent immune reconstitution results in paradoxical expansion above pretreatment levels (known as homeostatic proliferation276) of highly differentiated pathogenic TEM and TEMRA cells, identified as CD45RA−CD62L− T cells267, CD28−CD57+ T cells277 and CD45RO−CD62L− T cells278. Furthermore, T regu­latory cells, which are potentially beneficial to con­trolling autoimmune disease, are decreased in number compared with pretreatment levels after alemtuzumab immune reconstitution278.

Finally, other autoimmune diseases are known to be treatment refractory, including Sjögren syndrome and primary biliary cholangitis (PBC)279–282. Like IBM, both diseases involve CD8+ T cell­ mediated damage (in exo­crine epithelial cells in Sjögren syndrome283 and bile duct cholangiocytes in PBC284–286), progress slowly and have cytotoxic T cell genomic signatures and expansions of the highly differentiated CD8+ TEMRA population287,288.

Protein aggregates in autoimmune diseasesA role for ER stress and autophagy has been identified in other autoimmune diseases289–291. Two main histolog­ical markers of IBM that are argued to indicate degen­eration, p62 (refs211,212) and LC3 (ref.212), are aggregated in cholangiocytes in PBC292. Other markers of ER stress and autophagy are also aggregated in PBC cholangio­cytes293,294 and Sjögren syndrome salivary gland epithe­lial cells295. Why then has the field of IBM attracted so much more interest in protein aggregates than other autoimmune diseases? Perhaps it is simply easier to see these cytoplasmic aggregates under the microscope in skeletal muscle than in other tissues. Skeletal muscle fibres are unique syncytial structures that are densely packed with large proteins undergoing constant turno­ver; they have larger proportions of cytoplasm and larger cross­ sectional areas (10,000–20,000 μm2; approximately 50–100 times larger) than most other cells. There simply is not sufficient room in cell types other than myofibres for large cytoplasmic aggregates, such as p62 aggregates with sizes of 5–50 μm2, to accumulate and become visible by microscopy.

Nature reviews | Rheumatology

R e v i e w s

ConclusionsTremendous progress has been made in the clinical and pathogenic understanding of IBM over the past decade. Major advances in biomarker identification, including the notable whole­ genome linkage to an HLA autoimmune haplotype, the identification of a specific autoantibody and T cell phenotypical abnormalities, have advanced IBM diagnosis and pathogenic understanding. IBM is unique among muscle diseases owing to its molecular signature involving highly differentiated cytotoxic T cells that have escaped immune regulation. Although viewed

as treatment refractory, only very limited therapeutic approaches have been carefully studied to date, and none of these has been rationally directed towards targeting this population of T cells; some treatments (such as cor­ticosteroids and alemtuzumab) have had predictably counterproductive liabilities. Complete understanding of the pathogenesis of IBM, like most acquired diseases in humans, awaits successful therapeutic responses from mechanistically targeted therapies.

Published online xx xx xxxx

1. Unverricht, H. Polymyositis acuta progressiva. Z. Klin. Med. 12, 533–549 (1887).

2. Bohan, A. History and classification of polymyositis and dermatomyositis. Clin. Dermatol. 6, 3–8 (1988).

3. Uverricht, H. Dermatomyositis acuta. Dtsch. Med. Wochenschr. 17, 41–44 (1891).

4. Levine, T. D. History of dermatomyositis. Arch. Neurol. 60, 780–782 (2003).

5. Carpenter, S., Karpati, G., Heller, I. & Eisen, A. Inclusion body myositis: a distinct variety of idiopathic inflammatory myopathy. Neurology 28, 8–17 (1978).

6. Emslie- Smith, A. M. & Engel, A. G. Necrotizing myopathy with pipestem capillaries, microvascular deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration. Neurology 41, 936–939 (1991).

7. van der Meulen, M. F. et al. Polymyositis: an overdiagnosed entity. Neurology 61, 316–321 (2003).

8. Hoogendijk, J. E. et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10-12 October 2003, Naarden, The Netherlands. Neuromuscul. Disord. 14, 337–345 (2004).

9. van de Vlekkert, J., Hoogendijk, J. E. & de Visser, M. Myositis with endomysial cell invasion indicates inclusion body myositis even if other criteria are not fulfilled. Neuromuscul. Disord. 25, 451–456 (2015).

10. Dalakas, M. C. Inflammatory muscle diseases. N. Engl. J. Med. 372, 1734–1747 (2015).

11. Wolstencroft, P. W. & Fiorentino, D. F. Dermatomyositis clinical and pathological phenotypes associated with myositis- specific autoantibodies. Curr. Rheumatol. Rep. 20, 28 (2018).

12. Schmidt, J. & Dalakas, M. C. Inclusion body myositis: from immunopathology and degenerative mechanisms to treatment perspectives. Expert Rev. Clin. Immunol. 9, 1125–1133 (2013).

13. Machado, P. M. et al. Ongoing developments in sporadic inclusion body myositis. Curr. Rheumatol. Rep. 16, 477 (2014).

14. Dimachkie, M. M. & Barohn, R. J. Inclusion body myositis. Neurol. Clin. 32, 629–646 (2014).

15. Mastaglia, F. L. & Needham, M. Inclusion body myositis: a review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches. J. Clin. Neurosci. 22, 6–13 (2015).

16. Greenberg, S. A. Inclusion body myositis. Continuum 22, 1871–1888 (2016).

17. Gallay, L. & Petiot, P. Sporadic inclusion- body myositis: recent advances and the state of the art in 2016. Rev. Neurol. 172, 581–586 (2016).

18. Needham, M. & Mastaglia, F. L. Sporadic inclusion body myositis: a review of recent clinical advances and current approaches to diagnosis and treatment. Clin. Neurophysiol. 127, 1764–1773 (2016).

19. Schmidt, K. & Schmidt, J. Inclusion body myositis: advancements in diagnosis, pathomechanisms, and treatment. Curr. Opin. Rheumatol. 29, 632–638 (2017).

20. Benveniste, O. et al. Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: the inflammatory egg comes before the degenerative chicken. Acta Neuropathol. 129, 611–624 (2015).

21. Keller, C. W., Schmidt, J. & Lunemann, J. D. Immune and myodegenerative pathomechanisms in inclusion body myositis. Ann. Clin. Transl Neurol. 4, 422–445 (2017).

22. Chou, S. M. Myxovirus- like structures in a case of human chronic polymyositis. Science 158, 1453–1455 (1967).

23. Nishino, H., Engel, A. G. & Rima, B. K. Inclusion body myositis: the mumps virus hypothesis. Ann. Neurol. 25, 260–264 (1989).

24. Kallajoki, M. et al. Inclusion body myositis and paramyxoviruses. Hum. Pathol. 22, 29–32 (1991).

25. Fox, S. A., Ward, B. K., Robbins, P. D., Mastaglia, F. L. & Swanson, N. R. Inclusion body myositis: investigation of the mumps virus hypothesis by polymerase chain reaction. Muscle Nerve 19, 23–28 (1996).

26. Uruha, A. et al. Hepatitis C virus infection in inclusion body myositis: a case- control study. Neurology 86, 211–217 (2016).

27. Yunis, E. J. & Samaha, F. J. Inclusion body myositis. Lab. Invest. 25, 240–248 (1971).

28. Danon, M. J., Reyes, M. G., Perurena, O. H., Masdeu, J. C. & Manaligod, J. R. Inclusion body myositis. A corticosteroid- resistant idiopathic inflammatory myopathy. Arch. Neurol. 39, 760–764 (1982).

29. Eisen, A., Berry, K. & Gibson, G. Inclusion body myositis (IBM): myopathy or neuropathy? Neurology 33, 1109–1114 (1983).

