FOCUS ON MYOSITIS

REVIEWS
Treatment in myositis
Chester V. Oddis* and Rohit Aggarwal
Abstract | As with the treatment of many immune-mediated diseases, managing myositis
encompasses diverse factors, which present a challenge to the physician caring for these
patients. The idiopathic inflammatory myopathies (IIMs, also known as myositis), are
fundamentally heterogeneous; many contributory immunological perturbations are involved in
the pathogenesis of myositis, leading to varying clinical phenotypic presentations. Targeting any
one or several of these deleterious pathways with a therapeutic agent might seem reasonable,
but the desired response is not uniformly predictable. The presence of many serious
extramuscular manifestations, such as severe skin rash, interstitial lung disease and arthritis,
complicates the management of myositis. Myositis is rare, and very few large treatment trial
results are available to guide clinicians. Outcome measures to effectively gauge treatment
responses have been available for only a few years, and response criteria that incorporate critical
core set measures continue to evolve. Nevertheless, a multitude of immunosuppressive and
immunomodulatory agents are available to clinicians managing myositis, and the emergence of
biologic agents targeting potential pathogenic pathways offers hope for mitigating or curing this
enigmatic group of diseases. Paradigm shifts in the nonpharmacological approach to treat
myositis have also occurred as more aggressive exercise regimens have shown benefit in patients,
even those with active disease.

Division of Rheumatology and
Clinical Immunology,
University of Pittsburgh
School of Medicine,
Pittsburgh, PA, USA.
*e-mail: cvo5@pitt.edu
doi:10.1038/nrrheum.2018.42
Published online 29 Mar 2018
The idiopathic inflammatory myopathies (IIMs), also
referred to as myositis, are fundamentally hetero-
geneous, as discussed in this Review. Despite the simple
name, myositis encompasses much more than simply
autoimmune inflammation in muscle tissue, and the
presence of extramuscular disease manifestations might
limit the use of specific immunosuppressive agents. For
example, lung involvement is one of the most common
features in myositis, the presence of which requires a
thoughtful approach that might narrow the range of
general treatment options available. Advances in identi-
fying the many immunological perturbations involved
in the pathogenesis of myositis have certainly informed
research into myositis therapies, resulting in clinical
trials employing interesting biologic therapies as phar-
maceutical companies move in the direction of treating
patients with rare autoimmune diseases. Furthermore,
novel therapeutic approaches are addressing the treat-
ment of the many serious or stubborn extramuscular
manifestations of myositis, such as severe skin rashes
in dermatomyositis, interstitial lung disease (ILD) and
even inflammatory arthritis and dysphagia. However,
myositis is rare, and there are very few large treatment
trials available to guide clinicians managing patients
with myositis. Newly developed outcome measures
and response criteria for accurately assessing treatment
responses in myositis are discussed in this Issue in a
Review by Rider and colleagues1. The recognition of the
protean clinical features seen with myositis, advances
in the understanding of myositis immunopathogenesis
and the availability of targeted therapy coupled with
more sophisticated outcome measures and robust
response criteria all validate the necessity of a thoughtful
treatment approach to myositis.
In this Review, we examine the many immuno-
suppressive and immunomodulatory agents available to
clinicians managing patients with myositis, as well as the
increasing number of biologic agents available that target
potential pathogenic pathways (FIG. 1). We also discuss
exercise, an often-neglected area in the management of
myositis, including the molecular basis that such ther-
apy is indeed anti-inflammatory. As alluded to above,
skin manifestations might dominate the clinical course
of dermatomyositis, and ILD remains the major mor-
bid complication of this disease. Hence, we specifically
consider the management of myositis beyond treating
inflammation of the muscle. Finally, we briefly discuss
future prospects in the management of this enigmatic
subset of autoimmune disease. In this Review, we do not
address the treatment of inclusion body myositis, a sub-
set of myositis notoriously refractory to pharmacological
intervention.

