Idiopathic inflammatory myopathies (IIMs) comprise a group of autoimmune muscle disorders including polymyositis (PM), dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM) and possibly inclusion body myositis (IBM). There are some similarities in clinical presentation with proximal symmetric muscle weakness in PM, DM and IMNM; with the exception of IBM, which presents with distal arm and proximal leg asymmetric muscle weakness, finger flexor and knee extensor weakness being characteristic early clinical features of the disease.
The elevation of creatine kinase and the evidence of irritative myopathy in the electromyographic study are commonly present in IIMs. Histopathological findings can vary significantly among the IIM types, but some overlap can be seen particularly in PM and IBM patients. This heterogeneity can also be observed in the response to treatment, which leads to the placement of IBM in an isolated treatment group.
Principles of inflammatory myopathy treatment
Although the triggers of inflammatory muscle diseases have not been elucidated, it is believed that the pathologic mechanism involves an autoimmune process.
In DM, there is activation and deposition of complement C5b-9 attack complex on the endothelial cells and activation of B cells, CD4+ T-cells and plasmacytoid dendritic cells.1 In PM and IBM, there is evidence of CD8+ T cells-MHC class I complex expression in muscle biopsy. In addition to the inflammatory component in IBM, other pathogenic mechanisms have been proposed suggesting a multifactorial process. These include environmental factors (for example, viral infection), ageing, genetic susceptibility, accumulation of toxic proteins, myonuclear degeneration, endoplasmic reticulum stress, impairment of autophagy, disruption of the ubiquitin-proteasome system, myostatin signalling impairment, mitochondrial dysfunction and alteration of nucleic acid metabolism.2
The evidence of a degenerative process in the pathogenesis of IBM includes protein accumulation, namely β-amyloid precursor protein (β-APP), heat shock proteins (HSPs), phosphorylated tau (p-Tau), p62, and the cytoplasmic mis-localisation of RNA-binding proteins including transactive response DNA binding protein 43 (TDP-43), heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), and hnRNPA2B1.1,3,4
Current treatment approaches
Despite the lack of controlled trials, the current standard treatment for inflammatory myopathies consists of high-dose steroids, which is the first-line treatment for DM, PM, and IMNM. IBM is notoriously refractory to immunosuppressive treatment. Additional treatment can be done using second-line agents, physical, occupational, speech, and swallowing therapies.3
A proposed regimen of steroid therapy is prednisone 60mg/day (or 0.75mg/kg/day to 1.5mg/kg/day) as starting dose,3 up to 80–100mg/day.1 The duration of the starting dose depends on clinical improvement by measuring muscle strength (normalisation or improvement with a plateau). The normalisation of the CK level is sometimes used to guide initiation of prednisone taper; however, the decrease in CK level by itself is not considered a sign of improvement.5 A slow prednisone taper is recommended after 3–4 weeks of high-dose prednisone in patients showing clinical improvement.
A proposed prednisone taper is decrease prednisone by 10mg/day every four weeks until the patient is on 20mg/day; then decrease by 5mg/day every four weeks until the patient is on 10mg/day; then decrease by 2.5mg/day every 4–12 weeks. Intravenous methylprednisolone 1g/day for three days can be used prior to initiation of high-dose prednisone in patients with severe weakness, prominent extramuscular disease or rapidly worsening disease.3
Steroid-sparing immunosuppressive or immunomodulating therapy is usually used in patients with moderate to severe diseases or those with medical comorbidities making long-term prednisone use undesirable. The second-line agents usually used in patients with myositis include azathioprine, methotrexate, mycophenolate mofetil, tacrolimus, and intravenous immunoglobulin (IVIg). Treatment of IIMs is further complicated by the presence of extramuscular manifestations of myositis, such as interstitial lung disease (ILD), arthritis and typical skin rashes in DM.
Novel agents
Novel agents being evaluated for treatment of myositis include adrenocorticotropic hormone (ACTH) gel, rituximab, IMO-8400, belimumab, Octagam®, tocilizumab, abatacept, siponimod, JBT-101, IFN-kinoid, anakinra, bimagrumab, follistatin gene therapy, rapamycin, and arimoclomol.