30. Ringel, S. P., Kenny, C. E., Neville, H. E., Giorno, R. & Carry, M. R. Spectrum of inclusion body myositis. Arch. Neurol. 44, 1154–1157 (1987).

31. Calabrese, L. H., Mitsumoto, H. & Chou, S. M. Inclusion body myositis presenting as treatment- resistant polymyositis. Arthritis Rheum. 30, 397–403 (1987).

32. Lotz, B. P., Engel, A. G., Nishino, H., Stevens, J. C. & Litchy, W. J. Inclusion body myositis. Observations in 40 patients. Brain 112, 727–747 (1989).

33. Sayers, M. E., Chou, S. M. & Calabrese, L. H. Inclusion body myositis: analysis of 32 cases. J. Rheumatol. 19, 1385–1389 (1992).

34. Lindberg, C., Persson, L. I., Bjorkander, J. & Oldfors, A. Inclusion body myositis: clinical, morphological, physiological and laboratory findings in 18 cases. Acta Neurol. Scand. 89, 123–131 (1994).

35. Amato, A. A. et al. Inclusion body myositis: clinical and pathological boundaries. Ann. Neurol. 40, 581–586 (1996).

36. Felice, K. J., Relva, G. M. & Conway, S. R. Further observations on forearm flexor weakness in inclusion body myositis. Muscle Nerve 21, 659–661 (1998).

37. Phillips, B. A. et al. Patterns of muscle involvement in inclusion body myositis: clinical and magnetic resonance imaging study. Muscle Nerve 24, 1526–1534 (2001).

38. Badrising, U. A. et al. Inclusion body myositis. Clinical features and clinical course of the disease in 64 patients. J. Neurol. 252, 1448–1454 (2005).

39. Benveniste, O. et al. Long- term observational study of sporadic inclusion body myositis. Brain 134, 3176–3184 (2011).

40. Price, M. A. et al. Mortality and causes of death in patients with sporadic inclusion body myositis: survey study based on the clinical experience of specialists in Australia, Europe and the USA. J. Neuromuscul. Dis. 3, 67–75 (2016).

41. Felice, K. J. & North, W. A. Inclusion body myositis in Connecticut: observations in 35 patients during an 8-year period. Medicine 80, 320–327 (2001).

42. Needham, M. et al. Sporadic inclusion body myositis: phenotypic variability and influence of HLA- DR3 in a cohort of 57 Australian cases. J. Neurol. Neurosurg. Psychiatry 79, 1056–1060 (2008).

43. Cox, F. M. et al. A 12-year follow- up in sporadic inclusion body myositis: an end stage with major disabilities. Brain 134, 3167–3175 (2011).

44. Cortese, A. et al. Longitudinal observational study of sporadic inclusion body myositis: implications for clinical trials. Neuromuscul. Disord. 23, 404–412 (2013).

45. Hogrel, J. Y. et al. Four- year longitudinal study of clinical and functional endpoints in sporadic inclusion body myositis: implications for therapeutic trials. Neuromuscul. Disord. 24, 604–610 (2014).

46. Alfano, L. N. et al. Modeling functional decline over time in sporadic inclusion body myositis. Muscle Nerve 55, 526–531 (2016).

47. Rose, M. R. et al. A prospective natural history study of inclusion body myositis: implications for clinical trials. Neurology 57, 548–550 (2001).

48. Arahata, K. & Engel, A. G. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann. Neurol. 16, 193–208 (1984).

49. Engel, A. G. & Arahata, K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann. Neurol. 16, 209–215 (1984).

50. Arahata, K. & Engel, A. G. Monoclonal antibody analysis of mononuclear cells in myopathies. III: Immunoelectron microscopy aspects of cell- mediated muscle fiber injury. Ann. Neurol. 19, 112–125 (1986).

51. Arahata, K. & Engel, A. G. Monoclonal antibody analysis of mononuclear cells in myopathies. IV: Cell- mediated cytotoxicity and muscle fiber necrosis. Ann. Neurol. 23, 168–173 (1988).

52. O’Hanlon, T. P., Dalakas, M. C., Plotz, P. H. & Miller, F. W. The αβT cell receptor repertoire in inclusion body myositis: diverse patterns of gene expression by muscle- infiltrating lymphocytes. J. Autoimmun. 7, 321–333 (1994).

53. Lindberg, C., Oldfors, A. & Tarkowski, A. Restricted use of T cell receptor V genes in endomysial infiltrates of patients with inflammatory myopathies. Eur. J. Immunol. 24, 2659–2663 (1994).

54. Lindberg, C., Oldfors, A. & Tarkowski, A. Local T cell proliferation and differentiation in inflammatory myopathies. Scand. J. Immunol. 41, 421–426 (1995).

55. Fyhr, I. M., Moslemi, A. R., Tarkowski, A., Lindberg, C. & Oldfors, A. Limited T cell receptor V gene usage in inclusion body myositis. Scand. J. Immunol. 43, 109–114 (1996).

56. Fyhr, I. M. et al. Oligoclonal expansion of muscle infiltrating T cells in inclusion body myositis. J. Neuroimmunol. 79, 185–189 (1997).

57. Bender, A., Behrens, L., Engel, A. G. & Hohlfeld, R. T cell heterogeneity in muscle lesions of inclusion body myositis. J. Neuroimmunol. 84, 86–91 (1998).

58. Amemiya, K., Granger, R. P. & Dalakas, M. C. Clonal restriction of T cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time. Studies in repeated muscle biopsies. Brain 123, 2030–2039 (2000).

59. Muntzing, K., Lindberg, C., Moslemi, A. R. & Oldfors, A. Inclusion body myositis: clonal expansions of muscle- infiltrating T cells persist over time. Scand. J. Immunol. 58, 195–200 (2003).

60. Dimitri, D. et al. Shared blood and muscle CD8+T cell expansions in inclusion body myositis. Brain 129, 986–995 (2006).

61. Salajegheh, M. et al. T cell receptor profiling in muscle and blood lymphocytes in sporadic inclusion body myositis. Neurology 69, 1672–1679 (2007).

62. Pandya, J. M. et al. Expanded T cell receptor Vβ- restricted T cells from patients with sporadic inclusion body myositis are proinflammatory and

www.nature.com/nrrheum

R e v i e w s

cytotoxic CD28null T cells. Arthritis Rheum. 62, 3457–3466 (2010).

63. Allenbach, Y. et al. Th1 response and systemic treg deficiency in inclusion body myositis. PLOS ONE 9, e88788 (2014).

64. Greenberg, S. A., Pinkus, J. L., Amato, A. A., Kristensen, T. & Dorfman, D. M. Association of inclusion body myositis with T cell large granular lymphocytic leukaemia. Brain 139, 1348–1360 (2016).

65. Hohlfeld, R. & Schulze- Koops, H. Cytotoxic T cells go awry in inclusion body myositis. Brain 139, 1312–1314 (2016).

66. Lindberg, C., Trysberg, E., Tarkowski, A. & Oldfors, A. Anti- T-lymphocyte globulin treatment in inclusion body myositis: a randomized pilot study. Neurology 61, 260–262 (2003).

67. Dalakas, M. C. et al. Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion- body myositis. Brain 132, 1536–1544 (2009).

68. Hogrel, J. Y. et al. Rapamycin vs. placebo for the treatment of inclusion body myositis: improvement of the 6 min walking distance, a functional scale, the FVC and muscle quantitative MRI. Arthritis Rheumatol. 69, 5L (2017).