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Key points
• Managing myositis and its systemic complications represents a challenge to the
clinicians providing care as patients often have severe muscle weakness, notable skin
rashes and life-threatening organ involvement.
• Conventional therapies include glucocorticoids usually in combination with another
or multiple immunosuppressive agents, but biologic therapies targeting
immunopathogenic pathways are being increasingly utilized.
• Interstitial lung disease is a major cause of morbidity and mortality in myositis
requiring combinations of glucocorticoids, immunosuppressive drugs and agents that
modulate T cell function and deplete B cells.
• Exercise, once considered controversial in the management of myositis, has emerged
as an important adjunct in treating patients with myositis; molecular evidence
suggests that exercise regimens are both safe and anti-inflammatory.
Pathogenic pathways inform treatment
Insights from immunopathogenic pathways
The finding of T and B cell inflammatory infiltrates
in the skin and muscles of patients with polymyositis
or dermatomyositis, along with the identification of
myositis-associated autoantibodies, clearly point towards
a disease process that is responsive to glucocorticoid and
immunosuppressive therapy. Treatment with gluco-
corticoids and conventional immunosuppressive drugs
is a fairly nonspecific approach. However, B cells and
T cells, as well as the specific cytokines and receptors
implicated in myositis pathogenesis, serve as poten-
tially attractive therapeutic targets. In polymyositis,
myeloid dendritic cells activate B cells and contribute to
the formation of autoantibodies2, whereas in dermato-
myositis and to a lesser extent in polymyositis, plasma-
cytoid dendritic cells (professional producers of type I
interferon), are implicated in disease pathogenesis. In
dermatomyositis, genes induced by type I interferon
(known as a type I interferon signature) are highly
overexpressed in the muscle tissue; similarly, immuno-
histochemical analysis has demonstrated the deposition
of an interferon-inducible protein, interferon-induced
GTP-binding protein MX1, in muscle tissue3. In patients
with dermatomyositis, disease activity correlates with
both the expression of a type I interferon gene signa-
ture and serum levels of IL-6. Furthermore, IL-6 levels
correlate with the expression of a type I interferon gene
signature and the type I interferon chemokine signature
in such patients, suggesting that the co-regulation of
interferon-driven chemokines and IL-6 is linked to the
pathogenesis of dermatomyositis4.
Whereas CD4+ T cells are important in dermato-
myositis pathogenesis, CD8+ T cells are more often
implicated in polymyositis pathogenesis. T cells have
also been implicated in the pathogenesis of myositis-
associated ILD as activated CD8+ T cells have been noted
in both the lung tissue and bronchoalveolar lavage fluid
of patients with myositis5,6, whereas patients with inter-
stitial pneumonitis associated with various autoimmune
diseases (including myositis) have decreased levels of
regulatory T cells7. IL-17 is also emerging as a poten-
tial mediator of the inflammatory process in myositis
as levels of this cytokine correlate with disease duration
and levels of IL-15, particularly in patients with der-
matomyositis8. IL-17 and IL-23 levels are increased in
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early, as opposed to established, polymyositis and der-
matomyositis, providing evidence that these cytokines
might contribute to disease pathogenesis9. The linkage
of activated T cells to IL-17 is further supported by
the demonstration of this cytokine in the lymphocytic
infiltrates of muscle tissue.
Toll-like receptors (TLRs) serve as links between
the innate and adaptive immune systems. Patients with
polymyositis or dermatomyositis overexpress TLR3 and
TLR7, which are primarily detected in the inflammatory
infiltrates within the muscle tissue of these patients10. In
myositis, the TLR pathway is supposedly activated by
mediators released from necrotic muscle cells.
The emergence of biologic and small-molecule ther-
apies over the past several years that specifically attack
the aforementioned immunological targets that cause
or are associated with myositis provides the opportu-
nity for mitigating disease in ways that have not been
previously feasible.
Insights from non-immune pathways
Muscle weakness in myositis might persist even when
there is no evidence of muscle damage and/or no
demonstrable inflammatory cells within the muscle tis-
sue. There is increasing evidence that noninflammatory
or non-immune mechanisms might contribute to the
pathogenesis of myositis and muscle weakness. In
fact, in a murine model of myositis, muscle weakness
precedes the infiltration of inflammatory cells11, and
muscle weakness persists in patients with polymyositis
or dermatomyositis even when treatment has cleared
the myositis-associated inflammatory infiltrates12. The
precise mechanisms underlying the noninflammatory
component of muscle weakness are not well understood,
but investigators have shown that the endoplasmic retic-
ulum (ER) stress pathways are activated in myositis11–16.
Activation of these pathways is directly associated with
muscle fibre degeneration and muscle dysfunction in
myositis14. In non-muscle cells, ER stress also leads to
altered redox homeostasis and possible oxidative dam-
age14. In 2015, investigators proposed that the genera-
tion of modified reactive oxygen species (ROS) might
be involved in non-immune cell-mediated muscle
weakness in myositis through a mechanism involving
ER stress induction and that therapies that target ROS
generation could have a role in myositis14.
Treatment strategies in myositis
Immunosuppressive agents
Glucocorticoids. The management of myositis is not
guideline-based; however, despite the lack of controlled
clinical trials, it is generally agreed that glucocorti-
coids should remain the anchor drug of initial myosi-
tis treatment. The starting dose depends on various
factors (such as age and indication), but in adults with
prominent muscle weakness the dose approximates
to 1 mg per kg daily, with an average dose of 60 mg
daily for a patient with myositis, generally not exceed-
ing 80 mg per day. If a patient has severe myositis or
myositis with other prominent extramuscular com-
plications, such as ILD, pulse therapy with 1,000 mg of
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First-line
Glucocorticoids and Methotrexate or azathioprine and/or IVIG
therapy:
MMF, tacrolimus or ciclosporin
Second-line
Glucocorticoids and or combination therapy of and/or IVIG
therapy:
methotrexate and azathioprine
Third-line
Glucocorticoids and
Rituximab, cyclophosphamide,
and/or IVIG
therapy: RCI or other biologic agents
Figure 1 | Overview of pharmacological therapy in idiopathic inflammatory
myopathies. The management of myositis is not guideline-based but includes
Nature Reviews many
| Rheumatology
immunosuppressive, immunomodulatory and biologic agents that are noted in this
figure. The first-line therapy nearly always includes glucocorticoids in combination with
either methotrexate or azathioprine. The second-line therapy includes mycophenolate
mofetil (MMF), tacrolimus or ciclosporin or combination therapy such as azathioprine
and methotrexate. The third-line therapy includes rituximab, cyclophosphamide,
repository corticotropin injection (RCI) or other experimental biologic agents.
Intravenous immunoglobulin (IVIG) can be used alone as a first-line, second-line or
third-line therapy or as a concomitant therapy with any drug on the basis of the clinical
manifestation or refractoriness of the disease.
methylprednisolone for 3 consecutive days can often be
administered. Tapering guidelines vary, but a reasonable
approach is to drop the dose by 20–25% of the existing
dose monthly with the goal of achieving a low daily dose
of prednisone of approximately 5–10 mg daily within
6 months. Adrenocorticotropic hormone (ACTH) gel,
also known as repository corticotropin injection (RCI),
was approved for polymyositis and dermatomyositis in
1952 and approval was later retained in 2010. This long-
lasting agent contains full-sequence ACTH and other
pro-opiomelanocortin-derived peptides. Melanocortin
receptors are expressed by many immune-mediated
