REVIEWS

I­nclusion body myositis: clinical

features and pathogenesis
Steven 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.

1
Department of Neurology,
Brigham and Women’s
Hospital, Boston, MA, USA.
2
Children’s Hospital
Computational Health
Informatics Program, Boston
Children’s Hospital, Boston,
MA, USA.
3
Harvard Medical School,
Boston, MA, USA.
e-​mail: sagreenberg@
bwh.harvard.edu
https://doi.org/10.1038/
s41584-019-0186-x
Inclusion body myositis (IBM) is a slowly progressive
skeletal muscle disease with unique clinical and patho­
logical 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 myop­
athies. 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 refine­
ment, 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, dermato­
myositis, 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 clini­
cal features, and addresses key questions regarding
its pathogenesis.
History of IBM
A 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 iden­
tification 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 26-year-​old patient with a limb-​girdle pat­
tern 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

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Key points
• Inclusion body myositis (IBM) progresses slowly and is commonly misdiagnosed
initially as arthritis or polymyositis; IBM is associated with cardiovascular
complications and other autoimmune diseases and has a high economic cost.
• IBM has unique physical examination features (such as finger flexor and knee
extensor weakness) that distinguish it from most other muscle diseases.
• IBM has a greater range of autoimmune T cell abnormalities than any other muscle
disease; treatment refractoriness has paradoxically given rise to the view that IBM is
not an autoimmune disease.
• Degenerative abnormalities that can occur in IBM include numerous myofibre protein
aggregates associated with endoplasmic reticulum stress.
• Degenerative abnormalities might occur following autoimmunity in cell culture and
mouse models and following immune cell dysfunction in patients infected with HIV
or human T cell lymphotropic virus type 1.
• Treatment refractoriness probably reflects the inability of current therapies to inhibit
or deplete the highly differentiated population of effector memory and terminally
differentiated effector T cells present in IBM.
quadriceps weakness and distal weakness (not specified
as the wrist and finger flexor involvement now associ­
ated with the disease)5; in hindsight, the authors mis­
takenly 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 (mono­
clonal 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 rec­
ognition 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 char­
acterization 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 autoanti­
bodies78 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 dis­
cussed 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 second­
ary to autoimmunity83–85; the recognition of the genetic
linkage of IBM to the HLA region (like other auto­
immune diseases)86, which was confirmed by many sub­
sequent 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.
Nomenclature
Several similar abbreviations of other diseases have cre­
ated confusion regarding IBM. IBM is an abbreviation
for ‘inclusion body myositis’ not ‘inclusion body myop­
athy’. 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 dis­
orders that have been arbitrarily split off into heredi­
tary 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 infil­
tration. 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 patho­
logical 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 typi­
cal 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 scle­
rosis, and probably results from the associated genetic
risk from HLA variants present in IBM and common to
many autoimmune diseases.
Clinical features of IBM
Epidemiology and economic costs
Calculations of the prevalence of IBM are probably
underestimates because of the high rate of misdiag­
nosis. In a rigorous meta-​analysis published in 2017, the
pooled prevalence of IBM was 46 patients per million104.
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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

First clinical and Recognition of CD28+ (CD244–) highly

pathological case mitochondrial differentiated cytotoxic
series description abnormalities CD8+ T cell identified
Genome-wide studies
Identification of Congo Identification of B cell confirm linkage to
First description red protein aggregates role using microarray common autoimmune
of IBM pathology in 0.5% of myofibres technology disease haplotype

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

Identification of Recognition that rimmed Recognition of highly

cytotoxic CD8+ T cells vacuoles are commonly differentiated effector
using immunohisto- absent in IBM muscle and effector memory
chemistry CD8+ T cells in IBM
muscle and blood
Name Origin of First blinded overlapping with T-LGLL
‘IBM’ used β-amyloid placebo
in case theory controlled Identification of a
report trial (IVIG) IBM-associated
circulating autoantibody

1887 1891 1978 1991 2018

DM DM DM DM
PM
IBM IBM IBM
PM
PM IMNM IMNM
PM 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.