69. Targoff, I. N. Autoantibodies and their significance in myositis. Curr. Rheumatol. Rep. 10, 333–340 (2008).

70. Nishikai, M. & Reichlin, M. Heterogeneity of precipitating antibodies in polymyositis and dermatomyositis. Characterization of the Jo-1 antibody system. Arthritis Rheum. 23, 881–888 (1980).

71. Reichlin, M. & Mattioli, M. Description of a serological reaction characteristic of polymyositis. Clin. Immunol. Immunopathol. 5, 12–20 (1976).

72. McHugh, N. J. & Tansley, S. L. Autoantibodies in myositis. Nat. Rev. Rheumatol. 14, 290–302 (2018).

73. Greenberg, S. A. et al. Molecular profiles of inflammatory myopathies. Neurology 59, 1170–1182 (2002).

74. Greenberg, S. A. et al. Plasma cells in muscle in inclusion body myositis and polymyositis. Neurology 65, 1782–1787 (2005).

75. Bradshaw, E. M. et al. A local antigen- driven humoral response is present in the inflammatory myopathies. J. Immunol. 178, 547–556 (2007).

76. Salajegheh, M. et al. Permissive environment for B cell maturation in myositis muscle in the absence of B cell follicles. Muscle Nerve 42, 576–583 (2010).

77. Ray, A. et al. Autoantibodies produced at the site of tissue damage provide evidence of humoral autoimmunity in inclusion body myositis. PLOS ONE 7, e46709 (2012).

78. Salajegheh, M., Lam, T. & Greenberg, S. A. Autoantibodies against a 43kDa muscle protein in inclusion body myositis. PLOS ONE 6, e20266 (2011).

79. Larman, H. B. et al. Cytosolic 5′-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann. Neurol. 73, 408–418 (2013).

80. Pluk, H. et al. Autoantibodies to cytosolic 5′-nucleotidase IA in inclusion body myositis. Ann. Neurol. 73, 397–407 (2013).

81. Mendell, J. R., Sahenk, Z., Gales, T. & Paul, L. Amyloid filaments in inclusion body myositis. Novel findings provide insight into nature of filaments. Arch. Neurol. 48, 1229–1234 (1991).

82. Oldfors, A., Larsson, N. G., Lindberg, C. & Holme, E. Mitochondrial DNA deletions in inclusion body myositis. Brain 116, 325–336 (1993).

83. Schmidt, J. et al. Interrelation of inflammation and APP in sIBM: IL-1β induces accumulation of β- amyloid in skeletal muscle. Brain 131, 1228–1240 (2008).

84. Freret, M. et al. Overexpression of MHC class I in muscle of lymphocyte- deficient mice causes a severe myopathy with induction of the unfolded protein response. Am. J. Pathol. 183, 893–904 (2013).

85. Rygiel, K. A. et al. Mitochondrial and inflammatory changes in sporadic inclusion body myositis. Neuropathol. Appl. Neurobiol. 41, 288–303 (2015).

86. Garlepp, M. J., Laing, B., Zilko, P. J., Ollier, W. & Mastaglia, F. L. HLA associations with inclusion body myositis. Clin. Exp. Immunol. 98, 40–45 (1994).

87. Koffman, B. M., Sivakumar, K., Simonis, T., Stroncek, D. & Dalakas, M. C. HLA allele distribution distinguishes sporadic inclusion body myositis from hereditary inclusion body myopathies. J. Neuroimmunol. 84, 139–142 (1998).

88. Lampe, J. B. et al. Analysis of HLA class I and II alleles in sporadic inclusion- body myositis. J. Neurol. 250, 1313–1317 (2003).

89. Price, P. et al. Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA- DR3. Tissue Antigens 64, 575–580 (2004).

90. Scott, A. P. et al. Sporadic inclusion body myositis in Japanese is associated with the MHC ancestral haplotype 52.1. Neuromuscul. Disord. 16, 311–315 (2006).

91. Rojana- udomsart, A. et al. The association of sporadic inclusion body myositis and Sjögren’s syndrome in carriers of HLA- DR3 and the 8.1 MHC ancestral haplotype. Clin. Neurol. Neurosurg. 113, 559–563 (2011).

92. Rojana- udomsart, A. et al. High- resolution HLA- DRB1 genotyping in an Australian inclusion body myositis (s- IBM) cohort: an analysis of disease- associated alleles and diplotypes. J. Neuroimmunol. 250, 77–82 (2012).

93. Rojana- udomsart, A. et al. Analysis of HLA- DRB3 alleles and supertypical genotypes in the MHC class II region in sporadic inclusion body myositis. J. Neuroimmunol. 254, 174–177 (2013).

94. Rothwell, S. et al. Immune- array analysis in sporadic inclusion body myositis reveals HLA- DRB1 amino acid heterogeneity across the myositis spectrum. Arthritis Rheumatol. 69, 1090–1099 (2017).

95. Dalakas, M. C. et al. Treatment of inclusion- body myositis with IVIg: a double- blind, placebo- controlled study. Neurology 48, 712–716 (1997).

96. Greenberg, S. A., Pinkus, J. L. & Amato, A. A. Nuclear membrane proteins are present within rimmed vacuoles in inclusion- body myositis. Muscle Nerve 34, 406–416 (2006).

97. Chahin, N. & Engel, A. G. Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM. Neurology 70, 418–424 (2008).

98. Tawara, N. et al. Pathomechanisms of anti- cytosolic 5′-nucleotidase 1 A autoantibodies in sporadic inclusion body myositis. Ann. Neurol. 81, 512–525 (2017).

99. Johns Hopkins University. Myopathy, myofibrillar, 1; MFM1. OMIM https://www.omim.org/entry/601419 (2014).

100. Ahmed, M. et al. Targeting protein homeostasis in sporadic inclusion body myositis. Sci. Transl Med. 8, 331ra41 (2016).

101. Sivakumar, K., Semino- Mora, C. & Dalakas, M. C. An inflammatory, familial, inclusion body myositis with autoimmune features and a phenotype identical to sporadic inclusion body myositis. Studies in three families. Brain 120, 653–661 (1997).

102. Ranque- Francois, B. et al. Familial inflammatory inclusion body myositis. Ann. Rheum. Dis. 64, 634–637 (2005).

103. Tateyama, M. et al. Familial inclusion body myositis: a report on two Japanese sisters. Intern. Med. 42, 1035–1038 (2003).

104. Callan, A., Capkun, G., Vasanthaprasad, V., Freitas, R. & Needham, M. A. Systematic review and meta- analysis of prevalence studies of sporadic inclusion body myositis. J. Neuromuscul. Dis. 4, 127–137 (2017).

105. Tan, J. A. et al. Incidence and prevalence of idiopathic inflammatory myopathies in South Australia: a 30-year epidemiologic study of histology- proven cases. Int. J. Rheum. Dis. 16, 331–338 (2013).

106. Badrising, U. A. et al. Epidemiology of inclusion body myositis in the Netherlands: a nationwide study. Neurology 55, 1385–1387 (2000).

107. Lefter, S., Hardiman, O. & Ryan, A. M. A population- based epidemiologic study of adult neuromuscular disease in the Republic of Ireland. Neurology 88, 304–313 (2017).

108. Suzuki, N. et al. Increase in number of sporadic inclusion body myositis (sIBM) in Japan. J. Neurol. 259, 554–556 (2012).

109. Dobloug, G. C. et al. High prevalence of inclusion body myositis in Norway; a population- based clinical epidemiology study. Eur. J. Neurol. 22, 672 (2015).

110. Suzuki, N. et al. Multicenter questionnaire survey for sporadic inclusion body myositis in Japan. Orphanet J. Rare Dis. 11, 146 (2016).