cells, and activation of these receptors (for example, by
ACTH) leads to anti-inflammatory and immunomodula-
tory effects15. The efficacy of RCI was previously demon-
strated in retrospective case series16,17, but favourable
results from an open-label clinical trial are now available,
showing that treatment with RCI is safe and effective in
patients with refractory myositis and leads to a reduction
in concomitant steroid dosing 18.
Methotrexate. Glucocorticoids are rarely used alone
owing to their associated adverse effects and high relapse
rates. Methotrexate is often used in combination with
glucocorticoids as an initial therapy in myositis and in
the treatment of patients experiencing disease flares fol-
lowing the tapering of glucocorticoids, despite the lack
of clinical trials supporting the use of methotrexate in
adults with myositis. Older, retrospective studies support
the use of methotrexate as a first-line therapy in myosi-
tis, and this therapy can be administered either orally or
subcutaneously with a dose of up to 25 mg weekly 19,20. In
2016, results from an open-label, randomized, placebo-
controlled, multicentre trial of treatment-naive patients
with juvenile dermatomyositis demonstrated that treat-
ment with methotrexate in combination with prednisone
resulted in a better response than prednisone alone21. A
combination therapy of methotrexate or ciclosporin with
prednisone also resulted in a shorter median time to
clinical remission and prednisone discontinuation and a
longer time to treatment failure than prednisone alone21.
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By contrast, another open-label, randomized, placebo-
controlled, multicentre trial in Europe that assessed
the efficacy and safety of combined methotrexate and
glucocorticoid therapy versus glucocorticoids alone (the
Prometheus trial) in adults with dermatomyositis or
polymyositis failed to complete recruitment (62% target)
and the primary end point was not reached22.
Azathioprine. Azathioprine (2–3 mg per kg daily, orally),
a prodrug that is converted into the active metabolite
6-mercaptopurine, is preferred by some clinicians as the
initial immunosuppressive agent of choice (generally
in combination with glucocorticoids) for patients with
myositis, and comparative studies have suggested that
methotrexate and azathioprine have similar efficacies23.
Azathioprine therapy might be preferable to methotrexate
for patients with liver disease, patients unwilling to abstain
from alcohol or patients with severe ILD. In a study in the
early 1980s of patients with polymyositis, patients being
treated with azathioprine in combination with prednisone
failed to show considerable differences in muscle strength
or creatine kinase levels (a marker of muscle damage),
compared with patients being treated with prednisone
alone, at 3 months24,25, but a long-term follow-up of this
study showed that the combined prednisone plus aza-
thioprine therapy was superior in improving functional
status and reducing prednisone dose24,25. In a randomized
crossover study of 30 patients with an initial inadequate
response to methotrexate or azathioprine alone, a combi-
nation of oral methotrexate and azathioprine was better
than intravenous methotrexate26.
Mycophenolate mofetil. Mycophenolate mofetil (MMF)
is a prodrug of mycophenolic acid that inhibits purine
synthesis, leading to immunosuppression by impairing
B cell and T cell proliferation. Investigations of the use
of MMF in myositis have mainly been limited to case
series (generally involving doses of 2,000 − 3,000 mg
daily, orally)27–30, but in an open-label study of seven
patients with either refractory polymyositis or dermato-
myositis, all the patients achieved complete remission fol-
lowing treatment with MMF combined with intravenous
immunoglobulin (IVIG) therapy 31.
Calcineurin inhibitors. There is a rationale for targeting
T cells in both the treatment of myositis and the treat-
ment of ILD associated with myositis. Ciclosporin is a cal-
cineurin inhibitor that blocks the production and release
of IL-2 and IL-2-induced activation of T cells, whereas
tacrolimus is a second-generation calcineurin inhibitor
that binds to an intracellular protein, peptidyl-prolyl cis-
trans isomerase FKBP12, leading to inhibition of T cell
activation. In a case series of eight patients with refractory
myositis (six patients with anti-histidyl-transfer RNA
synthetase (Jo1) autoantibodies and two patients with
anti-signal recognition particle (SRP) autoantibodies),
treatment with tacrolimus led to an improvement in
muscle strength and a decrease in serum creatine kinase
levels32. In a Japanese observational study of 16 patients
with polymyositis and 15 patients with dermatomyositis,
treatment with tacrolimus led to a substantial decrease
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in serum creatine kinase levels 2–4 months after treat-
ment initiation and a similar improvement in muscle
strength scores33. However, tacrolimus therapy is gen-
erally reserved for patients with refractory myositis
owing to toxicity concerns associated with its use and
the necessity for checking tacrolimus blood levels.
Cyclophosphamide. Cyclophosphamide, an alkylating
agent that interferes with the growth of cells, is generally
reserved for the treatment of patients with severe myosi-
tis, patients with rapidly progressive ILD or overlapping
systemic vasculitis or patients refractory to several other
second-line or third-line agents. Cyclophosphamide can
be administered orally or intravenously, but its use is
limited owing to its toxic effects and the increased risk
of malignancy associated with this therapy.
Biologic agents
Whereas standard immunosuppressive therapies are
generally indirect and nonspecific, biologic therapies can
directly target the immune cells or cytokines implicated
in disease pathogenesis. A number of biologic therapies
have been investigated in the treatment of myositis,
including in some large clinical trials (TABLE 1).
Rituximab. Rituximab depletes CD20+ B cells, and several
case reports and case series of patients with myositis have
reported rituximab as an effective therapy 34–36, including
in the treatment of patients with the severe and refrac-
tory subset of immune-mediated necrotizing myopathy
(IMNM) associated with the anti-SRP autoantibody 37. In
an open-label trial of four patients with refractory poly-
myositis, all patients had a marked drop in serum creatine
kinase levels and regained full muscle strength at 28 weeks
following rituximab treatment 38, whereas the results of
another open-label trial of eight patients with dermato-
myositis were less encouraging, with only three patients
showing a modest improvement in muscle strength and no
patients showing substantial improvements in skin disease
by 24 weeks39. In the largest randomized, double-blind,
controlled clinical trial ever completed in myositis, the
Rituximab in Myositis (RIM) trial, 195 individuals (75
with polymyositis, 72 with dermatomyositis and 48 with
juvenile dermatomyositis) were randomly assigned to
receive two 1 g rituximab infusions either at baseline or
8 weeks later 40. The patients included were refractory to
glucocorticoids and at least one immunosuppressive agent
and had prominent muscle weakness on entry. The pri-
mary end point, which compared the time to achieve the
International Myositis Assessment and Clinical Studies
(IMACS) definition of improvement (DOI; which incor-
porates the IMACS’s six core set measures of disease
activity)41 in patients receiving rituximab at baseline and
patients receiving rituximab treatment 8 weeks later, was
not met. However, 83% of the patients included in the pri-
mary outcome analysis met the DOI by the end of the trial
(that is, by 44 weeks), with a median time to achieve the
DOI of 20 weeks. Rituximab use also had a considerable
steroid-sparing effect and was well tolerated, with a lack of
substantial adverse events. The presence of anti-aminoacyl
transfer RNA synthetase antibodies (in particular anti-Jo1
autoantibodies), commonly referred to as antisynthetase
autoantibodies, as well as anti-Mi2 autoantibodies and a
lower disease damage score at trial entry were strong pre-
dictors of a beneficial response to rituximab in the RIM
trial42. Patients with juvenile dermatomyositis also fared
better following B cell depletion in the RIM trial than
patients with other myositis subsets.