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 symp­
tom 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-​to-female
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 (ICD-
9CM) code existed for IBM, making estimates of the
prevalence and health-​care costs from US medical pay­
ment 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 dol­
lars per year in excess of the costs of matched controls and
a prevalence of 84 per million in people >65 years of age114.
Clinical features
IBM 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 neuromus­
cular 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 present­
ing symptom42,116 but is commonly present if sought by
history or radiological studies116,117. Dysphagia becomes
more evident as the disease progresses and might

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a b

c d e Normal

IBM

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.

result in nutritional deficiency, weight loss and aspira­
tion pneumonia, which is a major cause of mortality in
IBM40,43,118. Cricopharyngeal sphincter dysfunction can
be present116, and cricopharyngeal muscle biopsy sam­
ples 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 p ­ hysical
examination features is sufficiently high that, when prop­
erly appreciated, the additional value of muscle histo­
pathology 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 abduc­
tion. 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 find­
ings include the following: orbicularis oculi weakness
(41% in one series)38; greater weakness of elbow flex­
ion (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 paraly­
sis of all deep and superficial finger flexors with preser­
vation of the adductor pollicis and lumbricals (muscles
of the hands that flex the metacarpophalangeal joints)38
results in the common end-​stage IBM hand appear­
ance, allowing patients to grasp objects through thumb
adduction and finger flexion at the metacarpophalan­
geal 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 exten­
sor 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 charac­
teristic 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.

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Front view Back view
Shoulder
abduction
Elbow Elbow
flexion extension
Wrist
flexion
Finger
flexion Hip abduction
and extension
Hip
Knee
flexion
extension
Ankle
dorsiflexion
Muscles preferentially affected in IBM
Muscles preferentially affected in other inflammatory myopathies
Muscles commonly affected in both
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.
Abnormal laboratory test results typically include
modest increases in serum levels of creatine phospho­
kinase in most patients and a monoclonal immuno­
globulin population (by serum immunofixation) in
~15% of patients97,134. Antinuclear antibodies, anti-​Ro
or anti-​La antibodies, and rheumatoid factor positiv­
ity 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
(HTLV-1) might be considered in particular circum­
stances, such as young age of IBM onset or the pres­
ence of factors that suggest an underlying increased
risk of being infected with HIV or HTLV-1. Additional
blood b­ iomarkers 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 autoantibody
Serum 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 sen­
sitivity of anti-​cN1A antibody assays for IBM has varied
widely79,80,135–140, ranging from 37%140 to 76%135, and is
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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 preva­
lence of these antibodies in systemic lupus erythematosus
(0–20%) and Sjögren syndrome (0–36%)98,137,138,140–142.
Microscopic pathology
The 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 pres­
ence of COX−SDH+ and ragged red myofibres (Fig. 4e).
Haematoxylin and eosin staining and trichrome stain­
ing 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 com­
monly, 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 myopa­
thies145. 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 criteria
Various diagnostic criteria for IBM were proposed
from 1987 to 2002 through individual author opin­
ion31,150–152 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 diagnos­
tic sensitivity of these criteria, with many patients with
IBM failing to meet them122,158. In particular, the criteria
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a b c

20 µm 20 µm 20 µm

d e f

1
2

20 µm 20 µm 10 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.

for the detection of rimmed vacuoles by microscopy,
often referred to as biopsy-​proven IBM, can be restric­
tive9,122,158. Criteria with sensitivity of 90% and speci­
ficity 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 comorbidities
IBM 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 diagno­
stic criteria for LGLL, and a small number have overt
leukaemia with cytopenias64.
IBM might develop from HIV162–165 and HTLV-1
(refs 164,166) 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 preva­
lence 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% ver­
sus 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 corticoste­
roids114, and are probably instead related to the systemic
inflammatory environment resulting from autoimmun­
ity, as in other forms of inflammatory myopathy168–173
and other autoimmune diseases174,175.
Progression
IBM is a progressive disease, with mean or median loss
of device-​free ambulation from symptom onset esti­
mated at 7.5–10 years for a cane42,44 and 13–15 years
for a wheelchair38,39,44. Hand impairment and dyspha­
gia ­progression are less well quantified. Published
longitudinal data regarding IBM progression are insuf­
ficient41,43–47, 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.