111. Wilson, F. C., Ytterberg, S. R., St Sauver, J. L. & Reed, A. M. Epidemiology of sporadic inclusion body myositis and polymyositis in Olmsted County, Minnesota. J. Rheumatol. 35, 445–447 (2008).

112. Chilingaryan, A., Rison, R. A. & Beydoun, S. R. Misdiagnosis of inclusion body myositis: two case reports and a retrospective chart review. J. Med. Case Rep. 9, 169 (2015).

113. Paltiel, A. D. et al. Demographic and clinical features of inclusion body myositis in North America. Muscle Nerve 52, 527–533 (2015).

114. Keshishian, A., Greenberg, S. A., Agashivala, N., Baser, O. & Johnson, K. Health care costs and comorbidities for patients with inclusion body myositis. Curr. Med. Res. Opin. 34, 1679–1685 (2018).

115. Ko, E. H. & Rubin, A. D. Dysphagia due to inclusion body myositis: case presentation and review of the literature. Ann. Otol. Rhinol. Laryngol. 123, 605–608 (2014).

116. Cox, F. M. et al. Detecting dysphagia in inclusion body myositis. J. Neurol. 256, 2009–2013 (2009).

117. Houser, S. M., Calabrese, L. H. & Strome, M. Dysphagia in patients with inclusion body myositis. Laryngoscope 108, 1001–1005 (1998).

118. Oh, T. H., Brumfield, K. A., Hoskin, T. L., Kasperbauer, J. L. & Basford, J. R. Dysphagia in inclusion body myositis: clinical features, management, and clinical outcome. Am. J. Phys. Med. Rehabil. 87, 883–889 (2008).

119. Riminton, D. S., Chambers, S. T., Parkin, P. J., Pollock, M. & Donaldson, I. M. Inclusion body myositis presenting solely as dysphagia. Neurology 43, 1241–1243 (1993).

120. Verma, A., Bradley, W. G., Adesina, A. M., Sofferman, R. & Pendlebury, W. W. Inclusion body myositis with cricopharyngeus muscle involvement and severe dysphagia. Muscle Nerve 14, 470–473 (1991).

121. Rodriguez Cruz, P. M., Needham, M., Hollingsworth, P., Mastaglia, F. L. & Hillman, D. R. Sleep disordered breathing and subclinical impairment of respiratory function are common in sporadic inclusion body myositis. Neuromuscul. Disord. 24, 1036–1041 (2014).

122. Brady, S., Squier, W. & Hilton- Jones, D. Clinical assessment determines the diagnosis of inclusion body myositis independently of pathological features. J. Neurol. Neurosurg. Psychiatry 84, 1240–1246 (2013).

123. Dion, E. et al. Magnetic resonance imaging criteria for distinguishing between inclusion body myositis and polymyositis. J. Rheumatol. 29, 1897–1906 (2002).

124. Cox, F. M. et al. Magnetic resonance imaging of skeletal muscles in sporadic inclusion body myositis. Rheumatology 50, 1153–1161 (2011).

125. Inaishi, Y. et al. MRI for evaluation of flexor digitorum profundus muscle involvement in inclusion body myositis. Can. J. Neurol. Sci. 41, 780–781 (2014).

126. Tasca, G. et al. Magnetic resonance imaging pattern recognition in sporadic inclusion- body myositis. Muscle Nerve 52, 956–962 (2015).

127. Guimaraes, J. B. et al. Sporadic inclusion body myositis: MRI findings and correlation with clinical and functional parameters. AJR Am. J. Roentgenol. 209, 1340–1347 (2017).

128. Tsukita, K., Yagita, K., Sakamaki- Tsukita, H. & Suenaga, T. Sporadic inclusion body myositis: magnetic resonance imaging and ultrasound characteristics. QJM 111, 667–668 (2018).

129. Noto, Y. et al. Contrasting echogenicity in flexor digitorum profundus- flexor carpi ulnaris: a diagnostic ultrasound pattern in sporadic inclusion body myositis. Muscle Nerve 49, 745–748 (2014).

130. Nodera, H. et al. Intramuscular dissociation of echogenicity in the triceps surae characterizes sporadic inclusion body myositis. Eur. J. Neurol. 23, 588–596 (2016).

131. Albayda, J. et al. Pattern of muscle involvement in inclusion body myositis: a sonographic study. Clin. Exp. Rheumatol. 36, 996–1002 (2018).

132. Bachasson, D., Dubois, G. J. R., Allenbach, Y., Benveniste, O. & Hogrel, J. Y. Muscle shear wave elastography in inclusion body myositis: feasibility, reliability and relationships with muscle impairments. Ultrasound Med. Biol. 44, 1423–1432 (2018).

133. Olthoff, A. et al. Evaluation of dysphagia by novel real- time MRI. Neurology 87, 2132–2138 (2016).

134. Koffman, B. M., Rugiero, M. & Dalakas, M. C. Immune- mediated conditions and antibodies associated with sporadic inclusion body myositis. Muscle Nerve 21, 115–117 (1998).

135. Greenberg, S. A. Cytoplasmic 5′-nucleotidase autoantibodies in inclusion body myositis: Isotypes and diagnostic utility. Muscle Nerve 50, 488–492 (2014).

136. Goyal, N. A. et al. Seropositivity for NT5c1A antibody in sporadic inclusion body myositis predicts more severe motor, bulbar and respiratory involvement. J. Neurol. Neurosurg. Psychiatry 87, 373–378 (2016).

Nature reviews | Rheumatology

R e v i e w s

137. Lloyd, T. E. et al. Cytosolic 5′-nucleotidase 1A as a target of circulating autoantibodies in autoimmune diseases. Arthritis Care Res. 68, 66–71 (2016).

138. Kramp, S. L. et al. Development and evaluation of a standardized ELISA for the determination of autoantibodies against cN-1A (Mup44, NT5C1A) in sporadic inclusion body myositis. Auto Immun. Highlights 7, 16 (2016).

139. Felice, K. J. et al. Sensitivity and clinical utility of the anti- cytosolic 5’-nucleotidase 1 A (cN1A) antibody test in sporadic inclusion body myositis: Report of 40 patients from a single neuromuscular center. Neuromuscul. Disord. 28, 600–664 (2018).

140. Herbert, M. K. et al. Disease specificity of autoantibodies to cytosolic 5′-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases. Ann. Rheum. Dis. 75, 696–701 (2016).

141. Muro, Y., Nakanishi, H., Katsuno, M., Kono, M. & Akiyama, M. Prevalence of anti- NT5C1A antibodies in Japanese patients with autoimmune rheumatic diseases in comparison with other patient cohorts. Clin. Chim. Acta 472, 1–4 (2017).

142. Rietveld, A. et al. Autoantibodies to cytosolic 5′-nucleotidase 1A in primary Sjögren’s syndrome and systemic lupus erythematosus. Front. Immunol. 9, 1200 (2018).

143. Mhiri, C. & Gherardi, R. Inclusion body myositis in French patients. A clinicopathological evaluation. Neuropathol. Appl. Neurobiol. 16, 333–344 (1990).

144. Askanas, V. & Engel, W. K. Molecular pathology and pathogenesis of inclusion- body myositis. Microsc. Res. Tech. 67, 114–120 (2005).

145. Rodriguez Cruz, P. M. et al. An analysis of the sensitivity and specificity of MHC- I and MHC- II immunohistochemical staining in muscle biopsies for the diagnosis of inflammatory myopathies. Neuromuscul. Disord. 24, 1025–1035 (2014).

146. Ikenaga, C. et al. Clinicopathologic features of myositis patients with CD8-MHC-1 complex pathology. Neurology 89, 1060–1068 (2017).

