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FOCUS ON MYOSITIS REVIEWS Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of

FOCUS ON MYOSITIS

REVIEWS

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

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.

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 colleagues 1 . 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

early, as opposed to established, polymyositis and der- matomyositis, providing evidence that these cytokines might contribute to disease pathogenesis 9 . 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 patients 10 . 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.

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

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-

Treatment strategies in myositis

is

a fairly nonspecific approach. However, B cells and

sue. There is increasing evidence that noninflammatory

T

cells, as well as the specific cytokines and receptors

or non-immune mechanisms might contribute to the

implicated in myositis pathogenesis, serve as poten- tially attractive therapeutic targets. In polymyositis,

pathogenesis of myositis and muscle weakness. In fact, in a murine model of myositis, muscle weakness

myeloid dendritic cells activate B cells and contribute to the formation of autoantibodies 2 , 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

precedes the infiltration of inflammatory cells 11 , and muscle weakness persists in patients with polymyositis or dermatomyositis even when treatment has cleared the myositis-associated inflammatory infiltrates 12 . 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 myositis 1116 . Activation of these pathways is directly associated with

of

an interferon-inducible protein, interferon-induced

muscle fibre degeneration and muscle dysfunction in

GTP-binding protein MX1, in muscle tissue 3 . 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

myositis 14 . In non-muscle cells, ER stress also leads to altered redox homeostasis and possible oxidative dam- age 14 . In 2015, investigators proposed that the genera- tion of modified reactive oxygen species (ROS) might

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 dermatomyositis 4 . Whereas CD4 + T cells are important in dermato- myositis pathogenesis, CD8 + T cells are more often

also been implicated in the pathogenesis of myositis-

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 myositis 14 .

Immunosuppressive agents

implicated in polymyositis pathogenesis. T cells have

associated ILD as activated CD8 + T cells have been noted

Glucocorticoids. The management of myositis is not guideline-based; however, despite the lack of controlled clinical trials, it is generally agreed that glucocorti-

in

both the lung tissue and bronchoalveolar lavage fluid

coids should remain the anchor drug of initial myosi-

of

patients with myositis 5,6 , whereas patients with inter-

tis treatment. The starting dose depends on various

stitial pneumonitis associated with various autoimmune

factors (such as age and indication), but in adults with

diseases (including myositis) have decreased levels of

prominent muscle weakness the dose approximates

regulatory T cells 7 . IL-17 is also emerging as a poten- tial mediator of the inflammatory process in myositis

to 1 mg per kg daily, with an average dose of 60 mg daily for a patient with myositis, generally not exceed-

as

levels of this cytokine correlate with disease duration

ing 80 mg per day. If a patient has severe myositis or

and levels of IL-15, particularly in patients with der- matomyositis 8 . IL-17 and IL-23 levels are increased in

myositis with other prominent extramuscular com- plications, such as ILD, pulse therapy with 1,000 mg of

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First-line

therapy:

Second-line

therapy:

Third-line

therapy:

Glucocorticoids

Glucocorticoids

Glucocorticoids

and

and

and

Methotrexate or azathioprine

MMF, tacrolimus or ciclosporin or combination therapy of methotrexate and azathioprine

Rituximab, cyclophosphamide, RCI or other biologic agents

and/or

IVIG
IVIG

and/or

IVIG
IVIG

and/or

IVIG
IVIG

Figure 1 | Overview of pharmacological therapy in idiopathic inflammatory myopathies. The management of myositis is not guideline-based but includes many 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 effects 15 . The efficacy of RCI was previously demon- strated in retrospective case series 16,17 , 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 alone 21 . 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 alone 21 .

time to treatment failure than prednisone alone 2 1 . FOCUS ON MYOSITIS REVIEWS By contrast,

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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 reached 22 .

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 efficacies 23 . 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 months 24,25 , 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 dose 24,25 . 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 methotrexate 26 .

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) 2730 , 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 levels 32 . 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 scores 33 . 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 3436 , 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 weeks 39 . 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 trial 42 . 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 dermatomyositis and JDM (n =200)

Randomized,

IMACS DOI

Primary end point was not met, but 83% of study participants met the DOI

39

 

double-blind and

placebo-phase

Anti-SRP-positive individuals (n = 8)

Open-label

MMT and creatine kinase decline

Six of eight patients showed improvements

38

Infliximab

TNF

Adult polymyositis and dermatomyositis (n =12)

Randomized, double- blind, placebo-controlled and crossover

≥15% MMT improvement

<33% response rate

50

Etanercept

TNF

Adult dermatomyositis

Randomized,

Adverse events; time from randomization to treatment failure; prednisone wean

Five of 11 etanercept- treated patients were weaned off prednisone; no adverse events

43

 

(n =16)

double-blind and

 

placebo-controlled

Tocilizumab

IL-6

Adult polymyositis, dermatomyositis and IMNM (n =40)

Randomized,

Myositis Total Score Improvement

Study in progress

58

 

double-blind and

 

placebo-controlled

Abatacept a

T cells

Adult polymyositis and dermatomyositis (n =20)

Randomized, open-label and ‘delayed-start’

IMACS DOI

Treatment resulted in lower disease activity in nearly 50% of patients

63

Anakinra

IL-1 receptor

Adult polymyositis, dermatomyositis and IBM (n =15)

Open-label

IMACS DOI and functional index

Seven of the 15 patients responded to treatment

64

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. a Larger, international study in progress 65 .