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IBM therapeutics one showed directional trends towards minor benefit in

Standard of care for most patients with IBM involves limb and swallowing muscles, with some statistical effi­
strictly nonpharmacological management, includ­ cacy95, and the other two (one that included prednisone,
ing emotional support, physical therapy, education which might have been counterproductive) showed no
on fall precautions and exercise176–178, and dyspha­ directional trend or statistical benefit in limb or swallow­
gia evaluation. Dysphagia can be treated transiently ing muscles185,186. For such a slowly progressive disease,
with ­pharyngoesophageal dilatation or cricopharyn­ 3–6 months of therapy seems insufficient for a clinical
geal myotomy118. Few physicians routinely prescribe trial efficacy end point. Preliminary results of a trial of
immunosuppressant therapies, with the belief that such rapamycin have been reported in an abstract68.
­therapies result in transient responses at best14,38,97. Trials of two muscle-​building therapies (oxandro­
lone and bimagrumab), neither of which addresses the
Expert opinion and open-​label trials specific mechanism of myofibre injury, have shown
The use of corticosteroids in IBM derives from expert some statistical benefits. Oxandrolone190 showed statis­
opinion. Corticosteroids decrease serum levels of cre­ tical efficacy for multiple end points. In a small study
atine phosphokinase, which is sometimes mistaken for (n = 14)191, bimagrumab showed improvement in skeletal
a clinical response; however, the disease continues to muscle mass. In a registration trial (n = 240)192 presented
progress in almost all patients32. Some patients with in abstract, bimagrumab again showed improvement in
substantial proximal weakness, an atypical phenotype, whole-​b ody skeletal muscle mass and in a patient-​
do experience improvement in proximal strength32. reported secondary outcome measure, but no statis­
A view that corticosteroids might even worsen IBM tical efficacy in the primary outcome measure (the
has been suggested on the basis of retrospective cross-​ 6-minute walk distance). A trial of arimoclomol did not
sectional data in which there were more patients with achieve proof of concept of the hypothesized mechanis­
severe disease in a treated cohort than there were in tic effect (increase in muscle levels of HSP70) or show
an untreated cohort. However, this view is compli­ clinical efficacy100.
cated by an uncontrolled confounder — the treated
cohort also had substantially longer duration of disease Pathogenesis of IBM
diagnosis than the untreated cohort (50 months versus No feature of IBM has generated more debate and
18 months)39. The marked type 2 muscle fibre atrophy ­speculation than the nature of its pathogenesis. IBM is
present in IBM179 is expected to worsen with cortico­ often viewed as both a degenerative and an autoimmune
steroid treatment and is another theoretical argument disease. A number of perspectives have shaped these
against its use. views and are addressed here.
Broad lymphocyte depletion strategies achieved
­statistical efficacy for strength measurements in two Degenerative biomarkers and mechanisms
open-​label comparator group studies: antithymocyte Various IBM muscle histochemical abnormalities have
globulin (ATG) with methotrexate compared with collectively been called degenerative (Fig. 5). However,
methotrexate alone (P = 0.02)66 and alemtuzumab67 referring to IBM as a degenerative disease does not pro­
compared with baseline (pretreatment; P < 0.002). vide information on the mechanisms by which the mus­
Intravenous immunoglobulin (IVIG) or subcuta­ cle is injured. The degenerative features of IBM include
neous immunoglobulin (SCIG) has been reported to rimmed vacuoles and the related myonuclear degener­
be helpful specifically for patients with IBM-​associated ation5,193, mitochondrial pathology82,194,195 and myofibre
dysphagia180–182. Results of an open-​label trial of threecytoplasmic protein aggregates.
combined interventions (follistatin gene therapy, pred­ The concept of protein aggregation has dominated
nisone and exercise) were published as an interim mechanistic thought since the early 1990s, with inter­
analysis; somewhat c­ ontroversially, the efficacy was est initially focused on four muscle biomarkers (amy­
attributed to follistatin gene therapy alone despite beingloid detected by Congo red81, ubiquitin196, β-​amyloid197
tested only in combination183,184. An open-​label trial of and tau198). The number of distinct molecules reported
exercise alone has demonstrated statistical efficacy for as aggregated grew to >80 by 2010 (ref. 199) . A the­
strength measurements178. ory of β-​amyloid accumulation and myotoxicity has
­dominated144,200–202 and continues to be featured in con­
Blinded placebo-​controlled trials ceptual models of IBM10. In hindsight, a published belief
Although the literature is filled with the view that IBM in this theory now seems to be out of proportion to the
is treatment refractory, high-​quality data on therapy for data supporting it. Indeed, citation distortions in its cita­
IBM are very limited, with published blinded placebo-​ tion network might have contributed to overvaluing the
controlled clinical trials for only five FDA-​approved role of β-​amyloid deposition in IBM pathogenesis203,204.
therapeutics (IVIG with and without prednisone95,185,186, The supporting data were based on methods (immuno­
methotrexate187, IFNβ188,189 and oxandrolone190) and two histochemistry) and reagents (anti-​β-amyloid antibodies)
investigational therapeutic candidates (bimagrumab191 that do not distinguish β-​amyloid from its precursor pro­
and arimoclomol100) (Table 1). tein203, the latter reported as non-​specifically expressed in
Oral methotrexate, 5–20 mg daily for 1 year, showed regenerating myofibres in all muscle diseases205. Similar
a directional trend towards benefit but no statistical interest in tau protein deposits (using SMI-31 immuno­
efficacy187. Dysphagia was not assessed in this trial. reactivity) also occurred206 and has similar limitations207.
Of three trials of IVIG of 3–6 months treatment duration, Focus on these biomarkers proceeded for decades despite