147. Temiz, P., Weihl, C. C. & Pestronk, A. Inflammatory myopathies with mitochondrial pathology and protein aggregates. J. Neurol. Sci. 278, 25–29 (2009).

148. Pestronk, A. Acquired immune and inflammatory myopathies: pathologic classification. Curr. Opin. Rheumatol. 23, 595–604 (2011).

149. van der Meulen, M. F. et al. Rimmed vacuoles and the added value of SMI-31 staining in diagnosing sporadic inclusion body myositis. Neuromuscul. Disord. 11, 447–451 (2001).

150. Dalakas, M. C. Polymyositis, dermatomyositis and inclusion- body myositis. N. Engl. J. Med. 325, 1487–1498 (1991).

151. Mastaglia, F. L. & Phillips, B. A. Idiopathic inflammatory myopathies: epidemiology, classification, and diagnostic criteria. Rheum. Dis. Clin. North Am. 28, 723–741 (2002).

152. Tawil, R. & Griggs, R. C. Inclusion body myositis. Curr. Opin. Rheumatol. 14, 653–657 (2002).

153. Verschuuren, J. J., van Engelen, B. G. M., van der Hoeven, H. & Hoogendijk, J. Inclusion body myositis diagnostic criteria. Inclusion Body Myositis. http://ibmmyositis.com/emery81.pdf (1997).

154. Griggs, R. C. et al. Inclusion body myositis and myopathies. Ann. Neurol. 38, 705–713 (1995).

155. Hilton- Jones, D. et al. Inclusion body myositis: MRC Centre for Neuromuscular Diseases, IBM workshop, London, 13 June 2008. Neuromuscul Disord. 20, 142–147 (2010).

156. Benveniste, O. & Hilton- Jones, D. International Workshop on Inclusion Body Myositis held at the Institute of Myology, Paris, on 29 May 2009. Neuromuscul. Disord. 20, 414–421 (2010).

157. Rose, M. R. 188th ENMC International Workshop: Inclusion Body Myositis, 2–4 December 2011, Naarden, The Netherlands. Neuromuscul. Disord. 23, 1044–1055 (2013).

158. Lloyd, T. E. et al. Evaluation and construction of diagnostic criteria for inclusion body myositis. Neurology 83, 426–433 (2014).

159. Kanellopoulos, P., Baltoyiannis, C. & Tzioufas, A. G. Primary Sjögren’s syndrome associated with inclusion body myositis. Rheumatology 41, 440–444 (2002).

160. Misterska- Skora, M., Sebastian, A., Dziegiel, P., Sebastian, M. & Wiland, P. Inclusion body myositis associated with Sjögren’s syndrome. Rheumatol. Int. 33, 3083–3086 (2013).

161. Colafrancesco, S. et al. Myositis in primary Sjögren’s syndrome: data from a multicentre cohort. Clin. Exp. Rheumatol. 33, 457–464 (2015).

162. Lloyd, T. E. et al. Overlapping features of polymyositis and inclusion body myositis in HIV- infected patients. Neurology 88, 1454–1460 (2017).

163. Hiniker, A., Daniels, B. H. & Margeta, M. T- cell-mediated inflammatory myopathies in HIV- positive individuals: a histologic study of 19 cases. J. Neuropathol. Exp. Neurol. 75, 239–245 (2016).

164. Cupler, E. J. et al. Inclusion body myositis in HIV-1 and HTLV-1 infected patients. Brain 119, 1887–1893 (1996).

165. Couture, P. et al. Inclusion body myositis and human immunodeficiency virus type 1: a new case report and literature review. Neuromuscul. Disord. 28, 334–338 (2018).

166. Matsuura, E. et al. Inclusion body myositis associated with human T- lymphotropic virus- type I infection: eleven patients from an endemic area in Japan. J. Neuropathol. Exp. Neurol. 67, 41–49 (2008).

167. Cox, F. M. et al. The heart in sporadic inclusion body myositis: a study in 51 patients. J. Neurol. 257, 447–451 (2010).

168. Limaye, V. S., Lester, S., Blumbergs, P. & Roberts- Thomson, P. J. Idiopathic inflammatory myositis is associated with a high incidence of hypertension and diabetes mellitus. Int. J. Rheum. Dis. 13, 132–137 (2010).

169. Lai, Y. T. et al. Dermatomyositis is associated with an increased risk of cardiovascular and cerebrovascular events: a Taiwanese population- based longitudinal follow- up study. Br. J. Dermatol. 168, 1054–1059 (2013).

170. Wang, H., Tang, J., Chen, X., Li, F. & Luo, J. Lipid profiles in untreated patients with dermatomyositis. J. Eur. Acad. Dermatol. Venereol. 27, 175–179 (2013).

171. Wang, H. et al. Altered lipid levels in untreated patients with early polymyositis. PLOS ONE 9, e89827 (2014).

172. Diederichsen, L. P. et al. Traditional cardiovascular risk factors and coronary artery calcification in adults with polymyositis and dermatomyositis: a Danish multicenter study. Arthritis Care Res. 67, 848–854 (2015).

173. Rai, S. K., Choi, H. K., Sayre, E. C. & Avina- Zubieta, J. A. Risk of myocardial infarction and ischaemic stroke in adults with polymyositis and dermatomyositis: a general population- based study. Rheumatology 55, 461–469 (2016).

174. Sherer, Y. & Shoenfeld, Y. Mechanisms of disease: atherosclerosis in autoimmune diseases. Nat. Clin. Pract. Rheumatol. 2, 99–106 (2006).

175. Ahearn, J., Shields, K. J., Liu, C. C. & Manzi, S. Cardiovascular disease biomarkers across autoimmune diseases. Clin. Immunol. 161, 59–63 (2015).

176. Alexanderson, H. Exercise in inflammatory myopathies, including inclusion body myositis. Curr. Rheumatol. Rep. 14, 244–251 (2012).

177. Arnardottir, S., Alexanderson, H., Lundberg, I. E. & Borg, K. Sporadic inclusion body myositis: pilot study on the effects of a home exercise program on muscle function, histopathology and inflammatory reaction. J. Rehabil. Med. 35, 31–35 (2003).

178. Johnson, L. G., Edwards, D. J., Walters, S. E., Thickbroom, G. W. & Mastaglia, F. L. The effectiveness of an individualized, home- based functional exercise program for patients with sporadic inclusion body myositis. J. Clin. Neuromuscul. Dis. 8, 187–194 (2007).

179. Parker, K. C. et al. Fast- twitch sarcomeric and glycolytic enzyme protein loss in inclusion body myositis. Muscle Nerve 39, 739–753 (2009).

180. Cherin, P. et al. Intravenous immunoglobulin for dysphagia of inclusion body myositis. Neurology 58, 326 (2002).

181. Pars, K. et al. Subcutaneous immunoglobulin treatment of inclusion- body myositis stabilizes dysphagia. Muscle Nerve 48, 838–839 (2013).

182. Cherin, P., Delain, J. C., de Jaeger, C. & Crave, J. C. Subcutaneous immunoglobulin use in inclusion body myositis: a review of 6 cases. Case Rep. Neurol. 7, 227–232 (2015).

183. Mendell, J. R. et al. Follistatin gene therapy for sporadic inclusion body myositis improves functional outcomes. Mol. Ther. 25, 870–879 (2017).

184. Greenberg, S. A. Unfounded claims of improved functional outcomes attributed to follistatin gene therapy in inclusion body myositis. Mol. Ther. 25, 2235–2237 (2017).

185. Walter, M. C. et al. High- dose immunoglobulin therapy in sporadic inclusion body myositis: a double- blind, placebo- controlled study. J. Neurol. 247, 22–28 (2000).