Table 1 | Summary of biologic agents used in the treatment of myositis: selected trials
Biologic Therapeutic Study population Study design Primary end points Results Refs
agent target
Rituximab B cells Adult polymyositis and Randomized, IMACS DOI Primary end point was 39
dermatomyositis and double-blind and not met, but 83% of study
JDM (n = 200) placebo-phase participants met the DOI
Anti-SRP-positive Open-label MMT and creatine kinase Six of eight patients 38
individuals (n = 8) decline showed improvements
Infliximab TNF Adult polymyositis and Randomized, double- ≥15% MMT improvement <33% response rate 50
dermatomyositis (n = 12) blind, placebo-controlled
and crossover
Etanercept TNF Adult dermatomyositis Randomized, Adverse events; time Five of 11 etanercept- 43
(n = 16) double-blind and from randomization treated patients were
placebo-controlled to treatment failure; weaned off prednisone;
prednisone wean no adverse events
Tocilizumab IL-6 Adult polymyositis, Randomized, Myositis Total Study in progress 58
dermatomyositis and double-blind and Improvement Score
IMNM (n = 40) placebo-controlled
Abatacepta T cells Adult polymyositis and Randomized, open-label IMACS DOI Treatment resulted in 63
dermatomyositis (n = 20) and ‘delayed-start’ lower disease activity in
nearly 50% of patients
Anakinra IL-1 receptor Adult polymyositis, Open-label IMACS DOI and functional Seven of the 15 patients 64
dermatomyositis and index responded to treatment
IBM (n = 15)
DOI, definition of improvement; IBM, inclusion body myositis; IMACS, International Myositis Assessment and Clinical Studies; IMNM, immune-mediated
necrotizing myopathy; JDM, juvenile dermatomyositis; MMT, manual muscle testing; SRP, signal recognition particle. aLarger, international study in progress65.