PM and DM
ACTH gel, also known as repository corticotropin injection, showed favourable results in a small open-label refractory myositis clinical trial (NCT01906372), being safe and effective and leading to a reduction in concomitant steroid dosing.6
Rituximab, a monoclonal antibody that targets B-cells, is an approved drug for non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia and rheumatoid arthritis and in the US for microscopic polyangiitis and granulomatosis with polyangiitis. Rituximab for the treatment of refractory adult and juvenile DM and adult PM study was a Phase II clinical trial (RIM trial, 2013, NCT00106184) that showed no significant differences in the two treatment arms (group 1: rituximab followed by placebo; group 2: placebo followed by rituximab) for the primary (time to improve between the groups) and secondary (proportion of improved patients between the groups) end points, but 83% of adult and juvenile myositis patients with refractory disease met the definition of improvement.7
An ongoing clinical trial of rituximab in myositis is a randomised, double-blinded, controlled clinical trial comparing rituximab and cyclophosphamide in connective tissue disease associated with interstitial lung disease (RECITAL, NCT01862926).
IMO-8400 is an antagonist of the toll-like receptor 7, 8 and 9 (implicated in immune-mediated diseases).8 Its short-term use has been shown to be well tolerated and to reduce severity of psoriasis. Currently, IMO-8400 is being studied in adult patients with DM (NCT02612857).
Belimumab, a monoclonal antibody against B lymphocyte stimulator (BLyS, a B cell-activating factor),9 is an approved drug for systemic lupus erythematosus. It is currently being studied in myositis in a multicentre, double-blind, placebo-controlled trial (NCT02347891).
Octagam® is an intravenous immunoglobulin (IVIg), the mechanism of action of which is to downregulate antibody production by B-cells, interfere with B-cell proliferation and prevent its activation, and downregulate macrophage activity by interrupting complement activation cascade and blocking Fc-receptor-mediated activity.10 IVIg is approved for use in patients with allogenic bone marrow transplant, chronic lymphocytic leukaemia, idiopathic thrombocytopenic purpura, Kawasaki disease, paediatric HIV and primary immunodeficiencies. More than 150 unlabelled uses of IVIg, which includes myositis, have been described.11
The ongoing clinical trials of immunoglobulins in myositis include optimising treatment on idiopathic inflammatory myopathies (NCT03092180); a randomised, double-blinded, placebo-controlled Phase III study evaluating safety and efficacy of Octagam 10% in patients with DM (NCT02728752); and an open label study of subcutaneous immunoglobulin in patients with DM (NCT02271165).
Tocilizumab, an interleukin-6 (pro-inflammatory cytokine) receptor antagonist, is approved for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis.12 The ongoing tocilizumab study is a multicentre, randomised, placebo-controlled trial to determine effectiveness of tocilizumab in the treatment of patients with refractory adult PM and DM (NCT02043548).
Abatacept, a modulator of T-cell activation by binding to CD80 and CD86 molecules on antigen-presenting cells, thereby blocking interaction with CD28 on T cells,13 is approved for the treatment of adult rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and psoriatic arthritis. Recently, results of a randomised, open-label, ‘delayed-start’ treatment trial in DM/PM were published (ARTEMIS; NCT01315938). In this pilot study, treatment with abatacept resulted in lower disease activity in nearly half of the patients (42%). In patients with repeat muscle biopsies, an increased frequency of Foxp3+ Tregs at six months suggested a positive effect of treatment in muscle tissue.14
Abatacept is currently being studied in a randomised, double- blinded, controlled pilot trial to evaluate the efficacy and safety of subcutaneous abatacept in treating interstitial lung disease associated with anti-synthetase syndrome (NCT03215927); in an open label study of abatacept for the treatment of refractory juvenile DM (NCT02594735) and Phase III, randomised, double blind clinical trial to evaluate efficacy and safety of abatacept in adults with active IIM (NCT02971683). The later study is unique in that it includes not only DM and PM but also IMNM cases and adult JDM patients as well.
Siponimod is a selective modulator of sphingosine 1-phosphate receptor (S1P1,5) that inhibits the movement of lymphocytes out of lymph nodes.15 A double-blind, randomised, placebo-controlled study of siponimod in patients with active DM (NCT02029274) completed recruitment in 2016 and a previous multicentre double-blind, placebo controlled study of siponimod in PM (NCT01801917) was prematurely stopped in 2016 due to slow recruitment and small sample size.