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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 degen­
erative biomarkers (p62, LC3 and TDP43 (refs211,212)) has
evolved around the unfolded protein response and endo­
plasmic 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 show­
ing superior biomarker performance compared with
Congo red amyloid, ubiquitin, β-​amyloid or SMI-31
immunoreactivity. For example, one comparative study
found TDP43 aggregates in 23% of IBM myofibres
compared with Congo red amyloid in 0.6%, SMI-31 in
0.8% and β-​amyloid in 0%218. Another study found
both p62 and TDP43 aggregates in 12% of IBM myo­
fibres 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 mechanisms
T 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 obvi­
ous histological feature of IBM muscle. The invasion of

Table 1 | IBm clinical trials

therapeutic year of year of Number Duration of outcome measures: Refs
clinical trial publication of treatment primary (secondary)
registration patients (months)
Open-​label studies
Azathioprine + methotrexate + NA 1993 11 3–6 MMT 296

intravenous methotrexate
IVIG NA 1993 4 2 Muscle strength 297

1994 9 1–3 MMT 298

Prednisone NA 1995 8 6–12 Muscle strength 299

Antithymocyte NA 2003 11 12 QMT 66

globulin + methotrexate versus

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

therapy + prednisone + exercise

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 311

quadriceps
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.

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Perimysium
Endomysium
Muscle fibre
Muscle
fascicle
Infiltrating
T cells
Healthy IBM
Protein
aggregate
Capillary
Vacuole
Autoimmune features Degenerative features
Infiltrating cells • Rimmed vacuoles
• T cells (mainly CD8+ cytotoxic T cells) • Myonuclear degeneration
• Plasma cells • Mitochondrial pathology
• Macrophages • Protein aggregates
• Myeloid dendritic cells
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%).
myofibres by cytotoxic T cells is easily visible by micros­
copy. IBM might be the only muscle disease involving
cytotoxic T cell-​mediated myofibre injury; although
polymyositis has been said to share this feature, con­
siderable 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
Nature Reviews | Rheumatology
Reviews
of the effector memory T (TEM) cell and terminally differ­
entiated 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 cyto­
toxic capacities222–225. CD8+CD28− T cells in IBM blood
are major producers of IFNγ63. Highly d ­ ifferentiated
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 dif­
ferentiated 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-​killer-like 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 autoanti­
bodies have been known to be present in polymyosi­
tis 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, com­
pared with the large numbers of T cells (75%)48, com­
bined 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-​hypothesis-driven 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 pau­
city 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 identifica­
tion of circulating blood ­autoantibodies78 and the target
antigen of these autoantibodies, cN1A (NT5C1A)79,80.
Genetics. Strong genetic linkage of IBM has been estab­
lished exclusively to immune gene variants, specifi­
cally 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 experiments 73. The marked elevation
Reviews

Blood Chronic stimulation 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
TCR CD28 higher in myofibres invaded by CD8+ T cells than in
Naive or non-​invaded myofibres242.
memory
T cells Is IBM an autoimmune disease?
IBM has sometimes been viewed as not being an auto­
CD4+ T cell CD8+ T cell
immune disease202, or the autoimmunity is viewed as
• Treatment refractory being a secondary phenomenon. Some reviews have
• Leukaemia-like phenotype classified it as a non-​immune myopathy or excluded
