A persistent challenge to treatment of IIMs relies on the elucidation of their pathogenic mechanisms , particularly IBM . IBM has failed to respond to several drugs currently used for the treatment of PM , DM and IMNM |
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 dystrophy 24 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 placebocontrolled 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 , doubleblinded , 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 steroidsparing 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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References 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 moderateto-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 delayedstart trial . Ann Rheum Dis 2018 ; 77 ( 1 ): 55 – 62 . 15 Kappos L et al . Safety and efficacy of siponimod ( BAF312 ) in patients with relapsingremitting 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 . |
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