Ajulemic acid (JBT-101) is a synthetic compound that selectively binds to the cannabinoid receptor type 2 (CB2)16 promoting anti-inflammatory and anti-fibrotic effects by increasing production of PGJ2 (an endogenous anti-inflammatory ligand) and decreasing collagen neosynthesis by fibroblasts.17
Ajulemic acid is currently being studied in a Phase II, double-blinded, randomised, placebo-controlled study to investigate the safety, tolerability and efficacy in patients with DM (NCT02466243). Interferon (IFN)-Kinoid is an inactivated form of IFNα2b that has been studied as a therapeutic vaccine in patients with systemic lupus erythematosus. It has been shown to induce a polyclonal response against most of the IFNα subtypes, decreasing IFN and B cell-associated transcripts.18 It is currently being studied in a single-blind, randomised, proof of concept study to evaluate the production of anti-IFNα antibodies (immune response) in adults with DM (NCT02980198).
Anakinra is a recombinant IL‑1 receptor antagonist. It was studied in a small open-label study that included 15 patients with refractory PM, DM and IBM (NCT01165008).Seven patients showed a response in this non-randomised study.19 There are no ongoing studies of anakinra in the IIMs.
IBM
Bimagrumab is an antibody against the activin type II B receptor (ActRIIB) that results in inhibition of the activity of myostatin and activins (negative regulators of muscle mass). Bimagrumab has been shown to induce skeletal muscle hypertrophy in mice,20 to result in expedited recovery of skeletal muscle volume in acute disuse atrophy21 and to increase muscle mass and function in a small open-label study of patients with IBM.22 A randomised, multicentre, double-blinded, placebo-controlled study of safety and efficacy of bimagrumab in patients with IBM (NCT01925209) showed that bimagrumab was well tolerated; however, it did not reach the primary endpoint of improving the 6-minute walk distance (6MWD) test or showed improvement in muscle strength.23
Follistatin is a glycoprotein expressed in all tissues in variable concentrations.24 It promotes muscle growth by binding to ActRIIB and neutralising the effect of various members of the transforming growth factor-β (TGF-b) superfamily including myostatin and activin–inhibin complex.25,26 The follistatin role in regulating various members of the TGF-b family suggests follistatin as a potential gene therapy for muscle diseases including muscular dystrophy24 and IBM.27 A Phase I clinical trial of follistatin gene transfer to patients with IBM (NCT01519349) was recently published.
In this ‘proof-of-principle’ trial, six male IBM patients received bilateral intramuscular quadriceps injections of AAV1 vectors carrying an isoform of follistatin (FS344).27 This study observed an improvement in the 6MWD test and all post-treatment biopsies showed an increased number of muscle fibres. However, there were methodological concerns regarding the use of steroids and an exercise protocol that may have influenced study results.
Rapamycin is an mTOR inhibitor that can deplete T effector cells, preserve T regulatory cells and induce autophagy,28 potentially restoring abnormal protein degradation pathways that are evident in IBM.29 A randomised, double-blinded trial of rapamycin for the treatment of IBM (NCT02481453) was published in abstract format.30 At 12 months, the study did not meet its primary endpoint (quadriceps strength using quantitative muscle testing), however differences were observed for several secondary endpoints namely the 6MWD and MRI fat muscle replacement. An open phase continuation of this study is ongoing.
Arimoclomol is an agent that increases heat shock protein (HSP) expression by prolonging the main transcription factor of HSP, the heat shock factor 1 (HSF-1),31 and showed no effect in the non-stressed cells.32 In a small placebo-controlled pilot safety trial, arimoclomol was found to be safe and well tolerated in patients with sIBM. There were trends observed in some of the secondary clinical outcome measures but no statistically significant morphological changes in the repeat muscle biopsies from arimoclomol-treated patients as compared with placebo, however, studies in an in vitro cellular model and mouse model showed improvement in the pathological and functional deficits associated with sIBM.4 A randomised, double-blinded, Phase II clinical trial of arimoclomol for the treatment of sporadic IBM is ongoing (NCT02753530).
Conclusions
A persistent challenge to treatment of IIMs relies on the elucidation of their pathogenic mechanisms, particularly IBM. PM, DM and IMNM reasonably respond to immunosuppressive therapy with high-dose steroids and steroid-sparing agents. The new agents currently being studied in clinical trials target specific pathogenic mechanisms and are promising for the treatment of patients with diseases resistant to the conventional immunosuppressant treatment. By contrast, IBM has failed to respond to several drugs currently used for the treatment of PM, DM and IMNM. The progress in understanding the pathogenicity of IBM has allowed promising clinical trials of drugs involved in the pathogenic mechanism of IBM.
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