• Loss of CD28 expression
• Gain of expression of it from discussions of autoimmune myopathies243–245.
CD57, CD244 and KLRG1 Yet the magnitude of expression of numerous biomark­
ers of T cell autoimmunity is far higher in IBM muscle
than in any other muscle disease, including other forms
Clonal highly of myositis. These markers include an abundance of
differentiated T cells (particularly CD8+ cytotoxic T cells), the cytotoxic
cytotoxic
T cells molecules granzymes and perforin and an a­ bundance of
T cell-​related chemokines and cytokines.
The invasion of non-​necrotic muscle fibres by cyto­
Circulating T cells
toxic T cells has long been a diagnostic feature of IBM;
might lead to other invaded fibres were found to be approximately eight
autoimmune features times more common than myofibres containing amyloid
Endothelium
(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 iden­
tification 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
IFNγ
unrecognized Mendelian genetic disorder and further­
more has disclosed strong linkage to the HLA region,
viewed by some as providing the strongest evidence to
date that autoimmunity is causative in IBM246.
↑ MHC
MHC class I
class I Evidence for causality in IBM
Although IBM degenerative and autoimmune biomark­
ers are associated, establishing causality will ultimately
require human clinical trials of mechanistically unam­
Myofibre
Cytotoxic biguously specific interventions. Currently, the evidence
granules suggests that causality flows from autoimmunity to
degeneration, not the reverse (Fig. 6).
• ER stress First, genetic diseases with biomarkers of degener­
• Protein aggregation Myofibre damage
ation do not result in autoimmunity. Although most of
Fig. 6 | Proposed pathogenesis of IBM: highly differentiated cytotoxic T cells drive the >80 proteins that aggregate in IBM muscle have also
IBm myofibre injury. Chronic antigenic stimulation of T cells results over time in been reported to aggregate in hIBM, these diseases do
transformation of naive or early effector memory T cells (TEM1 and TEM2 cells) into a highly not manifest autoimmunity. Specifically, TDP43, p62 and
differentiated population of clonal cytotoxic CD8+ T cells (TEM3, TEM4 and terminally ubiquitylated protein aggregates are prominent in biopsy
differentiated (TEMRA) cells), identified by CD8+CD28−, CD8+CD244+, CD8+CD57+ or samples from patients with genetic myotilinopathies and
CD8+KLRG1+) and CD4+ T cells (CD4+CD28−) present in inclusion body myositis (IBM) desminopathies247,248 and VCP-​mutation hIBM217 with­
muscle and blood. These late stage T cells have the following features: they are out autoimmunity. Vacuolar myopathy produced by
highly cytotoxic and have escaped requirements for costimulation (for example, loss colchicine or hydrochloroquine in patients is associated
of CD28); they invade myofibres and injure them through release of cytotoxic granules with ER stress and with p62 and LC3 aggregates249, but
(such as perforin and granzymes); and they produce abundant IFNγ, which results in
not autoimmunity. Some genetic muscular dystrophies,
upregulation of MHC class I on myofibres and causes endoplasmic reticulum (ER) stress
and aggregation of proteins (including p62 and TDP43). These highly differentiated particularly facioscapulohumeral muscular dystrophy
CD8+ T cells have similar features to those present in large granular lymphocytic and dysferlinopathies, have inflammation, but only
leukaemia, including resistance to corticosteroids. Furthermore, some patients with necrotic myofibres are invaded and only by macrophages
IBM have features of disease other than just muscle manifestations, such as (which are CD4+) and perhaps CD4+ T cells250,251. Many
autoimmune features in bone marrow (cytopenias) or epithelial secretory tissue other genetic disorders have mouse models demon­
(Sjögren syndrome). TCR, T cell receptor. strating impaired autophagy, with p62 and LC3 mouse