186. Dalakas, M. C. et al. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology 56, 323–327 (2001).

187. Badrising, U. A. et al. Comparison of weakness progression in inclusion body myositis during treatment with methotrexate or placebo. Ann. Neurol. 51, 369–372 (2002).

188. Muscle Study, G. Randomized pilot trial of βINF1a (Avonex) in patients with inclusion body myositis. Neurology 57, 1566–1570 (2001).

189. Muscle Study, G. Randomized pilot trial of high- dose βINF-1a in patients with inclusion body myositis. Neurology 63, 718–720 ( 20 04 ).

190. Rutkove, S. B. et al. A pilot randomized trial of oxandrolone in inclusion body myositis. Neurology 58, 1081–1087 (2002).

191. Amato, A. A. et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology 83, 2239–2246 (2014).

192. Amato, A. A. et al. A randomized, double- blind, placebo- controlled study of bimagrumab in patients with sporadic inclusion body myositis [abstract 8L]. Arthritis Rheumatol. 68, 4367–4369 (2016).

193. Chou, S. M. Myxovirus- like structures and accompanying nuclear changes in chronic polymyositis. Arch. Pathol. 86, 649–658 (1968).

194. Rifai, Z., Welle, S., Kamp, C. & Thornton, C. A. Ragged red fibers in normal aging and inflammatory myopathy. Ann. Neurol. 37, 24–29 (1995).

195. Oldfors, A. et al. Mitochondrial abnormalities in inclusion- body myositis. Neurology 66, S49–S55 (2006).

196. Askanas, V., Serdaroglu, P., Engel, W. K. & Alvarez, R. B. Immunolocalization of ubiquitin in muscle biopsies of patients with inclusion body myositis and oculopharyngeal muscular dystrophy. Neurosci. Lett. 130, 73–76 (1991).

197. Askanas, V., Engel, W. K. & Alvarez, R. B. Light and electron microscopic localization of β- amyloid protein in muscle biopsies of patients with inclusion- body myositis. Am. J. Pathol. 141, 31–36 (1992).

198. Askanas, V., Engel, W. K., Bilak, M., Alvarez, R. B. & Selkoe, D. J. Twisted tubulofilaments of inclusion body myositis muscle resemble paired helical filaments of Alzheimer brain and contain hyperphosphorylated tau. Am. J. Pathol. 144, 177–187 (1994).

199. Greenberg, S. A. Theories of the pathogenesis of inclusion body myositis. Curr. Rheumatol. Rep. 12, 221–228 (2010).

200. Askanas, V. & Engel, W. K. Proposed pathogenetic cascade of inclusion- body myositis: importance of amyloid- β, misfolded proteins, predisposing genes, and aging. Curr. Opin. Rheumatol. 15, 737–744 (2003).

201. Askanas, V. & Engel, W. K. Inclusion- body myositis: a myodegenerative conformational disorder associated with Aβ, protein misfolding, and proteasome inhibition. Neurology 66, S39–S48 (2006).

202. Askanas, V., Engel, W. K. & Nogalska, A. Sporadic inclusion- body myositis: a degenerative muscle disease associated with aging, impaired muscle protein homeostasis and abnormal mitophagy. Biochim. Biophys. Acta 1852, 633–643 (2015).

203. Greenberg, S. A. How citation distortions create unfounded authority: analysis of a citation network. BMJ 339, b2680 (2009).

204. Fergusson, D. Inappropriate referencing in research. BMJ 339, b2049 (2009).

205. Sarkozi, E., Askanas, V., Johnson, S. A., McFerrin, J. & Engel, W. K. Expression of β- amyloid precursor protein gene is developmentally regulated in human muscle fibers in vivo and in vitro. Exp. Neurol. 128, 27–33 (1994).

206. Askanas, V. & Engel, W. K. Sporadic inclusion- body myositis: conformational multifactorial ageing- related degenerative muscle disease associated with proteasomal and lysosomal inhibition, endoplasmic reticulum stress, and accumulation of amyloid- β42 oligomers and phosphorylated tau. Presse Med. 40, e219–e235 (2011).

207. Salajegheh, M. et al. Nature of “Tau” immunoreactivity in normal myonuclei and inclusion body myositis. Muscle Nerve 40, 520–528 (2009).

208. Pruitt, J. N. 2nd, Showalter, C. J. & Engel, A. G. Sporadic inclusion body myositis: counts of different types of abnormal fibers. Ann. Neurol. 39, 139–143 (1996).

209. Banwell, B. L. & Engel, A. G. αB- Crystallin immunolocalization yields new insights into inclusion body myositis. Neurology 54, 1033–1041 (2000).

www.nature.com/nrrheum

R e v i e w s

210. Sherriff, F. E., Joachim, C. L., Squier, M. V. & Esiri, M. M. Ubiquitinated inclusions in inclusion- body myositis patients are immunoreactive for cathepsin D but not β- amyloid. Neurosci. Lett. 194, 37–40 (1995).

211. Dubourg, O. et al. Diagnostic value of markers of muscle degeneration in sporadic inclusion body myositis. Acta Myol 30, 103–108 (2011).

212. Hiniker, A., Daniels, B. H., Lee, H. S. & Margeta, M. Comparative utility of LC3, p62 and TDP-43 immunohistochemistry in differentiation of inclusion body myositis from polymyositis and related inflammatory myopathies. Acta Neuropathol. Commun. 1, 29 (2013).

213. Vattemi, G., Engel, W. K., McFerrin, J. & Askanas, V. Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis muscle. Am. J. Pathol. 164, 1–7 (2004).

214. Lunemann, J. D. et al. β- amyloid is a substrate of autophagy in sporadic inclusion body myositis. Ann. Neurol. 61, 476–483 (2007).

215. Nakano, S., Oki, M. & Kusaka, H. The role of p62/SQSTM1 in sporadic inclusion body myositis. Neuromuscul. Disord. 27, 363–369 (2017).

216. Pinkus, J. L., Amato, A. A., Taylor, J. P. & Greenberg, S. A. Abnormal distribution of heterogeneous nuclear ribonucleoproteins in sporadic inclusion body myositis. Neuromuscul. Disord. 24, 611–616 (2014).

217. Weihl, C. C. et al. TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia. J. Neurol. Neurosurg. Psychiatry 79, 1186–1189 (2008).

218. Salajegheh, M. et al. Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis. Muscle Nerve 40, 19–31 (2009).

219. Nogalska, A., Terracciano, C., D’Agostino, C., King Engel, W. & Askanas, V. p62/SQSTM1 is overexpressed and prominently accumulated in inclusions of sporadic inclusion- body myositis muscle fibers, and can help differentiating it from polymyositis and dermatomyositis. Acta Neuropathol. 118, 407–413 (2009).

220. Hengstman, G. J. & van Engelen, B. G. Polymyositis invasion of non- necrotic muscle fibres, and the art of repetition. BMJ 329, 1464–1467 (2004).

221. Callender, L. A. et al. Human CD8+ EMRA T cells display a senescence- associated secretory phenotype regulated by p38 MAPK. Aging Cell 17, e12675 (2018).

222. Chong, L. K. et al. Proliferation and interleukin 5 production by CD8hi CD57+ T cells. Eur. J. Immunol. 38, 995–1000 (2008).

223. Henson, S. M. & Akbar, A. N. KLRG1—more than a marker for T cell senescence. Age 31, 285–291 (2009).

224. Akbar, A. N. & Henson, S. M. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289–295 (2011).

225. Melis, L., Van Praet, L., Pircher, H., Venken, K. & Elewaut, D. Senescence marker killer cell lectin- like receptor G1 (KLRG1) contributes to TNF- α production by interaction with its soluble E- cadherin ligand in chronically inflamed joints. Ann. Rheum. Dis. 73, 1223–1231 (2014).