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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 rash 43 . 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 weeks 44 . Although a number of case reports and case series have reported beneficial responses to

infliximab therapy in some patients with myositis 4548 , 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 infliximab 49 . Furthermore, in an open-label pilot trial of 13 patients with refractory myositis, infliximab was ineffective 50 , 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 weeks 51 . 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 myositis 5254 . 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 dermatomyositis 55 .

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 MRI 56 , 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 strength 57 . 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 dermatomyositis 58 and uses the newly revised DOI 59 .

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 myositis 6063 , randomized controlled tri- als were lacking. In 2017, the results of a randomized,

tri- als were lacking. In 2017, the results of a randomized, FOCUS ON MYOSITIS REVIEWS open-label,

FOCUS ON MYOSITIS REVIEWS

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 samples 64 . 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 myositis 65 .

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 months 66 . 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-1 α 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 dermatomyositis 67 and was associated with sustained clinical improvement in 70% of patients with poly- myositis in an open-label trial 68 . 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 improve 69 . A pivotal double-blind, randomized, placebo-controlled, phase III study is ongoing to confirm the efficacy and safety of IVIG in patients with refractory dermatomyositis 70 . 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 medication 71 .

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 elsewhere 72 , 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 months 73 . 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 weeks 74 . 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 myositis 75 . 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

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-mediatednecrotizingmyopathy 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 features 77 . 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 myositis 37,78 .

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 ILD 79,80 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 days 81 . 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 ILD 82 . 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 series 8587 . In one case series, 11 of the 17 patients given monthly intravenous cyclophosphamide (300–800 mg/m 2 ) for a minimum of 6 months showed

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FOCUS ON MYOSITIS REVIEWS Induction therapy Mild to moderate disease Oral glucocorticoids (such as prednisone,

FOCUS ON MYOSITIS REVIEWS

Induction therapy

Mild to moderate disease

Oral glucocorticoids (such as prednisone, 1 mg per kg daily)

or

Intravenous glucocorticoids (pulse therapy)

Severe disease
Severe disease

Intravenous glucocorticoids (pulse therapy)

and

Cyclophosphamide (intravenous) or rituximab

Refractory cases

Cyclophosphamide (intravenous) or rituximab Refractory cases Maintenance therapy First-line therapy: Second-line

Maintenance therapy

First-line

therapy:

Second-line

therapy:

Glucocorticoid-sparing drugs:

Oral glucocorticoids

and

MMF or azathioprine

Oral glucocorticoids

and

Tacrolimus or ciclosporin

Oral glucocorticoids and Tacrolimus or ciclosporin Rituximab or cyclophosphamide or combination therapy of MMF

Rituximab or cyclophosphamide or combination therapy of MMF and tacrolimus

Combination of rituximab and cyclophosphamide

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 disease 119 . 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 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 oxygen 87 . 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 months 88 . IVIG use has also been described in case reports of patients with myositis-associated ILD 89,90 , 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 ILD 57 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 findings 91 . 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 parameters 93 . 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 alone 94 . Furthermore, in three small series of patients with myositis-associated ILD, in whom ciclosporin was previously ineffective, tacrolimus treat- ment improved their lung disease 93,95,96 . With tacrolimus therapy, serum trough levels should be monitored to limit toxicity.

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REVIEWS 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 DLCO 98 . 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 patients 99 . 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 agents 100 . 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 patients 101 . 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 RA 102,103 . 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

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 patients 104,105 . 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 dermatomyositis 106,107 . 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 papules 108 . In 2016, tofacitinib was reported to be effective in treating three patients with dermatomyositis who had multidrug-resistant cutaneous manifestations 109 , 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 report 110 . 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 dermatomyositis 111 . 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 dermatomyositis 112 . 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 dermatomyositis 113,114 .

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 beneficial 115 . 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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FOCUS ON MYOSITIS REVIEWS Genetic factors Environmental factors • HLA • Injury • Infection •

FOCUS ON MYOSITIS REVIEWS

Genetic factors Environmental factors • HLA • Injury • Infection • Non-HLA • Toxins •
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 MHC II MHC I T FH CD86 CD40 CD28 TCR
Abatacept
APC
CD40L
CD80/
Rituximab
MHC II
MHC I
T FH
CD86
CD40
CD28
TCR
CD4
CD8
B cell
BAFF
APRIL
T H 2
T H 17
T H 1
Belimumab
IL-4
IL-23
IL-17
IFNα
Secukinumab
Plasma cell
• Sifalimumab
• Anifrolumab
Autoantibodies
T cell
M1/M2 macrophage
• 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

Cytotoxic

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; T FH , T follicular helper cell; T H , T helper cell.

REVIEWS REVIEWS

dermatomyositis or polymyositis led to the study of 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 features 117 . The effect of blocking TLRs is currently being assessed in dermatomyositis in a multicentre international study 118 .

Conclusions

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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Publisher’s note

with myositis. Arthritis Rheumatol. 68, 1738–1750

interstitial lung disease. Rheumatology 54, 1420–1428 (2015).

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