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Anti-TNF therapies. Although one might expect ben-
eficial results with anti-TNF therapies in patients with
myositis, the use of such therapies has had variable
results. In a case series of five patients with dermato-
myositis, treatment with etanercept resulted in worsen-
ing of muscle weakness with persistently elevated creatine
kinase levels and no improvements in skin rash43. By con-
trast, in a randomized, double-blind, placebo-controlled
trial of patients with dermatomyositis, treatment with
etanercept was associated with a longer time to treatment
failure and a greater prednisone-sparing effect than pla-
cebo after 24 weeks44. Although a number of case reports
and case series have reported beneficial responses to
infliximab therapy in some patients with myositis45–48, in
a follow-up report of two such patients, their symptoms
worsened, and one of the patients developed anaphy-
laxis on a second infusion of infliximab49. Furthermore,
in an open-label pilot trial of 13 patients with refractory
myositis, infliximab was ineffective50, and a subsequent
randomized double-blind placebo-controlled cross-
over clinical trial in 2017 investigating infliximab in 12
patients with either polymyositis or dermatomyositis also
revealed discouraging results, with the patients receiving
infliximab treatment showing a response rate of <33%
after 14 weeks51. However, infliximab was well tolerated
in these studies, and whether a higher dose or longer
follow-up might lead to better response rates is yet to be
determined. Currently, the use of anti-TNF therapy can-
not be fully endorsed for patients with myositis, especially
given that some studies report that these agents might
cause myositis52–54. Nevertheless, in some patients with
a prominent and refractory inflammatory arthropathy,
anti-TNF therapy should be considered. Further, there
might be a role for anti-TNF inhibitors in the treatment
of calcinosis associated with juvenile dermatomyositis55.
Tocilizumab. Following the approval of tocilizumab, an
IL-6 receptor antagonist, for the treatment of rheumatoid
arthritis (RA), interest has grown in testing this drug in
other autoimmune diseases. In two patients with refrac-
tory polymyositis, treatment with tocilizumab resulted in
a decrease in creatine kinase levels along with the disap-
pearance of inflammatory changes in the thigh muscles
as assessed by MRI56, whereas in a patient with an over-
lap syndrome involving dermatomyositis and systemic
sclerosis who was refractory to multiple therapies, tocili-
zumab treatment resulted in the resolution of skin symp-
toms, a gradual decrease in serum creatine kinase levels
and an improvement in muscle strength57. An investi-
gator-initiated, multicentre, randomized, double-blind,
controlled trial is ongoing to assess the efficacy of tocili-
zumab in treating adults with refractory polymyositis or
dermatomyositis58 and uses the newly revised DOI59.
Abatacept. Abatacept is a fully human fusion protein of
cytotoxic T lymphocyte protein 4 (CTLA4) and the Fc
portion of human IgG1 that inhibits T cell co-stimulation.
Although there have been a number of case reports
demonstrating the effectiveness of abatacept in treating
patients with myositis60–63, randomized controlled tri-
als were lacking. In 2017, the results of a randomized,
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open-label, ‘delayed-start’ treatment trial were released;
this trial investigated abatacept treatment in 20 patients
with either refractory dermatomyositis (n = 11) or refrac-
tory polymyositis (n = 9), assessing both disease activity
and changes in muscle biopsy samples64. Patients received
active treatment (monthly intravenous abatacept) either
immediately or after a 3-month delayed start, and the
primary end point of the trial was the number of patients
achieving the IMACS DOI after 6 months of active treat-
ment. In this pilot trial, nearly half (42%) of the patients
achieved this primary end point, and in those patients in
whom a repeat muscle biopsy was performed, an increase
in regulatory T cell markers was observed in the muscle
tissue at 6 months compared with levels before treatment,
supporting a beneficial effect of this T cell-targeting ther-
apy. There were no unusual safety signals in this trial, and
the therapy was well tolerated. These encouraging results
have led to an ongoing phase III clinical trial assessing
abatacept therapy in patients with myositis65.
Anakinra. Anakinra, a recombinant IL-1 receptor antag-
onist (IL-1Ra), was investigated in a 2014 study of 15
patients with refractory myositis; in this study, the patients
received anakinra (100 mg daily, subcutaneously) for
12 months66. Seven of the patients had a clinical response
according to the IMACS DOI, whereas four patients
showed an improvement in function as measured by the
functional index score. Post-treatment muscle biopsy
samples from all patients who met the response criteria
demonstrated the expression of IL-1Ra whereas samples
from only three of the eight non-responders demon-
strated IL-1Ra expression. The investigators concluded
that patients with refractory myositis might respond
to anakinra, noting that IL-1α expression might be
associated with a beneficial treatment response.
The role of immunomodulation
IVIG suppresses immune-mediated processes, although
the precise mechanism of action of this immunomodula-
tory agent is unknown. IVIG is usually administered as
a monthly infusion (2 g per kg), but the dose or interval
of administration can vary depending on the disease
severity and subsequent therapeutic response of the
patient. IVIG therapy is beneficial when used in com-
bination with other immunosuppressive agents and in
the setting of infection or malignancy, but this therapy
is also expensive and has a long administration time,
dissuading its routine use.
IVIG therapy demonstrated efficacy in treating
myositis almost 25 years ago in a double-blind, cross-
over, placebo-controlled trial of 15 patients with refrac-
tory dermatomyositis67 and was associated with sustained
clinical improvement in 70% of patients with poly-
myositis in an open-label trial68. Efficacy was maintained
in half of the patients up to 3 years after stopping IVIG
therapy 68. However, in a randomized, double-blind,
placebo-controlled trial in Japan involving 26 individuals
(16 patients with polymyositis and 10 patients with der-
matomyositis, who were refractory to glucocorticoids),
patients receiving IVIG therapy failed to show improve-
ments in muscle strength (as assessed by manual muscle
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testing) compared with those receiving placebo, although
other secondary end points did improve69. A pivotal
double-blind, randomized, placebo-controlled, phase III
study is ongoing to confirm the efficacy and safety of
IVIG in patients with refractory dermatomyositis70.
Administration of subcutaneous gamma-globulin by
a programmable pump in seven patients (four patients
with dermatomyositis and three patients with poly-
myositis) led to a decrease in creatine kinase levels and an
improvement in muscle strength and quality of life, along
with a beneficial steroid-sparing effect and a reduction in
concomitant immunosuppressive medication71.
Exercise in the management of myositis
Historically, an active exercise programme would have
been discouraged in the management of myositis owing
to the rationale that exercise would damage the mus-
cles of a patient with myositis, perhaps inducing a form
of secondary inflammation. However, there has been a
clear shift in this paradigm as emerging data support
the safety and effectiveness of exercise in adults with
myositis. Physical exercise as a treatment for adult and
juvenile myositis has been comprehensively reviewed
elsewhere72, and in this section, we highlight selected
aspects of exercise intervention.
Exercise was originally reported to be safe in a 1998
study of patients with myositis with chronic and stable
disease activity 73; these patients showed improvements
in muscle strength and function after a 6-week exer-
cise programme in which effects were assessed for up
to 6 months73. The safety of exercise therapy was con-
firmed in patients with inactive myositis in another open
study in which a resistive home exercise programme
was implemented for 12 weeks74. A later study demon-
strated that a 12-week resistive programme, in combi-
nation with conventional immunosuppressive therapy,
was safe in 11 patients with polymyositis or dermato-
myositis who had active and new-onset myositis75. For
5 days each week, patients performed resistive exercise
for 15 minutes followed by a 15-minute walk. No signs
of increased inflammation were noted in these patients,
as assessed by creatine kinase levels, muscle MRI find-
ings and on a repeat muscle biopsy compared with their
original immunohistochemical results. Furthermore,
muscle function and quality of life improved during
the 12-week exercise programme. Although the relative
effects of exercise and pharmacological therapy could
not be distinguished, it was important to note that active
exercise was well tolerated, with no adverse effects, in
this small cohort of patients with active and recently
diagnosed myositis.
The molecular effects of exercise in polymyositis and
dermatomyositis were also studied in a controlled pilot
study; this study investigated the effects of a 12-week
endurance training programme on skeletal muscle com-
pared with a stable level of physical activity 76. The exer-
cise programme activated an aerobic phenotype (that
is, the upregulation of molecular pathways involved in
aerobic capacity, capillary growth and muscle remodel-
ling) while concomitantly mitigating the inflammatory
response in the patients’ muscles, as demonstrated by
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changes in gene expression, proteomics and capillary
density on repeat muscle biopsies. Taken together, these
clinical and experimental studies support the benefits
of exercise as being anti-inflammatory in patients with
both active and stable myositis.
Special treatment considerations
As alluded to above, patients with myositis can present
with various manifestations in clinical practice, includ-
ing necrotizing myopathy and extramuscular manifes-
tations such as ILD, skin rash and dysphagia, which
represent distinct scenarios. Such manifestations are
treated using the same agents already discussed in this
Review, but a separate discussion is warranted given the
severity and difficulty in managing these complications.
Immune-mediated necrotizing myopathy
IMNM is often a more severe subset of myositis and
is frequently associated with the presence of anti-
3-hydroxy-3-methylglutaryl-coA reductase (HMGCR)77
or anti-SRP autoantibodies. Patients with IMNM have
prominent symmetrical proximal upper and lower
extremity weakness and very high levels of serum cre-
atine kinase but generally lack other extramuscular
autoimmune features77. The initial treatment of patients
with IMNM should involve an aggressive therapy that
includes high-dose glucocorticoids in combination
with another immunosuppressive agent. Case series of
patients with this myositis subset have demonstrated
that IVIG and/or rituximab are effective and should
be considered early in the treatment of IMNM at the
same dosage recommended for the standard treatment
of myositis37,78.
Interstitial lung disease
ILD is a major cause of morbidity and mortality in
patients with myositis, and several drugs have been
studied in the treatment of this complication. An
algorithmic approach to the treatment of myositis-
associated ILD is provided in FIG. 2. Treatment with
MMF showed encouraging results in two small case
series of patients with myositis-associated ILD79,80 and
was later investigated in a large cohort of 125 patients
with autoimmune ILD (32 with polymyositis or der-
matomyositis) who were treated for a mean period of
897 days81. In this cohort, MMF treatment was associ-
ated with a trend towards improvement in the forced
vital capacity (FVC) and diffusing capacity of the lungs
for carbon monoxide (DLCO) at 52 and 104 weeks. In
a separate case study, MMF treatment was also benefi-
cial in a patient with amyopathic dermatomyositis with
rapidly progressive ILD82. Azathioprine treatment led
to some improvement in lung function in a retrospec-
tive case series of patients with myositis-associated ILD
as well as in a cohort of 70 such patients (in which 25
patients showed improvements)83,84.
Cyclophosphamide use in myositis-associated ILD
has primarily been reported retrospectively in case
reports and case series85–87. In one case series, 11 of the 17
patients given monthly intravenous cyclophosphamide
(300–800 mg/m2) for a minimum of 6 months showed
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Mild to moderate disease Severe disease