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 Reviews

muscle aggregates without autoimmunity252. Similarly, criteria that classify all patients with IBM as having poly­
the strong correlation between IBM muscle mitochon­ myositis269, corticosteroids did not result in a reduction
drial patho­logy (number of COX-​deficient myofibres) of invading CD28− T cells in the muscle266. In retrospec­
and auto­immunity (number of invading T cells)85 sug­ tive comparisons, patients with IBM receiving long-​term
gests that the mitochondrial pathology results from immunosuppressive treatment (a mean of 35 mg daily of
autoimmunity, as muscle genetic mitochondrial myopa­ prednisone for a mean of 5.7 years) had the same number
thies do not produce autoimmunity. Dermatomyositis, of invaded myofibres as patients with IBM not receiving
which is also autoimmune, is similarly accompanied by treatment208. In prospective intervention trials, patients
mitochondrial abnormalities253,254. with IBM receiving corticosteroids or IVIG did not expe­
Second, intervention studies show that manipulat­ rience substantial reduction in the total muscle-​invading
ing the immune system can produce skeletal muscle T cell population54,186. Because of its close mechanistic
and other cellular protein aggregate biomarkers. Thus, pathogenesis, experience with T-​LGLL is informative
in vitro treatment of cultured human myoblasts with for IBM. The T-​LGLL population of highly differenti­
cytokines (IL-1β and IFNγ) produces protein aggre­ ated clonal T cells is resistant to apoptosis237,270 and is
gates83, treatment of various mouse cells with IFNγ not reduced following treatment with corticosteroids271
causes ubiquitylated inclusions255,256, and forced overex­ or alemtuzumab 272, the latter potentially owing to
pression of MHC class I in mouse muscle cells causes variable expression of CD52, its target, on these cells273.
ER stress257. Inflammatory stimuli ­(lipopolysaccharide) Two other immune therapies have undergone open-​
cause in vitro cytoplasmic mislocalization of TDP43 in label IBM clinical trials and have shown trends towards
microglia and astrocytes258 and p62 accumulation in efficacy: ATG66 and alemtuzumab67. ATG274 and alemtu­
macrophages259. In vivo upregulation of muscle MHC zumab275 rapidly deplete nearly 100% of blood CD4+ and
class I (which is highly induced by IFNγ) alone is suffi­ CD8+ T cells, but the subsequent immune reconstitution
cient in mouse models to result in ER stress and a severe results in paradoxical expansion above pretreatment
myopathy with rimmed vacuoles84. Third, a single study levels (known as homeostatic proliferation276) of highly
found that purified serum blood immunoglobulin frac­ differentiated pathogenic TEM and TEMRA cells, identified
tions from patients positive for anti-​cN1A with IBM as CD45RA−CD62L− T cells267, CD28−CD57+ T cells277
cause muscle degenerative p62 protein aggregation in and CD45RO−CD62L− T cells278. Furthermore, T regu­
cell culture and mouse models, although only in a small latory cells, which are potentially beneficial to con­
proportion of muscle cells or fibres98. trolling autoimmune disease, are decreased in number
Finally, proof that causality flows from autoimmun­ compared with pretreatment levels after alemtuzumab
ity to degenerative muscle pathology in people comes immune reconstitution278.
from the existence of the clinical syndromes of HIV-​ Finally, other autoimmune diseases are known to be