226. Dumitriu, I. E. The life (and death) of CD4+CD28null T cells in inflammatory diseases. Immunology 146, 185–193 (2015).

227. Maly, K. & Schirmer, M. The story of CD4+CD28- T cells revisited: solved or still ongoing? J. Immunol. Res. 2015, 348746 (2015).

228. Lima, X. T. et al. Frequency and characteristics of circulating CD4+ CD28null T cells in patients with psoriasis. Br. J. Dermatol. 173, 998–1005 (2015).

229. Schirmer, M., Vallejo, A. N., Weyand, C. M. & Goronzy, J. J. Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4+CD28- T cells from rheumatoid arthritis patients. J. Immunol. 161, 1018–1025 (1998).

230. Schirmer, M. et al. Circulating cytotoxic CD8+ CD28- T cells in ankylosing spondylitis. Arthritis Res. 4, 71–76 (2002).

231. Liaskou, E. et al. Loss of CD28 expression by liver- infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis. Gastroenterology 147, 221–232 (2014).

232. Dejaco, C. et al. NKG2D stimulated T cell autoreactivity in giant cell arteritis and polymyalgia rheumatica. Ann. Rheum. Dis. 72, 1852–1859 (2013).

233. Dejaco, C., Duftner, C., Klauser, A. & Schirmer, M. Altered T cell subtypes in spondyloarthritis, rheumatoid arthritis and polymyalgia rheumatica. Rheumatol. Int. 30, 297–303 (2010).

234. Duftner, C. et al. Prevalence, clinical relevance and characterization of circulating cytotoxic CD4+CD28- T cells in ankylosing spondylitis. Arthritis Res. Ther. 5, R292–R300 (2003).

235. Pinto- Medel, M. J. et al. The CD4+T cell subset lacking expression of the CD28 costimulatory molecule is expanded and shows a higher activation state in multiple sclerosis. J. Neuroimmunol. 243, 1–11 (2012).

236. Garcia de Tena, J. et al. Active Crohn’s disease patients show a distinctive expansion of circulating memory CD4+CD45RO+CD28null T cells. J. Clin. Immunol. 24, 185–196 (2004).

237. Leblanc, F., Zhang, D., Liu, X. & Loughran, T. P. Large granular lymphocyte leukemia: from dysregulated pathways to therapeutic targets. Future Oncol. 8, 787–801 (2012).

238. Mastaglia, F. L. et al. Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms. Neuromuscul. Disord. 23, 969–974 (2013).

239. Gang, Q. et al. The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis. Neurobiol. Aging 36, 1766.e1–1766.e3 (2015).

240. De Paepe, B. & De Bleecker, J. L. The nonnecrotic invaded muscle fibers of polymyositis and sporadic inclusion body myositis: on the interplay of chemokines and stress proteins. Neurosci. Lett. 535, 18–23 (2013).

241. De Paepe, B., Creus, K. K. & De Bleecker, J. L. Chemokines in idiopathic inflammatory myopathies. Front. Biosci. 13, 2548–2577 (2008).

242. Ivanidze, J. et al. Inclusion body myositis: laser microdissection reveals differential up- regulation of IFN- γ signaling cascade in attacked versus nonattacked myofibers. Am. J. Pathol. 179, 1347–1359 (2011).

243. Mammen, A. L. Autoimmune myopathies. Continuum 22, 1852–1870 (2016).

244. Mammen, A. L. Autoimmune myopathies: autoantibodies, phenotypes and pathogenesis. Nat. Rev. Neurol. 7, 343–354 (2011).

245. Mammen, A. L. Which nonautoimmune myopathies are most frequently misdiagnosed as myositis? Curr. Opin. Rheumatol. 29, 618–622 (2017).

246. Britson, K. A., Yang, S. Y. & Lloyd, T. E. New developments in the genetics of inclusion body myositis. Curr. Rheumatol. Rep. 20, 26 (2018).

247. Olive, M. et al. Expression of mutant ubiquitin (UBB+1) and p62 in myotilinopathies and desminopathies. Neuropathol. Appl. Neurobiol. 34, 76–87 (2008).

248. Olive, M. et al. TAR DNA- binding protein 43 accumulation in protein aggregate myopathies. J. Neuropathol. Exp. Neurol. 68, 262–273 (2009).

249. Duleh, S., Wang, X., Komirenko, A. & Margeta, M. Activation of the Keap1/Nrf2 stress response pathway in autophagic vacuolar myopathies. Acta Neuropathol. Commun. 4, 115 (2016).

250. Arahata, K. et al. Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses. Muscle Nerve Suppl. 2, S56–S66 (1995).

251. Gallardo, E. et al. Inflammation in dysferlin myopathy: immunohistochemical characterization of 13 patients. Neurology 57, 2136–2138 (2001).

252. Castets, P., Frank, S., Sinnreich, M. & Ruegg, M. A. “Get the balance right”: pathological significance of autophagy perturbation in neuromuscular disorders. J. Neuromuscul. Dis. 3, 127–155 (2016).

253. Varadhachary, A. S., Weihl, C. C. & Pestronk, A. Mitochondrial pathology in immune and inflammatory myopathies. Curr. Opin. Rheumatol. 22, 651–657 (2010).

254. Meyer, A. et al. IFN- β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis. Acta Neuropathol. 134, 655–666 (2017).

255. Nathan, J. A. et al. Immuno- and constitutive proteasomes do not differ in their abilities to degrade ubiquitinated proteins. Cell 152, 1184–1194 (2013).

256. Seifert, U. et al. Immunoproteasomes preserve protein homeostasis upon interferon- induced oxidative stress. Cell 142, 613–624 (2010).

257. Nagaraju, K. et al. Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum. 52, 1824–1835 (2005).

258. Correia, A. S., Patel, P., Dutta, K. & Julien, J. P. Inflammation induces TDP-43 mislocalization and aggregation. PLOS ONE 10, e0140248 (2015).

259. Zhong, Z. et al. NF- κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896–910 (2016).

260. Ozden, S. et al. Direct evidence for a chronic CD8+- T cell- mediated immune reaction to tax within the muscle of a human T cell leukemia/lymphoma virus type 1-infected patient with sporadic inclusion body myositis. J. Virol. 78, 10320–10327 (2004).

261. Green, D. R., Droin, N. & Pinkoski, M. Activation- induced cell death in T cells. Immunol. Rev. 193, 70–81 (2003).

262. Vallejo, A. N., Schirmer, M., Weyand, C. M. & Goronzy, J. J. Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways. J. Immunol. 165, 6301–6307 (2000).

263. Spaulding, C., Guo, W. & Effros, R. B. Resistance to apoptosis in human CD8+T cells that reach replicative senescence after multiple rounds of antigen- specific proliferation. Exp. Gerontol. 34, 633–644 (1999).

264. Posnett, D. N., Edinger, J. W., Manavalan, J. S., Irwin, C. & Marodon, G. Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+CD28- cytotoxic effector clones. Int. Immunol. 11, 229–241 (1999).

265. Hodge, G. & Hodge, S. Steroid resistant CD8+CD28null NKT- like pro- inflammatory cytotoxic cells in chronic obstructive pulmonary disease. Front. Immunol. 7, 617 (2016).

266. Pandya, J. M. et al. Effects of conventional immunosuppressive treatment on CD244+(CD28null) and FOXP3+T cells in the inflamed muscle of patients with polymyositis and dermatomyositis. Arthritis Res. Ther. 18, 80 (2016).