Induction therapy

Oral glucocorticoids (such as prednisone, 1 mg per kg daily) Intravenous glucocorticoids (pulse therapy)
or and
Intravenous glucocorticoids (pulse therapy) Cyclophosphamide (intravenous) or rituximab

Maintenance therapy
Glucocorticoid-sparing drugs:
First-line Oral glucocorticoids and MMF or azathioprine
therapy:
Second-line Oral glucocorticoids and Tacrolimus or ciclosporin
therapy:

Refractory cases

Rituximab or cyclophosphamide or combination Combination of rituximab and cyclophosphamide

therapy of MMF and tacrolimus

Disease remains progressive

Abatacept or agents being tested in clinical trials

Figure 2 | Proposed approach to treating myositis-associated interstitial lung disease. The treatment of interstitial
lung disease (ILD) can be broken down into treating either mild to moderate disease or severe disease119. Treatment of
mild to moderate disease includes an aggressive approach involving high-dose glucocorticoids (either oral or intravenous
administration) as an induction therapy followed by maintenance therapy with slowly tapering Nature Reviews | Rheumatology
glucocorticoids and the
addition of any one of several immunosuppressive agents such as mycophenolate mofetil (MMF), azathioprine, tacrolimus
or ciclosporin. If mild to moderate disease is refractory to this induction or maintenance therapy, a more aggressive
approach with either rituximab or cyclophosphamide or a combination of MMF and tacrolimus is used. The management
of severe myositis-associated ILD includes induction therapy with pulse glucocorticoids along with more potent
immunosuppressive drugs, such as cyclophosphamide or rituximab, early on in the course of treatment followed by
maintenance therapy with MMF, tacrolimus or ciclosporin (or sometimes azathioprine). If severe disease is refractory to
induction or maintenance therapy, a more aggressive approach is used with a combination of rituximab and
cyclophosphamide. If disease is still progressive, then other biologic agents being investigated in clinical trials for myositis
are used, such as abatacept. Maintenance therapy of all forms of myositis-associated ILD depends on the response to
initial treatment and subsequent progression. In cases of relapse, high doses of steroids (oral, intravenous or pulse therapy,
depending on the disease severity) are given along with alternative immunosuppressive agents (not shown). Adapted from
REF. 119, Future Medicine.

