Novel treatments in the management of myositis

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.

 

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 

 

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 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.

 

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.

 

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). 

 

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. 

 

1 Dalakas MC. Inflammatory Muscle Diseases. N Engl J Med 2015;373(4):393–4.

2 Machado PM, Dimachkie MM, Barohn RJ. Sporadic inclusion body myositis: new insights and potential therapy. Curr Opin Neurol 2014;27(5):591–8.

3 Amato AA, Greenberg SA. Inflammatory myopathies. Continuum (Minneap Minn) 2013;19(6 Muscle Disease):1615–33.

4 Ahmed M et al. Targeting protein homeostasis in sporadic inclusion body myositis. Sci Transl Med 2016;8(331):331–41.

5 Dalakas MC. Immunotherapy of myositis: issues, concerns and future prospects. Nat Rev Rheumatol 2010;6(3):129–37.

6 Aggarwal R et al. Efficacy and safety of adrenocorticotropic hormone gel in refractory dermatomyositis and polymyositis. Ann Rheum Dis 2018;77(5):720–7.

7 Oddis CV et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum 2013;65(2):314–24.

8 Balak DM et al. IMO-8400, a toll-like receptor 7, 8, and 9 antagonist, demonstrates clinical activity in a phase 2a, randomized, placebo-controlled trial in patients with moderate-to-severe plaque psoriasis. Clin Immunol 2017;174:63–72.

9 Dubey AK et al. Belimumab: First targeted biological treatment for systemic lupus erythematosus. J Pharmacol Pharmacother 2011;2(4):317–9.

10 Hartung HP. Advances in the understanding of the mechanism of action of IVIg. J Neurol 2008;255 Suppl 3:3–6.

11 Leong H et al. Unlabeled uses of intravenous immune globulin. Am J Health Syst Pharm 2008;65(19):1815–24.

12 Moghadam-Kia S, Oddis CV, Aggarwal R. Modern therapies for idiopathic inflammatory myopathies (IIMs): Role of biologics. Clin Rev Allergy Immunol 2017;52(1):81–7.

13 Bonelli M, Scheinecker C. How does abatacept really work in rheumatoid arthritis? Curr Opin Rheumatol 2018;30(3):295–300.

14 Tjarnlund A et al. Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial. Ann Rheum Dis 2018;77(1):55–62.

15 Kappos L et al. Safety and efficacy of siponimod (BAF312) in patients with relapsing-remitting multiple sclerosis: Dose-blinded, randomized extension of the Phase 2 BOLD study. JAMA Neurol 2016;73(9):1089–98.

16 Tepper MA, Zurier RB, Burstein SH. Ultrapure ajulemic acid has improved CB2 selectivity with reduced CB1 activity. Bioorg Med Chem 2014;22(13):3245–51.

17 Burstein SH.The cannabinoid acids, analogs and endogenous counterparts. Bioorg Med Chem 2014;22(10):2830–43.

18 Ducreux J et al. Interferon alpha kinoid induces neutralizing anti-interferon alpha antibodies that decrease the expression of interferon-induced and B cell activation associated transcripts: analysis of extended follow-up data from the interferon alpha kinoid phase I/II study. Rheumatology (Oxford) 2016;55(10):1901–5.

19 Zong M et al. Anakinra treatment in patients with refractory inflammatory myopathies and possible predictive response biomarkers: a mechanistic study with 12 months follow-up. Ann Rheum Dis 2014;73(5):913–20.

20 Lach-Trifilieff E et al. An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy. Mol Cell Biol 2014;34(4):606–18.

21 Rooks DS et al. Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy. J Cachexia Sarcopenia Muscle 2017;8(5):727–34.

22 Amato AA et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology 2014;83(24):2239–46.

23 Amato AA et al. A randomized, double-blind, placebo-controlled study of bimagrumab in patients with sporadic inclusion body myositis [abstract]. Arthritis Rheumatol 2016;68(suppl 10).

24 Al-Zaidy SA et al. Follistatin gene therapy improves ambulation in Becker muscular dystrophy. J Neuromuscul Dis 2015;2(3):185–92.

25 Thompson TB et al. The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding. Dev Cell 2005;9(4):535–43.

26 Amthor H et al. Follistatin complexes myostatin and antagonises myostatin-mediated inhibition of myogenesis. Dev Biol 2004;270(1):19–30.

27 Mendell JR et al. Follistatin gene therapy for sporadic inclusion body myositis improves functional outcomes. Mol Ther 2017;25(4):870–9.

28 Nalbandian A et al. Rapamycin and chloroquine: the in vitro and in vivo effects of autophagy-modifying drugs show promising results in valosin containing protein multisystem proteinopathy. PLoS One 2015;10(4):e0122888.

29 Lilleker JB, Bukhari M, Chinoy H. Rapamycin for inclusion body myositis: targeting non-inflammatory mechanisms. Rheumatology (Oxford) 2018;Feb 26 [ePub ahead of print].

30 Benveniste O et al. Rapamycin vs. placebo for the treatment of inclusion body myositis: Improvement of the 6 min walking distance, a functional scale, the FVC and muscle quantitative MRI [abstract]. Arthritis Rheumatol 2017;69(suppl 10).

31 Kieran D et al. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 2004;10(4):402–5.

32 Vigh L et al. Bimoclomol: a nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects. Nat Med 1997;3(10):1150–4.