associated IBM and HTLV-1-associated IBM162–164,166,260. treatment refractory, including Sjögren syndrome and
HIV and HTLV-1 infect T cells; their antigens are primary biliary cholangitis (PBC)279–282. Like IBM, both
present in IBM endomysial T cells and macrophages diseases involve CD8+ T cell-​mediated damage (in exo­
but not myofibres164,166,260. These syndromes demon­ crine epithelial cells in Sjögren syndrome283 and bile duct
strate that an external event that alters the function of cholangiocytes in PBC284–286), progress slowly and have
the immune system can produce the full clinical and cytotoxic T cell genomic signatures and expansions of
pathological picture of IBM including the degenera­ the highly differentiated CD8+ TEMRA population287,288.
tive biomarkers of rimmed vacuoles and p62, LC3 and
TDP43 cytoplasmic aggregates163. Protein aggregates in autoimmune diseases
A role for ER stress and autophagy has been identified
Why is IBM treatment refractory? in other autoimmune diseases289–291. Two main histolog­
The refractoriness of IBM might suggest that it is a ical markers of IBM that are argued to indicate degen­
non-​autoimmune degenerative disease. However, treat­ eration, p62 (refs211,212) and LC3 (ref.212), are aggregated
ment refractoriness might instead suggest an autoim­ in cholangiocytes in PBC292. Other markers of ER stress
mune process in which the immune system has escaped and autophagy are also aggregated in PBC cholangio­
from typical checkpoints designed to restrain it, such cytes293,294 and Sjögren syndrome salivary gland epithe­
as lymphocyte apoptosis and lymphocyte activation-​ lial cells295. Why then has the field of IBM attracted so
induced cell death261. The highly differentiated effec­ much more interest in protein aggregates than other
tor memory and effector cytotoxic CD4+ and CD8+ autoimmune diseases? Perhaps it is simply easier to see
T cells (loss of CD28 and gain of CD244, CD57 and these cytoplasmic aggregates under the microscope in
KLRG1 expression, as discussed above) present in skeletal muscle than in other tissues. Skeletal muscle
IBM are resistant to apoptosis and activation-​induced fibres are unique syncytial structures that are densely
cell death229,262–264. packed with large proteins undergoing constant turno­
Unlike naive T cells, highly differentiated blood-​ ver; they have larger proportions of cytoplasm and larger
derived human T cells are resistant to corticosteroid cross-​sectional areas (10,000–20,000 μm2; approximately
inhibition ex vivo265–267. Individuals treated with cortico­ 50–100 times larger) than most other cells. There simply
steroids have reduced numbers of naive CD8+ T cells in is not sufficient room in cell types other than myofibres
their blood but increased numbers of highly differen­ for large cytoplasmic aggregates, such as p62 aggregates
tiated effector memory CD8+ T cells268. In a cohort of with sizes of 5–50 μm2, to accumulate and become
patients with a diagnosis of polymyositis, defined using visible by microscopy.

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Reviews

Conclusions as treatment refractory, only very limited therapeutic

Tremendous 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
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 cor­
ticosteroids 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

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Competing interests
S.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.
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