improvements in their dyspnoea, and 6 of the 7 patients
who had previously required oxygen treatment discontin-
ued their supplemental oxygen87. Twelve of these patients
had >10% improvement in their FVC and showed lung
improvements as assessed by high-resolution CT (HRCT)
scanning of the lung parenchyma. In addition, in a pro-
spective open-label study, cyclophosphamide treatment
resulted in stabilization and functional improvement in
patients with progressive ILD, with a median follow-up
of 35 months88. IVIG use has also been described in case
reports of patients with myositis-associated ILD89,90, with
some patients, including one patient with amyopathic
dermatomyositis-associated ILD (who was refractory to
high-dose glucocorticoids and ciclosporin A), showing a
response to IVIG therapy 89,90.
The notion that T cells are potential targets in the
management of ILD5–7 has led to the consideration
of ciclosporin and tacrolimus for use in myositis-
associated ILD. In a retrospective study of 14 patients
with dermatomyositis and interstitial pneumonia, early
treatment with a combination of prednisolone and ciclo-
sporin (4 mg per kg daily within 12 days of diagnosis)
improved both pulmonary function testing (PFT) and
HRCT findings91. Similarly, in 48 Asian patients with
dermatomyositis-associated ILD, early ciclosporin
treatment resulted in improved survival compared with
patients who received delayed ciclosporin treatment 92.
In 13 patients with ILD who were positive for anti-
synthetase autoantibodies, tacrolimus treatment for an
average of 51 months also resulted in improvements in
all PFT parameters93. In a retrospective study of 49 pre-
viously untreated patients with myositis-associated ILD,
treatment with tacrolimus plus conventional therapy led
to longer event-free survival than treatment with con-
ventional therapy alone94. Furthermore, in three small
series of patients with myositis-associated ILD, in whom
ciclosporin was previously ineffective, tacrolimus treat-
ment improved their lung disease93,95,96. With tacrolimus
therapy, serum trough levels should be monitored to
limit toxicity.

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REVIEWS
Rituximab has been increasingly studied in patients
with myositis-associated ILD, but no randomized con-
trolled trials have been performed to date. In a retrospec-
tive study of 50 patients with ILD associated with various
autoimmune diseases, rituximab therapy was most effec-
tive in patients with myositis-associated ILD out of all the
patients, with 5 of the 10 such patients demonstrating
an improvement in FVC (>10%) and/or an increase in
DLCO (>15%)97. In another retrospective report of 24
antisynthetase autoantibody-positive patients with severe
ILD, who were followed for >12 months, after rituximab
therapy, the patients demonstrated a median 24% increase
in FVC, a 22% increase in forced expiratory volume in
1 second (FEV1) and a 17% increase in DLCO98. The best
outcomes were noted in patients with a disease duration
of <12 months and/or in patients who had an acute onset
or exacerbation of their ILD. A limitation of this study
was the concomitant administration of another immuno-
suppressive agent; 10 of the 12 patients also received cyclo-
phosphamide, preventing the attribution of improvement
to rituximab alone. In a multicentre, open-label trial of
ten antisynthetase autoantibody-positive patients with
refractory ILD, treatment with rituximab on day 0, day
15 and then 6 months later resulted in a substantial ster-
oid-sparing effect along with reductions in the serum
creatine kinase levels and improvements in manual
muscle testing. ILD improvement (that is, increases in
FVC and/or DLCO) was noted in five of these patients,
and FVC stabilized in four of the patients99. In another
retrospective study, 16 of the 17 anti-Jo1-positive
patients who received rituximab therapy demonstrated
a more rapid and marked response (as assessed by
myositis and ILD outcomes) than the 30 patients who
were treated with conventional immunosuppressive
agents100. Rituximab is usually administered as two 1 g
doses 2 weeks apart, but the subsequent dosing inter-
val might vary, and no regimen has been standardized
for the treatment of myositis with or without ILD.
A randomized pilot trial assessing the effect of aba-
tacept is under way in the treatment of antisynthetase
autoantibody-positive patients101. Methotrexate was
often considered to be contraindicated in patients posi-
tive for the anti-Jo1 autoantibody or other antisynthetase
autoantibodies owing to its potential for inducing pul-
monary toxicity. However, there has been a shift in recent
years with the finding that methotrexate is highly effec-
tive in treating muscle and articular features of patients
with antisynthetase syndrome. Moreover, the reported
small increase in risk of methotrexate-induced pneu-
monitis is primarily seen in patients with RA102,103. Thus,
it is reasonable to administer methotrexate as long as
myositis-associated ILD is not the primary manifestation
being treated.
Skin rash in dermatomyositis
The cutaneous features of dermatomyositis can be quite
difficult to treat and, in some patients, might represent
the dominant disease manifestation. Simple measures of
treating dermatomyositis include wearing protective sun-
screen and avoiding the use of medications that increase
photosensitivity. Occasionally, topical glucocorticoid
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ointments and creams, as well as topical calcineurin
inhibitors (tacrolimus and pimecrolimus), are consid-
ered if the rash is mild and more limited. Antimalarials
are occasionally beneficial and used in combination
with other immunosuppressive agents, but hydroxy-
chloroquine use can lead to a diffuse erythroderma in
some patients104,105. In most patients, treatment of the
rash of dermatomyositis often requires a therapy that is
just as aggressive as the therapy required for targeting
muscle weakness in myositis; hence, the use of metho-
trexate, azathioprine, MMF, IVIG and tacrolimus is rec-
ommended in some instances. Two uncontrolled case
series suggest that MMF is effective in treating refrac-
tory cutaneous dermatomyositis106,107. In the RIM trial,
rituximab use was associated with notable improvements
in cutaneous disease activity in adult and juvenile der-
matomyositis subsets, including notable improvements
in erythroderma, erythematous rashes (without second-
ary changes of ulceration or necrosis), heliotrope rash,
Gottron sign and Gottron papules108. In 2016, tofacitinib
was reported to be effective in treating three patients with
dermatomyositis who had multidrug-resistant cutaneous
manifestations109, and tofacitinib treatment was simi-
larly associated with improvements in skin, joint and
muscle features in another patient with refractory
dermatomyositis in a subsequent case report110.
Calcinosis is probably the most challenging and diffi-
cult cutaneous feature to treat in myositis. The presence
of anti-nuclear matrix protein 2 (NXP2; also known as
MORC3) autoantibodies is associated with calcinosis in
both adult and juvenile dermatomyositis111. Many med-
ications have been tried, but none is uniformly effective,
and surgical excision might be the only option to con-
sider in severe cases. In a case series, bisphosphonates in
combination with immunosuppressive therapy and/or
IVIG reduced calcinosis in four of the six patients with
juvenile dermatomyositis112. Sodium thiosulfate ther-
apy, administered either intravenously or directly into
the calcinotic lesions, has been associated with some
improvement in skin outcomes in patients with adult or
juvenile dermatomyositis113,114.
Dysphagia in myositis
The proximal dysphagia seen in many patients with
severe myositis is a stubborn and severe manifestation.
Although many patients respond to glucocorticoids and
other immunosuppressive agents, additional IVIG should
also always be considered for dysphagia. In a retrospective
study of 73 patients with either polymyositis or dermato-
myositis who had steroid-refractory life-threatening
oesophageal dysphagia, a first-line therapy of combined
high-dose glucocorticoids and IVIG was beneficial115.
As with the standard treatment of myositis, IVIG can
be administered by monthly infusions of 2 g per kg over
2 consecutive days or over a 5-day period if necessary.
Future prospects
There are a number of potential and investigational
agents to be considered in the treatment of myositis
(FIG. 3). The prominent expression of a type I interferon
signature in the serum and tissues of patients with
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 F O C U S O N MRYEO
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TIS