267. Pearl, J. P. et al. Immunocompetent T cells with a memory- like phenotype are the dominant cell type following antibody- mediated T cell depletion. Am. J. Transplant. 5, 465–474 (2005).

268. Olnes, M. J. et al. Effects of systemically administered hydrocortisone on the human immunome. Sci. Rep. 6, 23002 (2016).

269. Bohan, A. & Peter, J. B. Polymyositis and dermatomyositis (first of two parts). N. Engl. J. Med. 292, 344–347 (1975).

270. Shah, M. V. et al. Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes. Blood 112, 770–781 (2008).

271. Bareau, B. et al. Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases. Haematologica 95, 1534–1541 (2010).

272. Dumitriu, B. et al. Alemtuzumab in T cell large granular lymphocytic leukaemia: interim results from a single- arm, open- label, phase 2 study. Lancet Haematol. 3, e22–e29 (2016).

273. Mohan, S. R. et al. Therapeutic implications of variable expression of CD52 on clonal cytotoxic T cells in CD8+large granular lymphocyte leukemia. Haematologica 94, 1407–1414 (2009).

274. Gitelman, S. E. et al. Antithymocyte globulin therapy for patients with recent- onset type 1 diabetes: 2 year results of a randomised trial. Diabetologia 59, 1153–1161 (2016).

275. Scarsi, M. et al. The number of circulating recent thymic emigrants is severely reduced 1 year after a single dose of alemtuzumab in renal transplant recipients. Transpl. Int. 23, 786–795 (2010).

276. Neujahr, D. C. et al. Accelerated memory cell homeostasis during T cell depletion and approaches to overcome it. J. Immunol. 176, 4632–4639 (2006).

277. Crepin, T. et al. ATG- induced accelerated immune senescence: clinical implications in renal transplant recipients. Am. J. Transplant. 15, 1028–1038 (2015).

278. Macedo, C. et al. Long- term effects of alemtuzumab on regulatory and memory T cell subsets in kidney transplantation. Transplantation 93, 813–821 (2012).

279. Ramos- Casals, M. & Brito- Zeron, P. Emerging biological therapies in primary Sjögren’s syndrome. Rheumatology 46, 1389–1396 (2007).

280. Lombard, M. et al. Cyclosporin A treatment in primary biliary cirrhosis: results of a long- term placebo controlled trial. Gastroenterology 104, 519–526 (1993).

281. Mitchison, H. C. et al. A pilot, double- blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss. Hepatology 10, 420–429 (1989).

282. Wiesner, R. H. et al. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N. Engl. J. Med. 322, 1419–1424 (1990).

Nature reviews | Rheumatology

R e v i e w s

283. Fujihara, T. et al. Preferential localization of CD8+αEβ7

+T cells around acinar epithelial cells with apoptosis in patients with Sjögren’s syndrome. J. Immunol. 163, 2226–2235 (1999).

284. Kita, H. Autoreactive CD8-specific T cell response in primary biliary cirrhosis. Hepatol. Res. 37 (Suppl. 3), 402–405 (2007).

285. Si, L., Whiteside, T. L., Schade, R. R., Starzl, T. E. & Van Thiel, D. H. T- Lymphocyte subsets in liver tissues of patients with primary biliary cirrhosis (PBC), patients with primary sclerosing cholangitis (PSC), and normal controls. J. Clin. Immunol. 4, 262–272 (1984).

286. Bjorkland, A. et al. Blood and liver- infiltrating lymphocytes in primary biliary cirrhosis: increase in activated T and natural killer cells and recruitment of primed memory T cells. Hepatology 13, 1106–1111 (1991).

287. Tasaki, S. et al. Multiomic disease signatures converge to cytotoxic CD8 T cells in primary Sjögren’s syndrome. Ann. Rheum. Dis. 76, 1458–1466 (2017).

288. Tsuda, M. et al. Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis. Hepatology 54, 1293–1302 (2011).

289. Yang, Z., Goronzy, J. J. & Weyand, C. M. Autophagy in autoimmune disease. J. Mol. Med. 93, 707–717 (2015).

290. Hosomi, S., Kaser, A. & Blumberg, R. S. Role of endoplasmic reticulum stress and autophagy as interlinking pathways in the pathogenesis of inflammatory bowel disease. Curr. Opin. Gastroenterol. 31, 81–88 (2015).

291. Grootjans, J., Kaser, A., Kaufman, R. J. & Blumberg, R. S. The unfolded protein response in immunity and inflammation. Nat. Rev. Immunol. 16, 469–484 (2016).

292. Sasaki, M., Miyakoshi, M., Sato, Y. & Nakanuma, Y. A possible involvement of p62/sequestosome-1 in the process of biliary epithelial autophagy and senescence in primary biliary cirrhosis. Liver Int. 32, 487–499 (2012).

293. Sasaki, M., Miyakoshi, M., Sato, Y. & Nakanuma, Y. Autophagy mediates the process of cellular senescence characterizing bile duct damages in primary biliary cirrhosis. Lab. Invest. 90, 835–843 (2010).

294. Sasaki, M., Yoshimura- Miyakoshi, M., Sato, Y. & Nakanuma, Y. A possible involvement of endoplasmic reticulum stress in biliary epithelial autophagy and senescence in primary biliary cirrhosis. J. Gastroenterol. 50, 984–995 (2015).

295. Katsiougiannis, S., Tenta, R. & Skopouli, F. N. Endoplasmic reticulum stress causes autophagy and apoptosis leading to cellular redistribution of the autoantigens Ro/Sjögren’s syndrome- related antigen A (SSA) and La/SSB in salivary gland epithelial cells. Clin. Exp. Immunol. 181, 244–252 (2015).

296. Leff, R. L., Miller, F. W., Hicks, J., Fraser, D. D. & Plotz, P. H. The treatment of inclusion body myositis: a retrospective review and a randomized, prospective trial of immunosuppressive therapy. Medicine 72, 225–235 (1993).

297. Soueidan, S. A. & Dalakas, M. C. Treatment of inclusion- body myositis with high- dose intravenous immunoglobulin. Neurology 43, 876–879 (1993).

298. Amato, A. A. et al. Inclusion body myositis: treatment with intravenous immunoglobulin. Neurology 44, 1516–1518 (1994).

299. Barohn, R. J., Amato, A. A., Sahenk, Z., Kissel, J. T. & Mendell, J. R. Inclusion body myositis: explanation for poor response to immunosuppressive therapy. Neurology 45, 1302–1304 (1995).

300. Barohn, R. J. et al. Pilot trial of etanercept in the treatment of inclusion- body myositis. Neurology 66, S123–S124 (2006).

301. Kosmidis, M. L., Alexopoulos, H., Tzioufas, A. G. & Dalakas, M. C. The effect of anakinra, an IL1 receptor antagonist, in patients with sporadic inclusion body myositis (sIBM): a small pilot study. J. Neurol. Sci. 334, 123–125 (2013).

302. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT00079768 (2010).

303. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT00917956 (2010).

304. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01519349 (2017).

305. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02483845 (2017).

306. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02250443 (2018).

307. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT00802815 (2014).

308. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT00769860 (2017).

309. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01423110 (2017).

310. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01925209 (2017).

311. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02481453 (2019).

312. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02753530 (2018).

Competing interestsS.A.G. is an inventor of intellectual property related to myosi-tis diagnostics and therapeutics, owned and managed by Brigham and Women’s Hospital; he receives sponsored research from Pfizer, Inc. and is a founder of Abcuro, Inc.

Publisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

www.nature.com/nrrheum

R e v i e w s