Genetic factors Environmental factors

• HLA • Injury • Infection
• Non-HLA • Toxins • UV light

Innate immunity
IMO-8400 • Toll-like receptors • Dendritic cells
• Macrophages • Chemokines

Abatacept
APC

CD40L CD80/
Rituximab TFH MHC II MHC I
CD40 CD86
CD28 TCR

B cell CD4 CD8

BAFF APRIL
TH2 TH17

TH1
Belimumab
IL-4 IL-23 IL-17

IFNα
Plasma cell Secukinumab

• Sifalimumab
• Anifrolumab
Autoantibodies
Cytotoxic
M1/M2 macrophage T cell

• Canakinumab
TNF IL-6 IL-1β • Anakinra

Anti-TNF Tocilizumab
Immune
complexes
Cytokines
and
chemokines
?
Immune complex Capillaries and myocytes Cell-mediated
IVIG deposition damage

Figure 3 | Immune-related potential therapeutic targets in myositis. There are several factors involved in the
pathogenesis of myositis that lead to the involvement or activation of both the innate and adaptive arms of the immune
system as well as non-immune mechanisms (not shown). Many of the current immunosuppressive agents studied in
myositis affect these immune pathways, whereas the biologic agents in this figure function in a more targeted fashion
to neutralize selected areas of these immune-mediated pathways. Noted in the figure are agents previously and
currently being studied in the treatment of myositis as well as those proposed in future clinical trials. APC,
antigen-presenting cell; APRIL, a proliferation-inducing ligand (also known as TNFSF13); BAFF, B cell activating
factor; CD40L, CD40 ligand; IVIG, intravenous immunoglobulin; TCR, T cell receptor; TFH, T follicular helper cell;
TH, T helper cell.

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dermatomyositis or polymyositis led to the study of Conclusions

sifalimumab, an anti-IFNα monoclonal autoantibody, in
treating these patients. In a phase Ib randomized, double-
blind, controlled trial, investigators noted a suppression
of the interferon signature in both the serum and mus-
cle of individuals with dermatomyositis or polymyositis
following sifalimumab treatment 116. Future studies of
anti-interferon agents are being considered. Similarly,
the blockade of interferon-mediated activation of Janus
kinase (JAK)–signal transducer and activator of tran-
scription (STAT) pathways with oral JAK inhibitors is
worthy of further study, particularly regarding dermat-
omyositis and the refractory cutaneous features117. The
effect of blocking TLRs is currently being assessed in
dermatomyositis in a multicentre international study 118.
The future of myositis treatment includes many poten-
tial therapies. The immunosuppressive agents discussed
in this Review will certainly continue to have a major
role in myositis therapy, and biologic therapies will
probably have an increasing role given that these ther-
apies target pathogenic pathways implicated in myosi-
tis. Investigators must use the technologies available,
including advanced immunochemistry, microarray and
RNA sequencing analysis, cytokine and chemokine pan-
els and sophisticated flow cytometry-based techniques,
to determine logical therapeutic targets. Although we
live in an exciting time in terms of myositis treatment
interventions, we must be cautious of the potential
short-term and long-term effects of these novel agents.

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Author contributions
Both authors wrote the article, provided substantial contri-
butions to discussions of its content and undertook review
and/or editing of the manuscript before submission.
Competing interests
Both C.V.O. and R.A. receive clinical trial support from
Genentech, Idera Pharmaceuticals, Bristol-Myers Squibb and
Mallinckrodt.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
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